Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Cl)cc2)=NN1
Yield: 81.5 %

Procedure:
To a solution of 3-(4-chlorobenzoyl)propionic acid (20 g) in absolute ethanol (200 ml) was added 5 g of hydrazine monohydrate. A thick solid was formed which dissolved after heating. The resulting solution was refluxed for 3 h, cooled and the solid formed filtered and dried to yield 16 g (80%) of 6-(4-chlorophenyl)-4,5-dihydropyridazinone.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Sodium hydride (60% dispersion in oil, 12 mg, 0.32 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (70 mg, 0.29 mmol) in THF (1.5 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude, prepared in accordance with example 11, step 2, ˜0.32 mmol) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (30×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 66 mg (59%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[I-].[K+].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][S:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([C:15]1[N:14]=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:6][CH2:7]3)=[CH:17][CH:16]=1)[CH:19]=[CH:20]2)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CCl)CC3)cn2)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CN4CCCC4)CC3)cn2)c1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 52.1 %

Procedure:
To a solution of 2-chloro-1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)ethanone (0.080 g, 0.179 mmol) in DMF (2 mL), potassium iodide (0.009 g, 0.054 mmol), pyrrolidine (0.044 mL, 0.536 mmol), potassium carbonate (0.025 g, 0.179 mmol) were added and stirred at 80° C. for 45 minutes. The reaction was quenched by adding water (20 mL), the mixture was extracted with ethyl acetate, organic layer was concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to give 1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)-2-(pyrrolidin-1-yl)ethanon (0.045 g, 52.32%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10]=2[CH:11]=1)#[N:2]>C(O)(=O)C.CO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:10]=2[CH:11]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(CN)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 40 °C

Procedure:
6-cyano-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.10 g, 0.257 mmol) was suspended in acetic acid (8 mL). The contents were placed heated at 40° C. under an atmosphere of hydrogen (50 psi; H-cube reactor) at a flow rate of 1 mL/min with recirculation 2 h. Then contents were diluted with MeOH, concentrated in vacuo, and dried under hi vacuum for 18 h. The crude product was dissolved in DCM and purified by silica gel chromatography (eluent: 10-100% gradient of chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The product was concentrated from MTBE and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected as 68 mg (66%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.75 (m, 2H), 1.82-1.93 (m, 2H), 1.94-2.04 (m, 2H), 2.06-2.17 (m, 6H), 2.21 (s, 3H), 3.85 (s, 2H), 4.35 (d, J=5.05 Hz, 2H), 5.14 (t, J=7.07 Hz, 1H), 5.89 (s, 1H), 7.54 (s, 1H), 7.76 (s, 1H), 8.27 (s, 1H), 8.32 (t, J=5.05 Hz, 1H); LC-MS (ES) m/z=394.0 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([N:20]([C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C=C(C)CNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CN(CC)c1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 41.3 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.29 mmol), N-ethyl-2-methylallylamine (Aldrich Chemical Company) (0.19 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by preparative TLC on silica gel with 1:1 EtOAc:hexanes as eluant to give 36.7 mg (42%) of the title compound as off-white solid. An analytical sample was obtained by recrystallization from EtOAc. Mp: 148-150° C. 1H NMR (CDCl3; 500 MHz): δ 1.32 (t, 3, J=7.1), 1.95 (s, 3), 2.59 (s, 3), 3.78 (q, 2, J=7.1), 4.20 (s, 2), 5.18 (s, 1), 5.24 (s, 1), 6.74 (s, 1), 7.35-7.48 (m, 3), 7.55 (d, 2, J=7.4), 8.47 (br s, 1). MS m/z: 307 (M+1), 305 (M−1). Anal. Calcd for C19H22N4: C, 74.48; H, 7.24; N, 18.28. Found: C, 74.36; H, 7.27; N, 18.19.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([S:12][CH3:13])=[N:5][CH:6]=[N:7]2.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=O)C1.[N:34]([C@@H:37]1[CH2:42][CH2:41][NH:40][CH2:39][C@H:38]1[OH:43])=[N+:35]=[N-:36]>C(Cl)(Cl)(Cl)Cl>[N:34]([C@@H:37]1[CH2:42][CH2:41][N:40]([CH2:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4]([S:12][CH3:13])=[N:5][CH:6]=[N:7]3)[CH2:39][C@H:38]1[OH:43])=[N+:35]=[N-:36]
Reactant: CSc1ncnc2cccc(C)c12
Reactant: [N-]=[N+]=N[C@@H]1CCNC[C@H]1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnc2cccc(CN3CC[C@@H](N=[N+]=[N-])[C@H](O)C3)c12
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a mixture of 1C (1.19 g, 6.25 mmol), AIBN (111.2 mg, 0.625 mmol), and NBS (1.129 g, 6.875 mmol) under N2 was added CCl4 (30 ml). The mixture was degassed under vacuum, purged with nitrogen (2×) and heated to 80° C. for 40 min. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloroethane (30 ml). (3R,4R)-4-azidopiperidin-3-ol (976 mg, 6.875 mmol), (prepared as described in U.S. patent application Ser. No. 11/019,901) and TEA (1.04 ml, 7.5 mmol) were subsequently added. The mixture was stirred at room temperature for 1 h, then at 75° C. for 30 min. After cooling to room temperature, the reaction mixture was washed with saturated NaHCO3, then extracted with 2N HCl (40 ml). The acidic aqueous layer was separated and basified with 50% NaOH. Solid product was collected by filtration, washed with water and dried under high vacuum to give 1D (1.51 g, 73%) as a solid. The compound has an analytical HPLC retention time=1.106 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=331+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:17][S:18]([O-:21])(=[S:20])=[O:19].[K+]>C(O)C>[CH3:17][S:18]([S:20][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])=[O:19]
Reactant: CCOC(=O)c1cccc(OCCBr)c1C
Reactant: CS(=O)([O-])=S
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cccc(OCCSS(C)(=O)=O)c1C

Procedure:
2 g (7 mmol) of ethyl 3-(2-bromoethoxy)-2-methylbenzoate and 1.1 g (7.3 mmol) of potassium thiomethanesulfonate are dissolved in 10 ml absolute ethanol. The reaction mixture is refluxed for 20 hours. The solvent is then distilled off and the residue taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed. The product of value is purified by column chromatography.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].C1C=CC=CC=1.[H-].[Na+].C[O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18][C:17](=O)[CH:16]=1>CCOCC>[CH3:1][S:2]([CH2:4][C:17]1[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[C:15](=[O:14])[CH:16]=1)=[O:3]
Reactant: CS(C)=O
Reactant: COc1cc(=O)oc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CS(=O)Cc1cc(=O)c2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A mixture of dimethyl sulfoxide (500 ml), benzene (375 ml) and sodium hydride (52 g of a 57% oil dispersion, 1.24 mole), was heated at 75° under nitrogen until all the solid dissolved giving a clear gray-green solution. The solution was cooled in an icebath and 4-methoxycoumarin (75 g, 0.425 mole) was added. The reaction mixture was stirred at room temperature for one hour and poured into excess anhydrous ether. Th ether was decanted from the insoluble salts, which were washed several times with fresh ether. The salts were dissolved in a minimum of cold water and acidified with ice-cold 5 N hydrochloric acid. The acidified solution was extracted with chloroform (5×40 ml). The extracts were combined, dried over Na2SO4, and evaporated at reduced pressure to give a solid product. Recrystallization from absolute ethanol gave white crystals (57.3 g, 61%), m.p. 142°-146°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.C(N(CC)CC)C>ClCCl.[Cu]>[N+:8]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([O:12][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:5][C:6]=1[CH3:11])([O-:10])=[O:9]
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (1.67 g), 3-trifluoromethylbenzene boronic acid (3.8 g), copper (1 acetate (1.82 g) and triethylamine (2.02 g) in dichloromethane (50 ml) was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and purified by silica gel chromatography eluting with light petroleum (b.p. 60-80° C.)/ethyl acetate (19:1) to give the title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:31][CH:20]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:31][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)nn1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (256.3 mg, 0.57 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (a solution of NH3 in MeOH (7 M)/MeOH/DCM (v/v/v)=3/60/600) to give the title compound as a beige solid (199.0 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-5-(4-isopropylphenyl)-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)-carbonyl]benzoate (0.037 mmol, 16.0 mg), methanol (3 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.184 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.184 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (6.8 mg, yield 44%).
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[CH:4]=[C:3]1[CH3:10].CC1C2C=CSC=2CC=1C.[Li]CCCC.[Cl:26][Si:27](Cl)([CH3:29])[CH3:28]>C1COCC1>[Cl:26][Si:27]([CH:4]1[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[C:2]([CH3:1])=[C:3]1[CH3:10])([CH3:29])[CH3:28]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2sccc2C1C
Agent: CC1=C(C)c2ccsc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, to a solution of 10.0 g (66.6 mmol) of a mixture of 4,5-dimethyl-4H-cyclopenta[b]thiophene and 4,5-dimethyl-6H-cyclopenta[b]thiophene in 150 ml of THF, 26.6 ml of 2.5 M (66.6 mmol) nBuLi in hexanes was added dropwise over 30 minutes at −60° C. This mixture was additionally stirred for 2 hours at room temperature and then added dropwise for 3 hours to a solution of 23.7 ml (25.2 g, 200 mmol) of dichlorodimethylsilane in 50 ml of THF. The resulting mixture was stirred for 12 hours at ambient temperature and then evaporated to dryness. Fractional distillation gave yellowish liquid, by 83-85° C./0.2 mm Hg. Yield 10.7 g (66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:29]=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>ClC(Cl)C.C(O)(=O)C>[CH:24]1([CH2:29][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Reactant: O=CC1CCCC1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CCCC3)cn(C)c12
Yield: 30.6 %

Procedure:
The product from Example 44A (55 mg, 0.166 mmol) and cyclopentanecarbaldehyde (58.64 mg, 0.597 mmol) in dichloroethane/acetic acid (1:1, 1 mL) was heated in a sealed tube at 60° C. for 24 hours, cooled, and concentrated. Purification by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.021 g, 31%).
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)c1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Yield: 16.1 %

Procedure:
2-Methylsulphinyl-3-nitro-4-phenylpyrrole (2.0g, 0.008 mol) was partially dissolved in ethanol (150 ml) and a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37g, 0.008 mol) in a little ethanol was added to it. The mixture was refluxed for seven days, after which the mixture was stripped and chromatographed on a silica gel column, collecting the required product by elution with ethyl acetate. The crude solid was recrystallised from 2-propanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-phenylpyrrole (0.46g), m.p. 182-184'.
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2].[N+:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CO.C(Cl)Cl>[P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[N:29][NH:28][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:31][CH:30]=1)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCSP(=S)(Oc1ccccc1C=O)SCC
Solvent: ClCCl
Solvent: CO
Product: CCCSP(=S)(Oc1ccccc1C=NNC(=O)c1ccc([N+](=O)[O-])cc1)SCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-ethyl S-propyl O-(2-formylphenyl) trithiophosphate (0.02 mole) in methanol (50 ml) and 4-nitrobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-ethyl S-propyl O-[2-(4-nitrobenzoylhydrazonomethyl)phenyl] trithiophosphate.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[CH2:25]([S:27]([NH-:30])(=[O:29])=[O:28])[CH3:26].Cl>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=[C:2]([NH:30][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CCS([NH-])(=O)=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OC
Reaction time: 240 h
Yield: 83.2 %

Procedure:
To a solution of 4,6-dichloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl (prepared as described in [6] and [11]) (1.74 g) in DMSO (5 ml) was added ethanesulfonamide potassium salt (1.62 g). Stirring was continued for 10 days at rt. The reaction mixture was poured onto ice/water and acidified by 2N HCl. The precipitate was filtered off, washed with water and dried at HV to give ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (1.75 g) as a white powder. LC-MS: tR: 3.77, [M+H]+: 422.15.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc(O)cc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-aminophenol (Aldrich) according to the method described in Example 1c. Melting Point: 167-169° C. (diethylether).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=[CH2:12].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([CH3:13])([CH3:12])[CH3:10]
Reactant: OCc1ccccc1O
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Oc1ccccc1CO
Temperature: -78 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
The procedure was adopted from the previously published literature (J. Org. Chem. 1986, 51, 113-114). To a flame-dried flask, 2-hydroxy benzyl alcohol (10 g, 80 mg) and 400 mL CH2Cl2 was added. The reaction mixture was cooled to −78° C. by use of a dry ice/acetone bath. Following the addition of liquefied 2-methylpropene (40 mL), trifluoromethanesulfonic acid (2 mL, 22 mmol) was added. The reaction mixture was stirred for 5 hr while maintaining the temperature at −78° C. The reaction was quenched with triethylamine and then allowed to warm to room temperature. The solvent was removed by distillation under reduced pressure and the oily product was triturated with 500 mL petroleum ether several times. Petroleum ether was then evaporated and the crude product was purified by silica gel column with the following eluents: 20% EtOAc/80% Hexane. The product was isolated as pale yellow oil (30% yield). 1H NMR (CDCl3) δ 7.286 (dd, 1H, Ar), 7.195 (ddd, 1H, Ar), 7.063 (d, 1H, Ar), 7.003 (ddd, 1H, Ar), 4.669 (s, 2H, —CH2—), 1.447 (s, 9H, —C(CH3)3—). Mass Spec.=180.24 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17](OC)=[O:18])[C:13]=1[CH2:14][CH3:15]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]([NH:2][NH2:3])=[O:18])[C:13]=1[CH2:14][CH3:15]
Reactant: NN
Reactant: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: O
Product: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 70624 %

Procedure:
Hydrazine hydrate (520 μL, 10.9 mmol) was added to a solution of the ester (780 mg, 2.18 mmol) of Example 9 in ethanol (25 ml) and the resulting mixture was heated under reflux for 18 hours. After cooling, the precipitate was collected by filtration and washed with ether (50 ml) to afford the title compound (550 g) as a white solid, m.p. >250° C.