Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.CN(C1C=CC=CN=1)C.CN1CC[O:44][CH2:43][CH2:42]1>ClCCl.C(OC(=O)C)(=O)C>[C:43]([NH:30][S:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:19])[C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=3[F:18])=[CH:6][N:5]=2)[CH2:22][CH2:23]1)(=[O:28])=[O:29])(=[O:44])[CH3:42]
Reactant: CN1CCOCC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(N)(=O)=O)CC2)nc1N
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)NC(C)=O)CC2)nc1N
Reaction time: 2 h

Procedure:
4-[4-Amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonic acid amide (50 mg, Example 285) in dichloromethane (10 mL), N-methyl morpholine (0.1 mL, Aldrich) and dimethylaminopyridine (1 mg, Aldrich) was chilled in ice and added acetic anhydride (5 drops). The mixture was stirred cold for two hours and quenched with methanol. The mixture was evaporated to dryness and chromatographed on silica gel (dichloromethane, then ethyl acetate). Fractions corresponding to product were combined and crystallized from dichloromethane/ethyl ether to give 45 mg of colorless material, MP 153° C. (dec). MS(ES) MH+ 485
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:19]C1C=CC(O)=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: Nc1ccc(O)cc1
Product: CNC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 3-aminophenol for 4-aminophenol. 1H-NMR (DMSO-d6) δ 8.75 (br q, J=4.8 Hz, 1H), 8.48 (d, J=6.3 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H), 7.15 to 7.07 (m, 2H), 5.51 to 6.47 (m, 1H), 6.31 to 6.24 (m, 2H), 5.40 (s, 2H), 2.77 (d, J=5.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].O>C(O)C>[C:13]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:20][CH:16]([CH3:17])[CH2:18][CH3:19])=[N:3][C:4]=1[CH3:15])#[N:14]
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Cl
Reactant: CCC(C)N
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C#N)c(C)nc1NC(C)CC

Procedure:
22.4 g of 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (1 mol) of Example 1(b) are treated in 100 ml of ethanol with 15 g sec. butylamine at reflux temperature with stirring. After the addition of the amine is completed, the solution is poured into 200 ml of cold water, and the amino compound is filtered off. Yield 22 g (84%); m.p. 55°-57° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:26][CH:25]=5)[N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:10][C:9]=2[F:46])=[O:6])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:26][CH:25]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:10][C:9]=2[F:46])=[O:6])[CH2:2][CH2:3]1
Reactant: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(F)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(F)c4)ncnc3[nH]2)cc1
Yield: 48.1 %

Procedure:
After dissolving 65 mg of N-cyclopropyl-N′-(4-(6-(4-(2-diethylaminoethoxy)-phenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea in 2 ml of tetrahydrofuran, there was added dropwise 0.5 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) and the mixture was refluxed for 3 hours. After returning it to room temperature, water was added, the mixture was stirred, and the precipitated crystals were filtered out, washed with water and ether-hexane (1:1) and dried under reduced pressure to obtain 25 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][CH2:11][N:6]2[CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH3:25]>C1COCC1>[CH3:25][N:3]1[CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH:7]2[C:2]1=[O:1]
Reactant: O=C1NCCN2CCN(C(=O)OCc3ccccc3)CC12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN2CCN(C(=O)OCc3ccccc3)CC2C1=O
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of (+/−)-benzyl 9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (160 mg, 0.553 mmol) in THF (5 mL) at 0° C. was added sodium hydride (24.33 mg, 0.608 mmol). The ice bath was removed and stirred for 10 min; saw bubbling but some NaH solid still remained. Then iodomethane (0.038 mL, 0.608 mmol) was added and after stirring for 10 min at room temperature, most NaIl solid was dissolved. After another 30 min, LC-MS indicated completion. It was quenched with water and diluted with EtOAc. After separating the layers, the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification via flash chromatography (0-5% MeOH in DCM, 12 g) gave (+/−)-benzyl 8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (120 mg) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)=[CH:8][C:7]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:45][O:46]CCO>>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([S:24]([C:7]2[CH:8]=[C:9]([C:10]3[NH:11][C:12](=[O:23])[C:13]4[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=4[N:15]=3)[C:4]([O:3][CH2:1][CH2:2][O:46][CH3:45])=[N:5][CH:6]=2)(=[O:26])=[O:25])[CH2:28][CH2:29]1)[CH3:34]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)nc12
Reactant: COCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCOC)nc12
Yield: 64 %

Procedure:
A mixture of the title compound of Example 124 (111 mg, 0.23 mmol) and potassium bis(trimethylsilyl)amide (226 mg, 1.13 mmol) in 2-methoxyethanol (5 ml) was stirred under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using dichloromethane: methanol (96:4) as eluant, and triturated with ether to afford the title compound (75 mg, 64%) as a white crystalline solid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10])=[O:25]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: O=C(O)c1ccccc1C(F)(F)F
Product: O=C(NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1C(F)(F)F)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-trifluoromethyl-benzoic acid.
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1C=CC=C[CH:21]=1.[Cl-].[Mg+2].[Cl-].C([Mg]Br)C>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH2:20][CH3:21]
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Yield: 28 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]-octane prepared from 1.76 g of (S)-2-(anilinomethyl)pyrrolidine, as described in Example 8, was dissolved in 50 ml of THF, then admixed with 1.05 g of anhydrous magnesium chloride and refluxed by heating for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution containing 1.46 equivalents of ethylmagnesium bromide. The resulting mixture was treated as described in Example 12 to obtain 694 mg (28%) of 2-propionyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ (ppm)=1.0 (3H, triplet), 1.4-2.1 (4H, multiplet), 2.1-2.6 (2H, multiplet), 2.6-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.2 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[C:2]1([C:1]2[S:32][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of ethyl 2-(2-benzoylhydrazinyl)-2-oxoacetate (1 g, 4.23 mmol) in dry THF (5 ml, 61.0 mmol) was added the Lawesson's Reagent (1.079 g, 2.67 mmol). The reaction was stirred at r.t. for 2 h without any reaction. The mixture was then heated to 50° C. and then heated to reflux. Additional Lawesson's Reagent (1.079 g, 2.67 mmol) was added and after 16 h at reflux, the reaction was halfway completed. The mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (50% CH2Cl2/hexanes up to 100% CH2Cl2) to provide the title material (0.35 g, 35%). LC (Method B): 2.063 min, LCMS (APCI) calcd for C11H11N2O2S [M+H]+ m/z 235.05. found 235.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.49 (t, J=1.00 Hz, 3H), 4.55 (q, J=1.00 Hz, 2H), 7.45-7.65 (m, 3H), 8.02-8.07 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[F:23][C:24]1([F:33])[CH2:27][N:26]([C:28](=[O:32])/[CH:29]=[CH:30]\I)[CH2:25]1.O>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:17][N:16](/[CH:30]=[CH:29]/[C:28]([N:26]3[CH2:27][C:24]([F:33])([F:23])[CH2:25]3)=[O:32])[C:15](=[O:18])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:8]=1
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Reactant: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1/C=C/C(=O)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
4-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-2-one (0.5 g, 1.0 eq.) was dissolved in DMF (5 mL) and cooled to 0° C. A solution of NaH in DMF (0.133 g, 2.0 eq.) was added at 0° C. (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.689 g, 1.5 eq.) was then introduced. The reaction mixture was stirred for 30 min at room temp. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.502 g of crude product, which was purified by chromatography (1% Methanol in DCM) to give 0.030 g of (E)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(3-(3,3-difluoroazetidin-1-yl)-3-oxoprop-1-enyl)pyrrolidin-2-one (Yield 4.03%). 1H NMR (400 MHz, CDCl3) δ 8.15-8.19 (d, J=14 Hz, 1H), 7.69-7.87 (m, 3H), 5.27-5.31 (d, J=14 Hz, 1H), 4.05-4.47 (m, 4H), 3.89-3.93 (s, 1H), 3.73-3.77 (s, 1H), 3.60-3.62 (s, 1H), 3.08-3.13 (s, 1H), 2.78-2.90 (s, 1H); LCMS calcd. for C18H14F8N2O2 [M+H]+. found 443.44 at retention time 2.97 min.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C@H:15]([O:17]C=O)[CH3:16])[C:9]1=[O:20])[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+]>CO.C(O)(=O)C>[CH3:21][C:2]([CH3:1])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C@H:15]([OH:17])[CH3:16])[C:9]1=[O:20])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H]1[C@@H]([C@@H](C)OC=O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CC[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Methyl 3-methyl-2-[(3S,4R)-3-[(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (23 mg) was dissolved in methanol (1 ml) and cooled to 0° C. To this solution was added a solution of sodium methoxide in methanol (0.49 M, 0.16 ml) and the mixture was stirred for 1 hour at the same temperature. An additional 0.08 ml of the sodium methoxide solution was added and the mixture was stirred for 30 minutes at the same temperature. Acetic acid (2 drops) was then added and the mixture was evaporated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (silica gel) developing with methylene chloride and ethyl acetate (2:1) to give methyl 3-methyl-2-[(3S,4R)-3-((1R)-1-hyroxyethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:3][CH2:4][CH:5]([C:8]4[C:9](=[O:18])[NH:10][C:11]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:6][CH2:7]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 46 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as off-white solid in 46% yield. MS m/e (M+H)+=574.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 11.76 (s, 1H), 8.36 (s, 1H), 7.70 (d, J=5.80, 1H), 7.61 (d, J=7.63, 1H), 7.43 (t, J=7.63, 1H), 7.28 (d, J=7.93, 1H), 7.24 (s, 1H), 7.15 (t, J=7.32, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=16.79, 1H), 4.55 (d, J=12.21, 1H), 4.13 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.15 (m, 2H), 3.03 (m, 3H), 2.88 (m, 1H), 2.63 (m, 1H), 2.34 (d, J=16.17 1H), 1.91 (d, J=1.22, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1.[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:31]3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=3)=[O:43])=[C:3]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:4]=2)[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1)#[N:17]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 95 %

Procedure:
A solution of 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (119 mg, 0.332 mmol, as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (123 mg, 0.398 mmol, as prepared in Example 1, step (d)) in CH2Cl2 (10 mL) was treated with PyBroP (217 mg, 0.465 mmol) and DIEA (231 μL, 1.33 mmol) at room temperature for 45 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with satd aq NaHCO3 (1×30 mL). The aqueous layer was extracted with CH2Cl2 (1×30 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column (FlashMaster system) with 10-25% EtOAc-hexane afforded the title compound (193 mg, 95%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C31H41N5O4SSi, 608.3 (M+H). found 608.3.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Solvent: ClCCl
Product: O=S(=O)(CCN1CCC(Cc2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a solution of 40.0 g 4-(2-chloro-ethanesulfonyl)-phenol (181 mmol) in 600 ml CH2Cl2 were added 69.9 g 4-benzylpiperidine (399 mmol). After stirring for 16 h at r. t. the reaction mixture was concentrated to 100 ml and directly purified by chromatography over silica gel (CH2Cl2/MeOH/NH3 19/1/0.1). Recrystallization from ethyl acetatelhexane (2:1) yielded 25 g product (70 mmol, 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]3[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=3)=[O:43])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:43])[C:44]3[CH:45]=[CH:46][C:47]([C:48]4[NH:10][C:9]5[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:27])[C:15]6[CH:20]=[CH:19][C:18]([N:21]7[CH2:26][CH2:25][O:24][CH2:23][CH2:22]7)=[CH:17][CH:16]=6)=[CH:5][C:4]=5[N:1]=4)=[CH:50][CH:51]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C=O)cc3)cc2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4nc5cc(NC(=O)c6ccc(N7CCOCC7)cc6)ccc5[nH]4)cc3)cc2)CC1

Procedure:
Compound 250 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-morpholinobenzamide and 4-(4-(4-methylpiperazinyl)phenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C36H37N7O3: 616.30; found: 616.13.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1Br.[CH2:10]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][NH:18][CH3:19])[CH2:11][CH3:12]>C(O)C>[Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[N:18]([CH2:17][C:16]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH2:10][CH2:11][CH3:12])[CH:15]=1)[CH3:19]
Reactant: O=c1[nH]ncc(Br)c1Br
Reactant: CCCOc1cc(CNC)ccc1OC
Solvent: CCO
Product: CCCOc1cc(CN(C)c2cn[nH]c(=O)c2Br)ccc1OC
Reaction time: 7 h

Procedure:
A mixture comprising 300 mg of 4,5-dibromo-3(2H)pyridazinone, 740 mg of 3-n-propoxy-4-methoxy-N-methylbenzylamine and 10 ml of ethanol, was refluxed under stirring for 7 hours. Then, ethanol was distilled off under reduced pressure, dilute hydrochloric acid was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed twice with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow solid substance. The product was crystallized from ethyl acetate, to obtain 310 mg of the above identified compound having a melting point of from 149° to 150° C. as light yellow crystals.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([S:13]([N:16]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](Cl)=[O:24])=[CH:17]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1.[NH2:26][OH:27]>O>[OH:27][NH:26][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]1[CH:19]=[CH:20][N:16]([S:13]([C:11]2[S:12][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:9][CH:10]=2)(=[O:15])=[O:14])[CH:17]=1
Reactant: NO
Reactant: O=C(Cl)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Agent: Cl
Solvent: O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1)NO
Temperature: 0 °C
Reaction time: 1.08 h

Procedure:
The above prepared solution of (E)-3-[1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acryloyl chloride hydrochloride was added to an aqueous hydroxylamine solution (50%, 150 g, 2.27 mop at 20-25° C. over a period of 45 min. After stirring for 65 min, water (300 mL) was added and cooled to 0° C. The suspension was filtered and the filter cake was washed with water (150 mL). The title compound was obtained as beige solid (17.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH2:10])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)[C@H](O)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(C)cc1)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2S,3R)-2-amino-3-hydroxy-4-methyl-pentanoic acid methyl ester (0.50 g, 3.4 mmol) and triethylamine (0.69 g, 6.8 mmol) in dichloromethane (10 mL) was added 4-methyl-benzenesulfonyl chloride (0.71 g, 3.7 mmol) at 0° C. After stirring for 2 hours at room temperature, the mixture was washed with water and the organic layer was separated and then dried over sodium sulfate. After removal of solvent, the residue was used in next step without purification. MS: calc'd (MH+) 316, measured (MH+) 316.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:18][C:19]([F:30])([F:31])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.053 mMol) 4-trifluoromethoxybenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.