Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:11]=[CH:12][CH:13]=2)[O:4][N:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[O:4][N:3]=1
Reactant: Cc1noc(Cc2cccc(CC(=O)OC(C)(C)C)c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(Cc2cccc(CC(=O)O)c2)n1
Reaction time: 2 h
Yield: 40.1 %

Procedure:
To a mixture of tert-butyl 2-(3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)phenyl)acetate 1099 (0.127 g, 0.44 mmol) in dioxane (3 mL) was added 4N HCl in dioxane (1 mL) and stirred under an atmosphere of argon for 2 hours. The volatiles were removed under reduced pressure and the residue diluted with water (5 mL) and the pH adjusted to 12 with 2.5 N NaOH. The mixture was washed with dichloromethane (4×2 mL) and the pH adjusted to 6 with 1 N HCl. The mixture was extracted with EtOAc (3×2 mL) and the organic layers combined, washed with brine and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure to give 0.041 g of 2-(3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)phenyl)acetic acid 1100. 1H NMR 300 MHz CDCl3: δ 7.40-7.18 (m, 4H), 4.18 (s, 2H), 3.63 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)[N:15]([CH:17]([CH3:18])[CH3:19])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Reactant: OB(O)c1ccsc1
Product: CC(C)n1nc2c(c1-c1ccsc1)CCN(Cc1ccccc1)C2
Yield: 27.5 %

Procedure:
The title compound (69 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 133 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C20H23N3S, 337.16. found, m/z 338.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.66-7.65 (m, 1H), 7.60-7.57 (m, 3H), 7.55-7.53 (m, 3H), 7.21-7.20 (m, 1H), 4.65-4.52 (m, 3H), 4.42-4.33 (m, 2H), 3.82-3.79 (m, 1H), 3.44-3.40 (m, 1H), 2.94-2.91 (m, 2H), 1.46-1.35 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
The title compound was prepared by adapting the method reported by Kita et al.[Kita, 1994] To a solution of methyl 4-bromo-3-hydroxybenzoate (4.0 g, 17.31 mmol) in anhydrous CH2Cl2 (30 mL) was added 3,4-dihydro-2H-pyran (3.95 mL, 43.28 mmol) and p-toluenesulfonic acid (0.01 g, 0.17 mmol) at 0° C. The mixture was stirred at this temperature for 90 min, warmed to room temperature and quenched with saturated NaHCO3 solution (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The pale yellow residue was purified by flash column chromatography [SiO2, Et2O/n-hexane (4:6)] affording a colourless oil. The oil solidified on standing at room temperature to give methyl 4-bromo-3-(tetrahydropyran-2-yloxy)benzoate as colourless needles (4.12 g, 76%); δH (270 MHz, CDCl3) 1.59-1.77 (m, 3H), 1.86-2.13 (m, 3H), 3.6-3.64 (m, 1H), 3.8-3.85 (m, 1H), 3.88 (s, 3H), 5.6-5.62 (m, 1H), 7.52 (dd, J=8.2, 1.7, 1H), 7.59 (d, J=8.4, 1H), 7.76 (d, J=2.0, 1H); LRMS (FAB+) m/z (rel. intensity) 316.9 (30, [C13H1581BrO4+H]), 314.9 (47, [C13H1579BrO4+H]; LC-MS (APCI+):tR=1.48 min, m/z 334.13 (C13H1581BrO4+H3O+), 332.11 (C13H1579BrO4+H3O+); HPLC: tR=3.21 min (98%); HRMS (FAB+) Found 317.02290; C13H1681BrO4 requires 317.02115.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCCCCN
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCCCCCNS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
Dissolve 1,9-diazanonane (13g, 0.1 mol) in pyridine (50 mL) and cool to ° C. Add, in portions, p-toluenesulfonyl chloride (41.9 g, 0.22 mol) and stir overnight. Extract into chloroform, wash with water, 5% hydrochloric acid, water and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 1,9-bis[(4-methylphenyl)sulfonyl]-1,9-diazanonane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]1(O)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)c(F)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)Nc1ccc(C2CCSCC2)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 2-methylpropyl [3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (See Org. Proc. Res. Dev. 2001, 5, 80-83, 4.00 g, 12.2 mmol) in trifluoroacetic acid (19 mL, 244 mmol) under N2 was treated with triethylsilane (5.85 mL, 36.6 mmol) dropwise, stirred for 1 hr, and then added dropwise to saturated aqueous potassium carbonate (250 mL) with vigorous stirring. The mixture was extracted with diethyl ether (200 mL), and the organic phase was washed with water (2×50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Trituration and filtration from diethyl ether/hexanes or ethyl acetate/hexanes gave the title compound, 1H NMR (CDCl3, 400 MHz) δ 7.26 (m, 1H), 7.11 (t, 1H), 6.97 (m, 1H), 6.59 (bs, 1H), 3.95 (d, 2H), 2.85 (m, 3H), 2.68 (m, 2H), 2.09 (m, 2H), 1.98 (m, 1H), 1.84 (m, 2H), 0.96 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:22])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)Cl
Reaction time: 3 h
Yield: 70.5 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (1.2 g, 46.0 mmol) was placed into 40 ml scintillation vial equipped with a small stir bar. 10.0 ml of anhydrous chloroform was added following by 1.8 ml of thionyl chloride and 2 drops of anhydrous DMF. After 3 hours, the solvent and excess thionyl chloride were evaporated under vacuum. The brown residue was treated with 40 ml of hexane, filtered, and concentrated to give 985 mg (Yield=70.5%) of the product as a greenish oil. 1H NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 7.95 (d, 1H), 7.3 (t, 1H), 2.75 (s, 3H), 1.4 (s, 12H). The reaction was run several times and the yield was ranging from 60 to 99%.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:10]=1.N1C=CC=CC=1.Cl[C:35]([C:37]1[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=1)[CH2:40][S:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:36]>O1CCCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:35]([C:37]2[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=2)[CH2:40][S:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:36])[CH:10]=1)=[O:22]
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccccc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Yield: 63.3 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-aminophenyl)isonicotinamide (240 mg, 0.65 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and pyridine (77 mg, 0.97 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (194 mg, 0.71 mmol, 1.10 equiv) in tetrahydrofuran (5 mL) with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched with 30 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over magnesium sulfate. The resulting mixture was concentrated under vacuum to yield 250 mg (64%) of product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[CH:3]1[OH:10].C1C=C[NH+]=CC=1.[O-:18][Cr](Cl)(=O)=O.CCOCC>ClC(Cl)C>[Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[C:3]1([OH:18])[OH:10]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: OC1C(F)(Cl)CCCC1(Cl)Cl
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: OC1(O)C(F)(Cl)CCCC1(Cl)Cl
Yield: 73.9 %

Procedure:
0.96 g (4.33 mmol) of trichlorofluoro alcohol 1b in solution in 10 cm3 of dichloroethane were introduced into a 25-cm3 round bottom flask fitted with a condenser and with magnetic stirring. 2.33 g (2.5 eq.) of PCC were added with a spatula and the mixture was heated to reflux under argon atmosphere for 7 h. The reaction mixture was allowed to cool and was then taken up with 100 cm3 of ether, the whole being filtered on florisil. The solvents were evaporated off, the residue was incorporated on silica and purified by flash chromatography (eluent: ether/petroleum ether=15/85 then 20/80). 0.03 g of starting alcohol 1b, that was approximately 3%, and 0.05 g of a mixture of alcohol 1b, diol 3a and 0.76 g of pure diol 3a were isolated. The yield of compound was therefore higher than 74%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])=[C:14]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.[CH2:31](Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOCC.CCOC(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([O:21][CH3:31])=[O:20])=[C:14]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: ClCCCl
Reactant: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2-oxo-2H-quinolizine-7-carboxylic acid (Example 53, 21 mg) in THF/MeOH (1/1) was added EDC (20 mg) and HOBt (10 mg) at room temperature. After stirring for 2 h, the mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (methylene chloride/methanol=20/1) to give the title compound (12 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].Cl>ClCCl>[O:25]=[S:24]1(=[O:26])[CH2:23][CH2:22][CH2:21][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-aminobenzoate (0.92 g) and triethylamine (1.5 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.9 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, 1N hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (8 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue (1.5 g) was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (8.4 mL) was added, and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture were added 1N hydrochloric acid (9.2 mL) and water, and the precipitate was collected by filtration to give the title compound (0.98 g).
Reaction SMILES: CO[CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.B(Br)(Br)[Br:18].O>C(Cl)Cl>[Br:18][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: BrB(Br)Br
Reactant: COCc1ccc2sc(S(N)(=O)=O)cc2c1
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-methoxymethyl-2sulfamoylbenzo[b]thiophene (7.4 g, 0.029 mol) in 300 ml of dry methylene chloride cooled to -30° C. was added boron tribromide (30 ml of a lM solution in methylene chloride, 0.03 mol) over a 20 minute period. The resulting solution was stirred for 11/2 hours as the temperature rose to ambient. The solution was cooled to 0° C. and there was added dropwise 150 ml of water keeping the temperature below 20° C. The methylene chloride layer was separated and the aqueous suspension was extracted with three portions (200 ml) of methanol-chloroform (50/50). The combined extracts were washed with ice water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 8.8 g of tan solid (quantitative yield of crude product) which after recrystallization from 1,2-dichloroethane had m.p. 171°-173° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[CH3:27]N(C)C=O>CI>[C:22]([C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]=1[OH:21])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[CH3:27])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CI
Product: CN(c1ccc(C(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 3.4 g (0.010 mole) of 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (prepared in Example 1) in 35 ml of N,N-dimethylformamide and 3.5 ml of methyl iodide was heated at 95° C. for about 48 hours under nitrogen. The reaction mixture was poured into cold water and the resulting solid was collected and then taken up in chloroform. The chloroform solution was filtered, washed with water, dried with magnesium sulfate and evaporated to give a tan solid. This material was recrystallized first from benzene and then from a mixture of ethanol and water to give 1.5 g of white crystalline 4-(3,5-di-tertiary-butyl-4-hydroxy-N-methylanilino)benzoic acid, m.p. 240°-244° C. Analysis: Calculated for C22H29NO3 : % C, 74.3; % H, 8.2; % N, 3.9. Found: % C, 74.4; % H, 8.3; % N, 3.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[H][H]>C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1N

Procedure:
321 mg (1.053 mmol) 1-(3-methoxy-4-nitro-phenyl)-4-pyrrolidin-1-yl-piperidine are dissolved in 10 ml THF, combined with 30 mg Raney nickel and then shaken for 9 days at 20° C. under 4 bar hydrogen atmosphere. The catalyst is filtered off and washed again with THF. The solvent is eliminated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-].[NH4+].S(S([O-])=O)([O-])=[O:16].[Na+].[Na+]>O>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:16])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(Cl)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
To a suspension of 5-chloro-2-cyano-3-nitropyridine (1.274 mL, 10.9 mmol) in water (22 mL) was added 28% aqueous ammonium hydroxide (3.94 mL, 28.3 mmol), and the reaction was stirred at RT for 20 minutes. Sodium hydrosulfite (2.68 mL, 32.7 mmol) was added, and the reaction mixture was stirred at RT for 70 minutes. The yellow precipitate was collected by vacuum filtration to provide the title compound (1.097 g, 6.39 mmol) as yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.88 (br. s, 1 H), δ 7.73 (s, 1 H), δ 7.39 (br. s, 1 H), δ 7.23 (s, 1 H), δ 7.06 (br. s, 2 H). LC/MS (ESI+) m/z=172 (M+H).
Reaction SMILES: [NH2:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C(O[C:16](=[NH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)C.Cl>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])=[NH:25]
Reactant: CCOC(=N)c1cccc(OC)c1
Reactant: NN1CCc2ccccc2C1=O
Agent: Cl
Product: COc1cccc(C(=N)NN2CCc3ccccc3C2=O)c1
Temperature: 125 °C

Procedure:
A mixture of 16.2 g. of 2-amino-3,4-dihydro-1(2H)-isoquinolinone (0.10 mole), 27 g. of m-methoxybenzimidic acid ethyl ester (0.15 mole) and 2.15 g. of the hydrochloride of m-methoxybenzimidic acid ethyl ester is heated under vacuum (200 mm Hg.) for 5 hours at about 90° C. and for 2 hours at about 125° C. Then 3.50 g. of m-methoxybenzimidic acid ethyl ester (0.02 mole) is added and the mixture is heated for a further 16 hours at about 125° C. under vacuum. All volatile materials are eliminated by distilling off at 125° C. and 5 mm Hg. The solid residue may be used as such for the cyclization step or, after washing with aqueous sodium bicarbonate and water, may be purified by crystallization from ethanol to isolate the intermediate III, 2-(m-methoxybenzimidoylamino)-3,4-dihydro-1-(2H)-isoquinolinone (m.p. 176°-177° C.). The crude reaction product is cyclized by heating for five hours in 150 ml. of ethanol containing 1.2 g. of 80% sodium hydride (0.040 mole). The reaction mixture is then evaporated to dryness in vacuo and then dissolved in dichloromethane. The organic solution after washing with water is evaporated and the crude residual compound is crystallized from 50% ethanol, yielding 20 g. (72%) of the title compound, m.p. 94°-96° C.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([OH:16])=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C:30]1[NH:34][N:33]=[N:32][N:31]=1>C(OCC)(=O)C>[NH:31]1[C:30]([NH:29][C:14]([C:2]2[N:3]=[C:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]3[CH:1]=2)=[O:16])=[N:34][N:33]=[N:32]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cn2c(ccc3ccccc32)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C(Nc1nnn[nH]1)c1cn2c(ccc3ccccc32)n1
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 100.3 %

Procedure:
0.85 g (4 mmol) of imidazo-[1,2-a]-quinoline-2-carboxylic acid [prepared as in published French application No. 2,378,301] was heated at 160° C. in vacuo for one hour to remove water of crystallization and was then dissolved in 25 ml of dimethylformamide. The solution was stirred at 90° to 100° C. with 0.72 g (4.4 mmol) of carbonyldiimidazole and the mixture was stirred at 100° C. for 40 minutes to obtain a slight suspension. 0.375 g of anhydrous 5-amino-tetrazole were added to the mixture which was then stirred at 100° C. for 45 minutes and was then cooled to room temperature. 20 ml of ethyl acetate were added to the mixture and the mixture was cooled in ice and was filtered to obtain 1.12 g of N-(1H-tetrazol-5-yl)-imidazo-[1,2-a]-quinoline-2-carboxamide in the form of colorless crystals melting at 266°-268° C. after crystallization from dimethylformamide.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][NH:9][C@H:8]([C:18]([NH:26][CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CCN
Product: C=CCON=C1CN[C@H](C(=O)NCCN(CC)CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z=283.0.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccccc2F)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccccc2F)cc1
Yield: 30 %

Procedure:
Prepared in analogy to example 3 from N-[4-(2-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=30%. Colorless solid. MS: m/e=303.2 (M++H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CN1C(=O)CCC1>[NH2:25][C:22]1[CH:23]=[CH:24][C:18]2[N:17]=[C:16]([C:8]3[C:9]4[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=4[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:7]=3)[NH:20][C:19]=2[CH:21]=1
Reactant: Nc1ncnc2c1c(-c1nc3ccc([N+](=O)[O-])cc3[nH]1)cn2C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN1CCCC1=O
Product: Nc1ccc2nc(-c3cn(C4CCCC4)c4ncnc(N)c34)[nH]c2c1

Procedure:
7-Cyclopentyl-5-(6-nitro-1H-benzoimidazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1E, 1.0 g) was combined with 10% Palladium on carbon (100 mg) in 50 mL of anhydrous NMP and subjected to 50 psi of hydrogen at room temperature for 24 hours. LCMS monitor suggested pure desired product (M/Z 333.5, retention time 0.70 min. with analytical HPLC method 4). The mixture was filtered through celite. Desired product was used as an NMP stock solution (concentration of about 0.92 g in 45 mL).