Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2ccc3ncnc(Cl)c32)c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (955 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added methyl 3-(bromomethyl)benzoate (671 mg), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water (40 mL), and extracted with a mixed solvent (40 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine (120 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (4/1) was added to the residue, and the resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (319 mg) as a pale-brown powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=O)[CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N>[Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([CH2:13][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH3:23])=[CH:19][CH:20]=2)[CH:3]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)c3c(c2Cl)CC(C)O3)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(Br)c3c(c2Cl)CC(C)O3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.2 %

Procedure:
To a solution of crude methanone 89 (3.15 g, 7.96 mmol) in CH2Cl2/CH3CN (25 mL/25 mL) were added triethylsilane (3.8 mL, 23.9 mmol) and boron trifluoride diethyl etherate (3.0 mL, 23.9 mmol) at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 hours. To the mixture was added aq. saturated K2CO3 solution (70 mL) slowly and extracted with EtOAc (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by normal phase column chromatography to provide the desired product 90 (2.68 g, 85% (2-steps)).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH:28]([CH3:47])[C:29]([C:35]1[CH:46]=[CH:45][C:38]2[N:39]([CH3:44])[C:40](=[O:43])[N:41]([CH3:42])[C:37]=2[CH:36]=1)([OH:34])[C:30]([F:33])([F:32])[F:31]>CN(C1C=CN=CC=1)C.C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[CH:28]([CH3:47])[C:29]([C:35]1[CH:46]=[CH:45][C:38]2[N:39]([CH3:44])[C:40](=[O:43])[N:41]([CH3:42])[C:37]=2[CH:36]=1)([OH:34])[C:30]([F:33])([F:31])[F:32])[O:27][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(OCC#N)cc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(c1ccc(Oc2ccc(OCC#N)cc2)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Copper(II)acetate (26 mg), 4-cyanomethoxy-phenylboronic acid pinacol ester (CAS Reg. No. 475272-13-0, 38 mg), and DMAP (30 mg) were added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 20 mg) in acetonitrile (3 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 h at 80° C., and then filtered over Celite concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (24 mg) as a white solid. MS (m/e)=546.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:19]=C)=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:30].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([CH:19]=[O:30])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: C=Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(C=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 8-chloro-4,6-dimethyl-9-vinylbenzo[c][2,7]naphthyridin-5(6H)-one (600 mg, 2.107 mmol), osmium tetroxide (2.5% in 2-methyl-2-propanol) (0.794 mL, 0.063 mmol), and 2,6-dimethylpyridine (0.491 mL, 4.21 mmol) in 1,4-dioxane (30 mL) and water (30 mL) cooled to 0° C. was added sodium periodate (1803 mg, 8.43 mmol). The mixture was warmed to room temperature and stirred for 3 h. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth (Celite®). The organic layer was concentrated under reduced pressure to afford a brown solid. The solid was washed with hexane (3×20 mL) and dried under vacuum to afford 8-chloro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-9-carbaldehyde 0.6 g, 2.107 mmol, 84% yield) as a gummy brown solid. LC/MS (ESI) m/e 287.0 [(M+H)+, calcd for C15H12ClN2O2, 287.1]; LC/MS retention time (method B): tR=2.03 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:60])([F:59])[CH2:49][C:50]1[N:54]2[CH2:55][CH2:56][NH:57][CH2:58][C:53]2=[N:52][N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([CH2:49][C:48]([F:47])([F:59])[F:60])=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)(F)Cc1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[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: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2CC(F)(F)F)C1
Reaction time: 12 h
Yield: 22 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (801 mg, 2.69 mmol) was dissolved in 25 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.27 g, 3.36 mmol), crude 3-(2,2,2-trifluoro ethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 26b (460 mg, 2.24 mmol) and N, N-diisopropylethylamine (0.8 mL, 4.48 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O and extracted with ethyl acetate (30 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 30 mL of ethyl acetate, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 26 (240 mg, yield 22.1%) as a white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([NH:9][C:10]([CH2:13][C:14]([CH3:17])([CH3:16])C)([CH3:12])[CH3:11])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(N)(N)(=O)=O.ClO[C:25](C)([CH3:27])[CH3:26].[H-].C(N=NC(CC(C)(C)C)(C)C)(C)(C)C>>[C:1]([NH:5][S:6]([NH:9][C:10]12[CH2:11][CH:26]3[CH2:25][CH:27]([CH2:16][CH:14]([CH2:17]3)[CH2:13]1)[CH2:12]2)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OCl
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)NC(C)(C)C
Agent: CC(C)(C)CC(C)(C)N=NC(C)(C)C
Agent: NS(N)(=O)=O
Agent: [H-]
Product: CC(C)(C)NS(=O)(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 45 %

Procedure:
Treatment of tertiary alcohols with chlorosulfonyl isocyanate gives monoalkyl sulfamyl chlorides (J. B. Hendrickson and J. Joffe, J. Am Chem. Soc., 95, 4084, 1973). Timberlake used this method to synthesize N-tert-butyl-N'-tert-octylsulfamide in 44% yield (J. W. Timberlake, M. L. Hodges and A. W. Garner, Tetrahedron Lett., 3843, 1973 and J. W. Timberlake, J. Alender, A. W. Garner, M. L. Hodges, C. Ozmeral and S. Szilagyi, J. Org. Chem., 46, 20282, 1981). The sulfamide was oxidized with tert-butyl hypochlorite and sodim hydride to tert-butyl tert-octyldiazene. N-tert-Butyl-N'-(adamant-l-yl) sulfamide was prepared in 45% yield by the same route. There is no evidence it was oxidized to the azo. Apparently, tert-butyl tert-2,2,4,6,6-pentamethyl-4-heptyldiazene was also prepared by this route (J. W. Timberlake and A. W. Garner, J. Org. Chem., 41, 1666, 1976).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[C:21](C(O)=O)=[N:20]2)[CH:5]=[C:6]([Cl:18])[C:7]=1[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:9]#[N:10].SCC(O)=O.C(=O)([O-])O.[Na+]>O>[Cl:18][C:6]1[CH:5]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:9]#[N:10]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc1Cl
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 180 °C

Procedure:
A mixture of 11.1 parts of 2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid (intermediate 5) and 15 parts of 2-mercaptoacetic acid is stirred and heated for 2 hours at 180 degrees C. The reaction mixture is cooled, water is added and the whole is treated with sodium hydrogen carbonate. The product is extracted with trichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:21]4)[N:14]=2)=[CH:9][C:8]=1[O:34][CH3:35])[CH3:5].Cl>C1COCC1.C(O)(C)C.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:21]4)[N:14]=2)=[CH:9][C:8]=1[O:34][CH3:35])[CH3:3]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cc(-c2nc(-c3ccc4[nH]c(CCC(=O)O)cc4c3)no2)cnc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
Sodium hydroxide (3 mg) was added to a solution of ethyl 3-(5-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-2-yl)propanoate (D118) (35 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The crude product was purified by Mass Directed Auto Prep to afford 3-(5-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-2-yl)propanoic acid (E93) (5 mg). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.70 (2H, t), 2.99 (2H, t), 3.94 (3H, s), 5.42 (1H, m), 6.34 (1H, s), 7.45 (1H, d), 7.76 (1H, dd), 7.83 (1H, d), 8.23 (1H, s), 8.54 (1H, d), 11.34 (1H, s), 12.26 (1H, s); MS (ES): C22H22N4O5 requires 422; found 423.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC(=CC)C.[OH:21]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+].OS([O-])(=O)=O.[K+]>C1COCC1.CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([OH:21])=[O:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc(Sc2ccc(Cl)cc2)s1
Agent: CC=C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(Sc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
The product of Step 14a (6.1 g, 24 mmol) is dissolved in a mixture of THF, t-BuOH, and water (3:3:1, 255 mL). 2-Methyl-2-butene (20.3 mL, 192 mmol) is added followed by KH2PO4 (9.8 g, 72 mmol) and then NaClO2 (80%, 8.17 g, 72.3 mmol). The mixture is stirred at rt for 2 hr. Aqueous KHSO4 (0.5M, 200 mL) is added and the organic solvents are removed in vacuo to produce an aqueous suspension of the product. The precipitate is collected by filtration, dissolved in 1N NaOH and washed two times with ether. The aqueous solution is then acidified to pH<6 with concentrated HCl and a precipitate formed. The precipitate is collected by filtration and washed with 0.5M KHSO4 then water. The solid is dried in vacuo to give 5-(4-chlorophenylsulfanyl)-thiophene-2-carboxylic acid (5.7 g, 87%). MS for C11H7ClO2S2 (ESI) (M−H)− m/z 269.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[CH3:15][NH:16][CH3:17].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([N:16]([CH3:17])[CH3:15])[N:3]=[C:4]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:5]=1
Reactant: CNC
Reactant: FC(F)(F)CNc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: O
Product: CN(C)c1nc(Cl)nc(NCC(F)(F)F)n1
Yield: 93 %

Procedure:
14.8 g (0.06 mol) of 2,4-dichloro-6-(2,2,2-trifluoroethylamino)-s-triazine (prepared as described in Example 3) were dissolved in 100 ml of acetone, and 12 ml of an approximately 45% strength aqueous dimethylamine solution were added dropwise at room temperature. The temperature was kept below 30° C. by cooling with water. The reaction product was precipitated by further addition of water. 14 g (=93% of theory) of 2-chloro-4-dimethylamino-6-(2,2,2-trifluoroethylamino)-s-triazine were obtained; melting point 181° to 184° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].Cl>[OH-].[K+]>[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc2cc(C(=O)c3cccc(C(C)C(=O)OC)c3)sc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 72.8 %

Procedure:
Methyl 2-{3-(5-methoxycarbonyl-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionate (36 g) in solution in a mixture of potassium hydroxide pellets (26.4 g), distilled water (160 cc) and ethanol (400 cc), is stirred for 17 hours at a temperature of about 20° C. The resulting suspension is diluted with distilled water (800 cc) and filtered. The filtrate is stirred with decolourizing charcoal (3 g) and filtered. The solution obtained is added dropwise to a 5 N aqueous solution of hydrogen chloride (400 cc) cooled in an ice bath, the rate of addition being regulated in such a way that the temperature of the mixture remains below 10° C. The reaction mixture is stirred for a further hour in the ice bath, and then the resulting crystals are filtered off, washed three times with distilled water (total 150 cc), and dried in air. Crude 2-{3-(5-carboxy-thieno[2,3-b]thien-2-yl)carbonylphenyl}propionic acid (24.3 g), melting at 244° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.ClCCl.CO.N>>[NH2:21][C:19]1[CH:18]=[CH:17][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:3]([O:2][CH3:1])[CH:20]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C(N)=O)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1 g (3.1 mmol) of 1-[2-(2-methoxy-4-nitrophenoxy)ethyl]piperidine-4-carboxylic acid amide. Yield: 0.8 g (88% of theory); C15H23N3O3 (M=298.38); calc.: molecular ion peak (M+H)+: 294; found: molecular ion peak (M+H)+: 294; Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([O:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[C:40]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH:41]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([O:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)=[C:40]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)[CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(Cl)ccc4Oc4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(Cl)ccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 46 was prepared analogous to compound of example 8 by hydrolysis of compound of example 45.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:28])[CH2:8][S:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([N:19]2[CH2:23][CH:22]([O:24][CH3:25])[CH2:21][NH:20]2)=[S:18])[C:13]([F:26])=[CH:12][C:11]=1[Cl:27]>C1(C)C=CC=CC=1>[Cl:27][C:11]1[C:10]([S:9][CH2:8][C:7]([O:6][CH3:5])=[O:28])=[CH:15][C:14]([N:16]=[C:17]2[N:19]3[N:20]([CH2:21][CH:22]([O:24][CH3:25])[CH2:23]3)[C:1](=[O:2])[S:18]2)=[C:13]([F:26])[CH:12]=1
Reactant: COC(=O)CSc1cc(NC(=S)N2CC(OC)CN2)c(F)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CSc1cc(N=c2sc(=O)n3n2CC(OC)C3)c(F)cc1Cl
Temperature: 22 °C
Reaction time: 2 h

Procedure:
At 0°-5° C., 4.2 ml of phosgene solution in toluene (20%) are added to a solution of 2.8 g of α-[2-chloro-4-fluoro-5-(4-methoxypyrazolidinyl-thiocarbonylamino)-phenylthio]-acetic acid methyl ester in 20 ml of toluene. After stirring for 2 hours at 22° C., the organic phase is washed with water, dried and concentrated. The product is purified by means of column chromatography to yield 2.21 g of the desired product, 8-(4-chloro-2-fluoro-5-methoxy-carbonylmethylthio-phenylimino)-3-methoxy-7-thia-1,5-diazabicyclo[3.3.0]octan-6-one, in the form of a yellow oil.
Reaction SMILES: Br.[N:2]1[CH:3]=[CH:4][N:5]2[C:13]=1[C:12]1[C:11]([C:14]([OH:16])=O)=[CH:10][NH:9][C:8]=1[CH2:7][CH2:6]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>O.CN(C)C=O>[F:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:14]([C:11]2[C:12]3[C:13]4[N:5]([CH:4]=[CH:3][N:2]=4)[CH2:6][CH2:7][C:8]=3[NH:9][CH:10]=2)=[O:16])=[CH:51][CH:50]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1c[nH]c2c1-c1nccn1CC2
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1c[nH]c2c1-c1nccn1CC2
Temperature: 25 °C

Procedure:
A mixture of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide (58 mg), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (181 mg), triethylamine (0.07 mL), 4-fluoroaniline (30 mg), and N,N-dimethylformamide (4 mL) is heated at 400 for 18 hours. The mixture is cooled to room temperature, treated with water (15 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with water (2×15 mL) and brine (1×15 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane, to give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid (4-fluorophenyl)amide, pale brown solid, 18 mg: LRMS calcd 296.30, found [M+H] 297.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([CH3:21])([CH:18]=[CH:19][CH3:20])[CH:16]=O>C(O)=O>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([CH3:21])([CH2:18][CH:19]=[CH2:20])[CH2:16][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC=CC(C)(C=O)Cc1ccc(Cl)cc1Cl
Reactant: C1CCNC1
Solvent: O=CO
Product: C=CCC(C)(Cc1ccc(Cl)cc1Cl)CN1CCCC1
Temperature: 100 °C
Yield: 47.2 %

Procedure:
149 g of formic acid were added dropwise to 45.8 g of pyrrolidine, while cooling with ice. 181 g of 3-(2,4-dichlorophenyl)-2-methyl-2-propen-1-ylpropionaldehyde were then added, after which the mixture was heated at 100° C. for 12 hours and then evaporated down under reduced pressure. The residue was made alkaline with 25% strength NaOH and extracted with ether, and the organic phase was dried over KOH and evaporated down. Distillation of the residue gave 95 g of (X) of boiling point 130°-138° C./0.1 mbar.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:25][C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:34][C:26]([F:35])([C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])[CH2:25][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CC(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 3 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 3.3 g of 2,2,3,3,4,4,4-heptafluorobutyl trifluoromethanesulfonate were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.07 g of 2-(2,2,3,3,4,4,4-heptafluorobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (79)).