Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1[C:42](C)=[CH:41]C=[CH:39][C:38]=1C.C(NCC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:24])[N:37]([CH2:42][CH3:41])[CH2:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, diethylamine (25 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-diethylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (66 mg, 59%) as a white solid: ESI-LRMS m/e calcd for C24H33ClN4O4S [M+] 508.19, found 509.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.18 (m, 5H, CH3 and CH2), 1.21 (t, J=7.2 Hz, 3H, CH3), 1.43-1.94 (m, 8H, 4×CH2), 2.18-2.27 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.33 (q, J=7.2 Hz, 2H, CH2), 3.39 (q, J=7.2 Hz, 2H, CH2), 3.54 (t, J=7.6 Hz, 1H, CH), 4.80 (s, 2H, NCH2), 6.71 (d, J=2.4 Hz, 1H, Ar), 7.36 (d, J=2.4 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.93 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]I)[N:12]=2)=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.CCOC(C)=O>[N:15]([CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:10]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(-c2nc(CI)co2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1coc(-c2ccc(F)cc2)n1
Temperature: 70 °C
Yield: 84.5 %

Procedure:
A solution of 2-(4-fluorophenyl)-4-(iodomethyl)oxazole (1.2 g, 3.96 mmol) in dry DMF (10 mL) was added sodium azide (515 mg, 7.9 mmol) and the reaction mixture was heated to 70° C. for 8 h. The reaction mixture was allowed to cool down to room temperature and diluted with EtOAc. The mixture was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.73 g, yield 85%) as a pale orange liquid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.67 (s, 1H), 7.16-7.12 (m, 2H), 4.34 (s, 2H). MS (ESI) m/z: Calculated for C10H7FN4O: 218.06. found: 219.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude product in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), LC Rt=3.81 min.
Reaction SMILES: C[CH2:2][O:3]CC.CO.[CH3:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10]>>[CH2:8]=[C:9]([CH3:11])[CH3:10].[CH3:2][OH:3].[CH3:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10]
Reactant: CCOCC
Solvent: COC(C)(C)C
Solvent: CO
Product: C=C(C)C

Procedure:
Another embodiment of the present invention is the use of pervaporation membranes to separate alcohols from ethers and/or hydrocarbons in a process for producing high purity alkenes by the decomposition of ethers. FIG. 4 depicts such a process for producing high purity isobutene by the decomposition of MTBE, although the present invention can be applied to other ether decomposition reactions. An impure C4 feed stream 70 is combined with a methanol feed stream 71 and recycled methanol stream 72 and fed to an MTBE synthesis system 74. The MTBE synthesis system 74 produces a MTBE product stream 76. A portion of the MTBE product stream 76 is collected as final MTBE product stream 78, while another portion of the MTBE product stream 76 is taken off at stream 80 and is heated and vaporized in the heat exchanger 81 and subsequently fed to a decomposition reactor 82 containing a fixed bed of acid cation exchange resin. The decomposition reactor 82 decomposes the MTBE feed to produce an effluent stream 83 containing isobutene/methanol/MTBE, which is cooled and condensed in heat exchanger 84 to produce a liquid mixture 85 which is subsequently fed through a pervaporation membrane system 86. The isobutene/methanol/MTBE mixture is separated by the pervaporation membrane system 86 to produce a high purity methanol permeate vapor 87 and a methanol-depleted liquid concentrate reject stream 88. The high purity methanol permeate vapor stream 87 is withdrawn from the membrane system, cooled and condensed if necessary, and subsequently recycled to the MTBE synthesis reactor 74 as stream 72. The methanol-depleted liquid concentrate reject stream 88 from the pervaporation membrane system 86 is fed to a distillation column 89 to undergo separation. The high purity isobutene stream 90 is taken as overhead product, and a high purity MTBE stream 91 is taken as bottom product and recycled to the feed to the MTBE decomposer 82. A liquid side draw containing isobutene/MTBE/methanol is taken from the distillation column 89 as stream 93 and is fed through a pervaporation membrane 94 where it is separated to form a high purity methanol vapor permeate stream 95 and isobutene/MTBE stream 96. The high purity methanol vapor permeate stream 95 is subsequently combined with the methanol permeate stream from the first pervaporation membrane system 86 and recycled as combined methanol stream 72 to the MTBE synthesis step 74. The isobutene/MTBE reject stream 96 from pervaporation membrane system 94 is returned to the distillation column 89 for further separation.
Reaction SMILES: [CH:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:30]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[C:14]([I:30])=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](C5CCCC5)CC4)ccc3c2)COC(=O)N1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O[C@H]4CC[C@H](C5CCCC5)CC4)ccc3c2)COC(=O)N1

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(trans-4-Cyclopentyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (89 mg, 0.00023 mol), N-iodosuccinimide (110 mg, 0.00050 mol), zirconium chloride (0.007 g, 0.00004 mol), and methylene chloride (3 mL, 0.04 mol). ESI-MS: 519 (M+H). 1H NMR (400 MHz, CDCl3) δ=8.17 (d, J=9.0 Hz, 1 H), 7.72-7.59 (m, 2 H), 7.45 (dd, J=1.9, 8.9 Hz, 1 H), 7.24 (d, J=9.0 Hz, 1 H), 5.90 (s, 1 H), 4.44-4.28 (m, 2 H), 4.20 (t, J=4.1 Hz, 1 H), 2.09 (d, J=10.5 Hz, 2 H), 1.91-1.30 (m, 16 H), 1.15-0.87 (m, 5 H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1>CC#N.CC(N=NC(C#N)(C)C)(C#N)C>[Br:23][CH2:12][C:5]1[CH:4]=[C:3]([N+:13]([O-:15])=[O:14])[C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1CBr
Temperature: 70 °C
Yield: 88.3 %

Procedure:
A mixture of methyl 5-chloro-2-methyl-4-nitrobenzoate (862 mg, 4 mmol) and NBS (854 mg, 4.8 mmol) in MeCN (16 mL) was degassed and then AIBN (14 mg, 0.08 mmol) was added. The mixture was heated to 70° C. for 18 h. The solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) in order to remove baseline impurities gave methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (1.09 g, 89%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.98 (s, 1H), 4.91 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH:40]2[CH2:41][CH2:42][CH2:43][O:39]2)=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCC1CCCO1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 1-(tetrahydro-2-furanyl)methanamine (0.252 mL, 2.44 mmol) for 15 min.@150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49-1.61 (m, 1H), 1.80-2.00 (m, 3H), 2.78 (t, J=6.46 Hz, 2H), 3.25-3.41 (m, 1H), 3.49-3.59 (m, 1H), 3.68 (t, J=6.81 Hz, 1H), 3.75-3.86 (m, 1H), 3.95-4.05 (m, 1H), 4.16 (s, 2H), 4.18-4.26 (m, 2H), 7.14 (ddd, J=8.95, 6.91, 1.82 Hz, 2H), 7.35-7.43 (m, 2H), 8.15 (d, J=1.40 Hz, 1H), 8.51 (s, 1H), 10.44-10.53 (m, 1H); ES+ MS: 441 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH2:15].C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>ClCCl>[F:25][C:26]([F:43])([F:44])[C:27]1[CH:28]=[C:29]([C:37]([CH3:41])([CH3:42])[C:38]([NH:15][C:3]2[CH:4]=[N:5][C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)=[CH:7][C:2]=2[I:1])=[O:39])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CN1CCN(c2cc(I)c(N)cn2)CC1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
To a suspension of 1.60 g (5.03 mmol) 4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine and 975 mg (7.54 mmol) N,N-diisopropyl ethyl amine in 16 ml dichloromethane was added dropwise 1.76 g (5.53 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride at 0° C. The reaction mixture was stirred for 2 h at room temperature and 2 h at reflux. After cooling to room temperature the reaction mixture was washed with 20 ml of a 1 M aqueous sodium carbonate solution and 20 ml water. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.39 g (100%) of the crude title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[C:38](O)=[O:39]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:34]3[NH:33][CH:37]=[CH:36][N:35]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(O)c1ncc[nH]1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)c3ncc[nH]3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and 1H-imidazole-2-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(1H-imidazol-2-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.13 (br s, 3H), 3.06 (br s, 4H), 3.33-3.39 (m, 4H), 3.69 (br s, 4H), 3.84-3.85 (m, 2H), 4.66-4.69 (m, 2H), 6.50 (br s, 1H), 7.11-7.16 (m, 1H), 7.18-7.20 (m, 1H), 7.28-7.31 (m, 2H), 7.54 (br s, 1H), 7.79 (s, 1H), 8.38 (br s, 1H), 12.96 (s, 1H). Mass Spectrum (ESI) m/e=534.9 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42](O)=[O:43])[CH:38]=[CH:39][CH:40]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cccc(Cl)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-phenylacetic acid (0.41 g, 2.4 mmol) were added. The reaction was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 30% EtOAc in CH2Cl2 for 10 min, then increase to 60% EtOAc in CH2Cl2 over 20 min) to afford 2-(3-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as a white solid (0.73 g, 76%): mp, 185-187° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.56 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 13 Hz, 1H), 7.23-7.82 (m, 7H), 8.70 (t, J=6 Hz, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.87, 41.53, 48.83, 121.93, 126.40, 127.15, 127.82, 128.94, 130.04, 131.52, 132.74, 133.25, 134.66, 138.54, 139.01, 166.88, 167.41, 169.77, 170.03, 172.73. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.92; H, 3.85; N, 9.55; Cl, 8.37.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[C:8]([Cl:18])=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[Cl:16])[C:10](O)=[O:11])#[N:6].[ClH:19].S(=O)=O>N1C=CC=CC=1>[C:5]([C:7]1[C:8]([Cl:18])=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[Cl:16])[C:10]([Cl:19])=[O:11])#[N:6]
Reactant: Cl
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)O)c1Cl
Agent: O=S=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Yield: 95.7 %

Procedure:
4100 ml of thionyl chloride and 41 ml of pyridine were introduced into a stirred apparatus fitted with metering device and gas outlet leading to a scrubber via a reflux condenser, and, at 20° C., 2050 g of 3-cyano-2,4-dichloro-5-fluorobenzoic acid (99.5% strength) were introduced at the rate of hydrogen chloride/sulphur dioxide evolution. At the end of the addition, the mixture was heated to reflux until the evolution of gas ceased. The mixture was then distilled. In the boiling range from 142 to 145° C./10 mbar, 2150 g (95.7% of theory) of 3-cyano-2,4-dichloro-5-fluorobenzoyl chloride were obtained (content according to GC: 98.0%).
Reaction SMILES: [C:1]([S:5][CH2:6][CH:7]([CH3:11])[C:8](O)=[O:9])(=[O:4])[CH2:2][CH3:3].S(Cl)([Cl:14])=O>>[C:1]([S:5][CH2:6][CH:7]([CH3:11])[C:8]([Cl:14])=[O:9])(=[O:4])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCC(=O)SCC(C)C(=O)O
Product: CCC(=O)SCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-propanoylthio-2-methylpropanoic acid (19.7 g) and thionyl chloride (16 g) was stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure to give the title compound, b.p. 135°-137° C. (35 mmHg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4](=[O:21])[C:3]=1[C:22]#[N:23].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4](=[O:21])[C:3]([C:22]#[N:23])=[C:2]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of Compound 46 (2.0 g, 6.04 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.56 g, 18.21 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 2.18 g (95%) yellow solids. M.P. 240° C. 1H NMR (DMSO-d6): δ 2.84 (s, 1H), 2.94 (m, 4H), 3.54 (m, 4H), 5.45 (s, 2H), 7.15 (m, 2H), 7.27 (m, 2H), 7.44 (dd, J=4.4, 9.3 Hz, 1H), 7.53 (td, J=2.4, 8.0 Hz, 1H), 7.58 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 381 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[N:24]1([C:30]2[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:27]3[CH2:26][CH2:25][N:24]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=4)[CH2:29][CH2:28]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2 g, 8.99 mmol) and ethyl 4-(piperazin-1-yl)benzoate (2.316 g, 9.89 mmol, CAS 80518-57-6) in DMF (20 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, then evaporated to dryness and redissolved in DCM (150 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was triturated with ether. The solid was collected by filtration and dried under vacuum to give ethyl 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoate (3.40 g, 90%) as a solid.
Reaction SMILES: ClCCCCC(OCC)CC.[CH2:12]([O:14][CH:15]([CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]=[CH:21]1)[CH3:13].[Cl:27][C:28]1([Cl:46])[C:34](=[O:35])[CH:33]2C1CCC2CCCCC(OCC)CC.[N+](=C)=[N-]>>[Cl:27][C:28]1([Cl:46])[C:34](=[O:35])[CH2:33][CH:24]2[CH:23]1[CH2:22][CH2:21][CH:20]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([O:14][CH2:12][CH3:13])[CH2:25][CH3:26]
Reactant: CCOC(CC)CCCCC1CCC2C1C(=O)C2(Cl)Cl
Reactant: CCOC(CC)CCCCC1C=CCC1
Agent: C=[N+]=[N-]
Agent: CCOC(CC)CCCCCl
Product: CCOC(CC)CCCCC1CCC2C1CC(=O)C2(Cl)Cl

Procedure:
The corresponding 2-(5-ethoxyhept-1-yl) homologs are prepared by substituting an equivalent amount of 1-chloro-5-ethoxyheptane in the Grignard reaction of Example 1 in place of the 5-methoxy homolog and using the reaction sequence shown above to prepare first the 3-(5-ethoxyhept-1-yl)cyclopentene, which is then converted to the 6,6-dichloro-2-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-6-one} of this invention. The diazomethane reaction described for the methoxy homolog produces the 6,6-dichloro-2-(5-ethoxyhept-1yl) bicyclo[3.3.0]octan-7-one {7,7-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-6-one}.