Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
A mixture of 2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=2)[C:15]([Cl:28])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:15]1[C:16]([NH:18][C:19]2[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=2)=[N:17][C:12]([NH:10][CH:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[CH3:9])=[N:13][CH:14]=1
Reactant: CC(N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 160 °C
Yield: 27.3 %

Procedure:
A microwave reaction vessel was charged with 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 1, 0.25 g, 1.77 mmol), 2,5-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 2, 0.50 g, 1.77 mmol), and DIPEA (0.30 g, 2.34 mmol). Anhydrous n-BuOH (2 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 10 hours. The reaction mixture was purified by silica gel chromatography twice (by ISCO Combiflash with gradient EtOAc and DCM) to afford the title compound as a white solid (0.19 g, 27%). LC-MS, 393 (M+1). 1H NMR (CDCl3) δ 8.50 (s, 2H), 7.75 (s, 1H), 5.50 (s, 1H), 5.20 (m, 1H), 4.68 (m, 1H), 1.55 (d, 3H), 1.20 (d, 6H).
Reaction SMILES: C1C[O:4][CH2:3]C1.Cl[C:7]1[N:12]=[C:11]([N:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[CH:20]/[CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=4)[CH2:24][CH2:23]3)[CH:15]=[N:14]2)[CH:10]=[C:9]([CH3:36])[N:8]=1.CO[C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[F:35][C:30]1[CH:29]=[C:28]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21]/[CH:20]=[CH:19]/[C:16]3[CH:15]=[N:14][N:13]([C:11]4[CH:10]=[C:9]([CH3:36])[N:8]=[C:7]([NH:44][CH2:43][C:42]5[CH:41]=[CH:40][CH:39]=[CH:46][C:45]=5[O:4][CH3:3])[N:12]=4)[C:17]=3[CH3:18])[CH2:23][CH2:24]2)[CH:33]=[C:32]([F:34])[CH:31]=1
Reactant: Cc1cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)nc(Cl)n1
Reactant: C1CCOC1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1CNc1nc(C)cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)n1

Procedure:
To 15 ml of a THF solution of 155 mg of the compound obtained in Example 35 were added 240 mg of p-methoxybenzylamine and 50 mg (0.362 mmol) of potassium carbonate, followed by refluxing for 60 hours. Chloroform was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride aqueous solution. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography using a 99:1 mixture (by volume) of chloroform and methanol as a developing solution. The fraction containing the desired compound was concentrated to give 183 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].Cl.[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31]>>[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared by saponification of 4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 204D, followed by coupling with methionine methyl ester hydrochloride and saponification as described in Examples 304E-G. 1H NMR (300 MHz, CDCl3) δ 8.40 (bs, 1H), 8.25 (dd, J=4.1, 1.9 Hz, 1H), 7.99 (dd, J=22.8, 8.1 Hz, 1H), 7.53-7.50 (m, 1H), 7.36-7.21 (m, 7H), 5.91 (bd, J=7.7 Hz, 1H (NH)), 5.18 (s, 2H), 4.70-4.58 (m, 1H), 3.66 (s, 3H, OMe), 2.18-2.00 (m, 5H), 1.95-1.82 (m, 1H), 1.65-1.55 (m, 4H, contains SMe). MS (CI) 465 (M+H)+. Anal calcd for C26H28O4N2S: 0.30H2O solvate: C, 66.45; H, 6.13; N, 5.96. Found: C, 66.45; H, 6.15; N, 5.97. HRMS FAB Calcd m/z MH+ for C26H28O4N2S 465.1848, found 465.1869.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10]P(OC)(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CC[O:22][C:23]([CH3:25])=[O:24].Cl.[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH2:1]([O:8][C:9](=[O:17])[CH:10]=[C:27]1[CH2:31][CH:25]([C:23]([OH:22])=[O:24])[CH2:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: O=C(C=C1CC(C(=O)O)C1)OCc1ccccc1
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of cyclobutaneone-3-carboxylic acid (5 g, 43.82 mmol), benzyl-2-(dimethoxyphosphoryl)acetate (13.58 g, 52.59 mmol), LiOH (4.20 g, 23.95 mmol) and 3 Å activated molecular sieves (25 g, powder form) in THF (250 ml) was heated to reflux under nitrogen for 4 h. The reaction was allowed to cool to RT and EtOAc (100 ml) followed by HCl (1N, 100 ml) were added. This mixture was filtered through celite. The phases were separated and the aqueous layer was extracted with EtOAc (4×50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield a colorless oil. Dry flash chromatography over SiO2, eluting with Hept:EtOAc from 7:3 to 1:1 gave the desired product as a colorless oil (5.2 g, 39%); MS (ESI+) for C14H14O4 m/z 269.05 [M+Na]+; MS (ESI−) for C14H14O4 m/z 245.15 [M−H]−; HPLC purity 81% (ret. time, 1.85 min); 1H NMR (250 MHz, CHLOROFORM-d) δH ppm 2.95-3.62 (5 H, m), 4.96-5.31 (2 H, m), 5.75 (1 H, t, J=2.21 Hz), 7.27-7.45 (5 H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.O>CCO.[Pd]>[CH3:9][C:7]1[C:5]2[NH:6][C:14](=[O:16])[NH:10][C:4]=2[CH:3]=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Reaction time: 3 h

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (10.0 g, 60.2 mmol) and 10% Pd/C (1.0 g) in EtOH (300 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 3 h, then filtered through a Celite pad and concentrated in vacuo. The crude solid was dissolved in CH3CN (200 mL) and triphosgene (15.0 g, 50.5 mmol) was added. The mixture was stirred for 1 h, then H2O (200 mL) was added slowly and stirring was continued for 1 h. The precipitate was isolated by filtration and dried to give the title compound. MS: m/z=163 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](N(CC)CC)C.CI>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][CH3:31])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CI
Product: CNc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1

Procedure:
2-[4-(4-amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5050, 38 mg, 0.092 mmol) was dissolved in 3.5 mL of methylene chloride. To this solution was added triethylamine (12.8 μL, 0.092 mmol) followed by 6 μL (0.092 mmol) of methyl iodide. This solution was heated under reflux for 1 hour. It was evaporated and redissolved in 5 mL of DMF. The crude was purified using reverse phase HPLC to furnish the desired product. MS: 437.1 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[CH:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[H][H].I[CH2:25][CH2:26][CH2:27][CH:28]([O:41][C:42](=[O:44])[CH3:43])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.Cl>CN(C)C=O.O.CCOCC>[CH3:20][S:17]([C:6]([C:5]([O:4][CH3:3])=[O:21])([CH2:25][CH2:26][CH2:27][CH:28]([O:41][C:42](=[O:44])[CH3:43])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:18]
Reactant: COC(=O)CCCCCCC(C(=O)OC)S(C)(=O)=O
Reactant: [H][H]
Reactant: CC(=O)OC(CCCI)COc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCCCC(CCCC(COc1cccc(C(F)(F)F)c1)OC(C)=O)(C(=O)OC)S(C)(=O)=O
Temperature: 5 °C
Reaction time: 48 h
Yield: 87.5 %

Procedure:
A 50% oil dispersion of sodium hydride (2.11 g., 0.044 mole) in mineral oil is washed with petroleum ether and then suspended in dry dimethylformamide (30 ml.) under a nitrogen atmosphere at room temperature. To this suspension is added a solution of dimethyl-2-methylsulfonyl-azelate (11.8 g., 0.04 mole) in dry dimethylformamide (30 ml.). After the evolution of hydrogen is completed, the mixture is cooled to 5° C. in an ice bath and a solution of 1-iodo-4-acetoxy-5-(3-trifluoromethylphenoxy)pentane (18.3 g., 0.044 mole) in dry dimethylformamide (30 ml.) is added dropwise. After 48 hours, ether is added to the reaction mixture to precipitate sodium iodide which is removed by filtration. The filtrate is concentrated in vacuo to give a residue which is diluted with water, acidified with 6N hydrochloric acid, and extracted with ether. The ether extracts are washed with water until neutral, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (20.5 g., 0.035 mole, 88%).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[S:7][C:6]=1[C:18]([NH2:20])=[O:19])=[O:3].B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[S:7][C:6]=1[C:18]([NH2:20])=[O:19])=[O:3]
Reactant: COc1ccccc1-c1cc(NC(N)=O)c(C(N)=O)s1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2ccccc2O)sc1C(N)=O
Reaction time: 1 h

Procedure:
3-[(Aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide (0.1 g), boron tribromide (2 ml of a 1M solution in dichloromethane) and dichloromethane (10 mL) were stirred at room temperature for 16 h. Methanol (5 mL) was added and after 1 h, the solvent was evaporated. 2M Hydrochloric acid (10 mL) was added and, after stirring for 1 h, the phenol was filtered off and used directly in step (b).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[CH3:13][O:14][C:15](=[O:31])[C:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH:29]=O)([CH2:19][CH3:20])[CH2:17][CH3:18].N1CCCC1>CO>[CH3:13][O:14][C:15](=[O:31])[C:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1/[CH:29]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][C:3]([F:12])=[C:2]([Cl:1])[CH:10]=2)([CH2:17][CH3:18])[CH2:19][CH3:20]
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Solvent: C1CCNC1
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)c(F)cc21)C(=O)OC
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (500 mg, 2.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-ethyl-butyric acid methyl ester (844 mg, 2.97 mmol) in methanol (5 mL) was added pyrrolidine (95 mg, 1.35 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was partitioned between EtOAc and diluted HCl solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product as a red-yellow solid, which was used for the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13](OC(Cl)(Cl)Cl)=[O:14].O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:13](=[O:14])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: O=c1[nH]nc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To a suspension of 4-chlorobenzhydrazide (8.53 grams (g), 0.05 mole) in methylene chloride (100 milliliters (ml)), was dropwise added trichloromethyl chloroformate (5.94 g, 0.03 mole). After addition, the reaction mixture was heated to reflux for 2 hours. The reaction was cooled down to room temperature and poured into a mixture of water (500 ml) and hexane (200 ml) and stirred for 10 to 20 min. The resultant precipitate was collected by suction-filtration and was washed with hexane to give a solid product. The product was dried in air at room temperature overnight yielding 5.5 g (60% yield) of 2-(4-chlorophenyl)-1,3,4-oxadiazolin-5one as a solid, m.p. 225°-227° C. NMR and IR spectra showed the desired structure. Without further purification, this product was subjected to the next step.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[C:16]([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28][C:27]1[CH:26]=[CH:25][C:24]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:35][CH:34]=1)=[O:4]
Reactant: COC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 24 h
Yield: 18.3 %

Procedure:
Methyl trifluoroacetate (89.6 μL, 891 μmoles) and triethylamine (104 μL, 743 μmoles) were added to a suspension of 4-benzoylphenylalanine (200 mg, 743 μmoles) in methanol (0.5 mL). The reaction was stirred vigorously for 24 h and then acidified with 1 N HCl until a pH of 2 was obtained. The mixture was added to ethyl acetate (10 mL), washed with 1 N HCl (2×10 mL), dried over MgSO4, and concentrated in vacuo to yield a white solid (49.7 mg, 136 μmoles, 18%). LRMS: not performed. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[CH:12][CH:13]=[CH2:14])[CH3:2].[CH2:16]([O:18][C:19]([N:21]=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]1[CH:12]=[CH:13][CH2:14][N:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]1[C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH3:2]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: C=CC=Cc1ncccc1C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1C1C=CCN(C(=O)OCC)N1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9.8 g of 2-(1,3-butadienyl)nicotinic acid ethyl ester and 9.2 g of diethyl-azodicarboxylate are mixed with 30 ml of toluene and heated to 80° under nitrogen. After 1 hr a further 3 g of diethyl-azodicarboxylate are added and after 3 hrs a further 5 g. After a further 4 hrs the reaction mixture is allowed to cool to RT and stirred overnight. The solvent is removed by evaporation under vacuum and the resulting oil chromatographed on silica gel and eluted with ethylacetate/hexane to give the title compound as black oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:12][CH2:13][CH2:14][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: ClCCCl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Yield: 83.9 %

Procedure:
A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 ml) was refluxed for 24 hours. The mixture was cooled and filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue that was dissolved in ethyl acetate (500 ml). The organic layer was washed with 1 N sodium hydroxide (250 ml), water (500 ml) and brine (2×500 ml) and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituration of the residue with hexanes afforded 37.8 g (84.6%) of product as an orange solid: mp 71-73° C.; MS EI m/e 216 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH3:18][NH2:19].C1COCC1>>[CH3:18][NH:19][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: CN1CCN(c2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cn1
Yield: 93 %

Procedure:
1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine (265.9 mg, 1.036 mmol) and methylamine 2M in THF (2.590 mL of 2 M, 5.180 mmol) were heated overnight in a sealed tube at 60° C. The mixture was purified by chromatography on silica (Companion 12 g) eluting with 0.5-15% MeOH:DCM, yielding N-methyl-4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine (243 mg, 93%). MS (ES+) 252.1.
Reaction SMILES: [Si](O[CH2:19][C@H:20]1[O:27][C@@H:24]([O:25][CH3:26])[C@H:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:22]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:21]1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[S:67]([O:74]S(C(F)(F)F)(=O)=O)([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68]>ClCCl>[CH2:29]([O:28][C@@H:23]1[C@@H:22]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:21]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:20]([CH2:19][O:74][S:67]([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68])[O:27][C@H:24]1[O:25][CH3:26])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside (800 mg, 1.71 mmol) in 8.55 mL of dry dichloromethane at −78° C. was added 2,6-di-tert-butyl-4-methyl pyridine (632 mg, 3.08 mmol) followed by triflic anhydride (345 μl, 2.05 mmol). After stirring 15 minutes at −78° C., the mixture was warmed to room temperature over 20 minutes, and then poured into a solution of saturated aqueous NaHCO, (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 (3×20 mL), saturated aqueous NaCl (1×20 mL), and dried over magnesium sulfate. Concentration provided crude target compound, which was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:15][C:16]([O:18]CC)=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[O-:21][C:22]#[N:23].[Na+].[CH3:25]COCC>O>[CH3:25][N:23]1[C:16](=[O:18])[CH2:15][CH:2]2[C:7]3[NH:8][C:9]4[C:14]([C:6]=3[CH2:5][CH2:4][N:3]2[C:22]1=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: CCOC(=O)CC1NCCc2c1[nH]c1ccccc21
Reactant: N#C[O-]
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1C(=O)CC2c3[nH]c4ccccc4c3CCN2C1=O
Reaction time: 8 h

Procedure:
26 g (0.088 mol) of ethyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate hydrochloride are dissolved in 1 liter of hot water. The pH should be 4-5. When the temperature of the reaction medium is 50° C., a solution of 8.7 g (0.13 mol) of sodium cyanate in 150 cm3 of water is added. The reaction medium is kept at 50° C., whilst stirring. It is stirred for 4 hours at 50° C. and left to stand overnight at ambient temperature; the supernatant water is drawn off. 200 cm3 of ether are added, the mixture is stirred, the ether solution is then drawn off and the same operation is repeated. The expected product is very soluble in ether. The ether extracts are combined and washed with acidified water, in order to remove traces of the starting material, and then with water. They are dried over Na2SO4 and the solvent is evaporated off. This yields an oil which changes into a foam on more thorough drying. The product is used as such in the following step.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C[N+]([O-])=O>[OH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:2]([NH2:5])(=[O:3])=[O:4]
Reactant: Oc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: NS(=O)(=O)c1ccccc1O
Temperature: 45 °C

Procedure:
To a solution of chlorosulfonylisocyanate (Aldrich; 2 mL) in 76 mL MeNO2 at 0° C. was added phenol (2 g) in 10 mL MeNO2. The solution was heated at 45° C. for 30 minutes then AlCl3 (3.46 g) was added and the temperature raised to 100° C. for 30 minutes. The reaction mixture was poured onto ice/H2O, extracted (2× Et2O), and washed with H2O. The organic layer was extracted with K2CO3 (saturated solution) and the aqueous phase then acidified with 1N HCl. Extraction of the aqueous phase with Et2O followed by drying (MgSO4) and evaporation yielded a black oil. Purification of this oil by chromatography (hexane/EtOAc 1:1) gave the title compound as a white solid.