Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1[C:13]([CH:14]([C:16]2[C:21]([N:22]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])[CH2:23][O:24][CH3:25])=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O=[Mn]=O>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1[C:13]([C:14]([C:16]2[C:21]([N:22]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=3)(=[O:27])=[O:28])[CH2:23][O:24][CH3:25])=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of [3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzene sulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (750 mg, 1.18 mmol) and MnO2 (512.6 mg, 5.9 mmol) in THF (10 mL) was stirred at 50° C. for overnight. The reaction mixture was cooled to room temperature, filtered through sintered funnel, washed with THF (2×10 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to afford (3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-carbamic acid tert-butyl ester (456 mg) 61% in yield. ESMS m/z (relative intensity): 635 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:13](C(OC)=O)[C:14](OC)=[O:15].[Cl-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CCO)c(Cl)cc1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
A solution of dimethyl 2-(2-chloro-5-methoxy-4-nitrophenyl)malonate (15.5 g, 48.7 mmol), sodium chloride (5.70 g, 97.5 mmol) and water (0.876 mL, 48.7 mmol) in DMSO (200 mL) was heated to 120° C. for 2 hours. The cooled reaction mixture was partitioned between water (1000 mL) and EtOAc (200 mL) and the separated aqueous phase was extracted with EtOAc (200 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral silica gel using 3-10% EtOAc in hexane to give the title compound (10.2 g, 86%) as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH:2]=[O:1]
Reactant: O=[N+]([O-])c1ccc(CO)c(O)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc([N+](=O)[O-])cc1O

Procedure:
6.0 g (35.5 mmol) of 2-(hydroxymethyl)-5-nitrophenol and 3.1 g (35.5 mmol) of activated manganese (IV) oxide in 100 ml of chloroform are heated under reflux for 20 h. The mixture is filtered through kieselguhr, concentrated and dried under high vacuum. The title compound is directly reacted further.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@@H:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][C@H:5]1[CH2:6][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C@H:4]1[NH2:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 94.9 %

Procedure:
Ethyl (1R*,3S*,4R*)-4-azido-3-(tert-butoxy-carbonylamino)cyclohexane-1-carboxylate (5.4 g) was dissolved in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml), and a catalytic amount of 10% palladium on carbon was added to stir the mixture at room temperature for 20 hours in a hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.7 g) as a pale yellow oil.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:12]=1[C:19]1[N:24]=[CH:23][C:22]([CH:25]=[O:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH3:10].[Cl-].[NH4+]>CCOCC>[CH:1]1([CH:25]([C:22]2[CH:23]=[N:24][C:19]([C:12]3[C:13]([CH2:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:9][CH3:10])=[CH:20][C:21]=2[O:27][CH2:28][CH3:29])[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C=O
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cyclohexylmagnesium chloride solution (2 M in THF, 1 mL) is slowly added to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-pyridine-3-carbaldehyde (prepared as described D above) (142 mg, 0.5 mmol) in ether (2 mL) at 0° C., and the resulting mixture is stirred at room temperature for 30 minutes. Saturated ammonium chloride solution (1 mL) is added to quench the reaction. The organic layer is separated and dried over anhydrous Na2SO4. The solvents are removed in vacuo and the crude is purified with PTLC (hexanes/ethyl acetate 3:1) to give cyclohexyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol. 1H NMR: (CDCl3) 8.40 (s, 1H), 7.28 (t, 1H), 7.16 (d, 2H), 6.76 (S, 1H), 4.54 (t, 1H), 4.08 (q, 2H), 2.32 (m, 4H), 2.05 (br, 1H), 1.75 (m, 4H), 1.40 (m, 4H), 1.05 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]3[O:12][CH:13]=[N:14][N:15]=3)[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]3[O:12][CH:13]=[N:14][N:15]=3)[N:10]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Clc1ccc2[nH]c(-c3nnco3)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(Cn2c(-c3nnco3)cc3nc(Cl)ccc32)c1
Reaction time: 1 h

Procedure:
5-Chloro-2-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (0.060 g, 0.27 mmol, from Example 139, Step 1) in DMF (5 mL) was treated with Cs2CO3 (0.222 g, 0.681 mmol) and 1-(bromomethyl)-3-chloro-benzene (0.046 mL, 0.35 mmol). After 1 hour, additional 1-(bromomethyl)-3-chloro-benzene (0.040 mL, 0.30 mmol, Aldrich) was added and stirring continued for 1 hour. Water was added, and the solution was extracted with three portions of EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded purified product. Yield: (67 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH2:19]([O:23][C:24](Cl)=[O:25])[CH:20]([CH3:22])[CH3:21]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:24]([O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:25])[N+:7]([O-:8])=[C:6]([NH:9][C:24]([O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:25])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCC(C)C)[n+]1[O-]
Reaction time: 2 h

Procedure:
20.7 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed with 250 ml. of methylene chloride and 35 ml. of triethylamine and cooled to 5° C. 40 Ml. of chloroformic acid isobutyl ester are added dropwise while stirring. After completion of the addition, the mixture is stirred at 50° C. for 15 minutes and then at room temperature for 2 hours. The solution is treated with 200 ml. of water and extracted with methylene chloride. The organic phase is evaporated and the residue is crystallized from ethanol. There is obtained diisobutyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 137°-139° C. (decomposition).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[CH3:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[CH3:39][N:29]([CH3:28])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: CN(C)CCc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCc1ccc(OCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Yield: 92 %

Procedure:
The title compound was prepared as its TFA salt in 92% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-(2-dimethylaminoethyl)-phenol.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:13][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:26]
Reactant: COc1cc(C(C)C)c(O)cc1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(OC)cc1C(C)C
Yield: 82.3 %

Procedure:
To a solution of 2-isopropyl-4-methoxy-5-methyl-phenol (3.933 g, 21.8 mmol) in acetone (100 ml) was added potassium carbonate (20 g, 145 mmol) and ethyl bromoacetate (5 ml, 45.1 mmol). The mixture refluxed over night and was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (10% to 15% methylene chloride in hexane) to yield (2-isopropyl-4-methoxy-5-methyl-phenoxy)-acetic acid ethyl ester as white solid (4.78 g, 82%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19].C(O[C:26](=[O:28])[CH3:27])(=O)C>N1C=CC=CC=1>[C:18]([C:1]([C:26](=[O:28])[CH3:27])([C:16](=[O:21])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19])(=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Solvent: c1ccncc1
Product: CC(=O)C(CCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO)(C(C)=O)C(C)=O

Procedure:
In a procedure similar to Grode and Cardellina D-erythro-sphingosine (4, 2 mg, 6.7 μmol, Sigma) in acetic anhydride (1 ml) and pyridine (2 ml) was stirred at 25° C. for 4.5 h, at which time no starting material could be observed by TLC. The solvent was removed by a stream of nitrogen to give 133: white solid; silica TLC Rf 0.86 (3:12:2:2 CHCl3/1-BuOH/AcOH/H2O, phosphomolybdic acid), 0.65 (9:1 CHCl3/MeOH, phosphomolybdic acid); FABMS m/z 580, 426, 366, 306, 264; CIMS m/z 468, 454, 426, 424, 394, 366, 364, 306, 264, 144, 85, 84, 83, 61.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[C:13]1([CH2:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccccn1
Temperature: -78 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
A solution of ethyl picolinate (1.0 g, 6.62 mmol) in anhydrous tetrahydrofuran (15 mL) was added benzylmagnesium chloride (3.64 mL, 7.28 mmol) at −78° C. The mixture was stirred at −78° C. for 5 h, and poured into saturated aqueous ammonium chloride solution (70 mL), and extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine (80 mL), and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give Intermediate 27 (700 mg, yield 53.6%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=1[CH3:22].O>O1CCOCC1>[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]=[C:5]=[O:11])=[CH:16][C:15]=1[CH3:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)cc(C)c1Br
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N=C=O)cc(C)c1Br
Temperature: 100 °C
Reaction time: 15 h
Yield: 117.6 %

Procedure:
Triphosgene (2.23 g, 7.52 mmol) was added to a solution of 4-bromo-3,5-dimethyl-phenylamine (4.3 g, 21.49 mmol) in dioxane (71 ml). After stirring at 100° C. for 15 hours, water was added to the reaction solution. After extraction with ethyl acetate, the organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure to give 2-bromo-5-isocyanato-1,3-dimethylbenzene (2.0 g, 41%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC(=O)c1c(N)ncn1CCc1ccccc1
Product: CN(CC(=O)Nc1ncn(CCc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 94 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.84 g (7.99 mmol) of 4-amino-1-(2-phenylethyl)-5-imidazolecarboxamide prepared in the same manner as in Example 56 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.03 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(2-phenylethyl)-5-imidazolecarboxamide (yield 94%).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:4][C:3]1=[O:22].O.O.Cl[Sn]Cl>CO>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:5]3[O:4][C:3](=[O:22])[N:2]([CH3:1])[N:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1
Reactant: Cn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Yield: 87.5 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with CH3I (0.68g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at 27° C. for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-methyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6a, 1.10 g, 91%). Nitro compound (6a, 1.21 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 960 mg, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylamino propyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7b, 0.27 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8b, 351 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]#[N:18])[S:11]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([NH:20][OH:21])=[NH:18])[S:11]3)=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1c(C#N)sc2nc(-c3ccc(F)cc3)cn12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c(C(=N)NO)sc2nc(-c3ccc(F)cc3)cn12
Yield: 63 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile (example 20, 140 mg, 0.54 mmol), hydroxylamine hydrochloride (226.9 mg, 3.26 mmol) and triethylamine (529 μl, 3.8 mmol) were stirred in 10 ml of isopropanol at 90° C. for 2 hours. The solvent was removed in vacuo and water was added. The solid was filtered, washed with diluted hydrochloric acid and water and was dried. Yield: 63%. MS: M+H+=291.15.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH:13](Br)([CH3:15])[CH3:14]>>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH:13]([CH3:15])[CH3:14])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(C)Br
Product: CC(C)Oc1cccc([N+](=O)[O-])c1C#N
Yield: 64 %

Procedure:
Prepared in a similar manner as Example 115c from 2-hydroxy-6-nitrobenzonitrile (Example 115d) and isopropyl bromide to provide 2-nitro-6-isopropoxybenzonitrile (324 mg, 64%). 1H NMR (400 MHz, MeOD) 61.43 (d, J=6.2 Hz, 6H), 4.89 (sept, J=6.2 Hz, 1H), 7.61 (dd, J=8.0, 1.0 Hz, 1H), 7.80 (t, J=8.2 Hz, 1H), 7.85 (dd, J=8.2, 1.2 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(C(C)C)CC)(C)C.[C:35]([C:39]1[CH:43]=[C:42]([C:44](O)=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([C:39]1[CH:43]=[C:42]([C:44]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C@H:7]3[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]3[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]2=[O:25])=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cc(C(C)(C)C)nn3C)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (40 mg, 0.08 mmol) in DMF (2 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol), 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (18 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol). The reaction was stirred at RT for 14 h, partially concentrated, and purified by RP-HPLC to affor 20 mg of the title compound. MS found: (M+H)+=538.
Reaction SMILES: C(O[C:4](=[O:16])[CH:5]([O:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:6])C.[NH2:17][CH2:18][CH2:19][NH2:20]>C(O)C>[NH2:17][CH2:18][CH2:19][NH:20][C:4](=[O:16])[CH:5]([O:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:6]
Reactant: CCOC(=O)C(C)Oc1c(Cl)cccc1Cl
Reactant: NCCN
Solvent: CCO
Product: CC(Oc1c(Cl)cccc1Cl)C(=O)NCCN
Yield: 76.7 %

Procedure:
42.0 g (=0.160 mols) of (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester are stirred for 6 hours at room temperature with 194.0 g (=3.228 mols) of 1,2-diaminoethane and, after working up, produce 34.0 g of (+)-2-(2,6-dichlorophenoxy)-propionic acid-N-(2-aminoethyl)amide, C11H14Cl2N2O2 [277.2] as a high viscosity oil, [α]D20 =+5.6° (c=1/ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CC(C)=O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc(C#N)c(OCCN(C)C)c1
Temperature: 60 °C
Yield: 71.1 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (200 mg, 1.341 mmol) in acetone (5 mL) were added cesium carbonate (1.312 g, 4.023 mmol) and (2-chloroethyl)-dimethylamine hydrochloride (390 mg, 2.682 mmol). The resulting mixture was heated at 60° C. for overnight. The solid was filtered off and washed with methylene chloride (6×10 mL). The filtrate was washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-5% methanol in methylene chloride yielded 2-(2-dimethylamino-ethoxy)-4-methoxy-benzonitrile as a pale-yellow oil (210 mg, 71%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>O1CCOCC1>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: C1COCCO1
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
First, 11-(chloroacetyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one (5.0 g, 0.0174 mol) is dissolved in anhydrous dioxan (100 ml) and refluxed for 2 hours after the addition of 2-[(diethylamino)methyl]piperidine (6.0 g, 0.035 mol).