Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[O:13].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([O:34][CH3:35])[CH2:31][O:32][CH3:33])=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(#N)C>[CH3:35][O:34][CH:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([NH:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[O:13])=[CH:28][CH:27]=1)[CH2:31][O:32][CH3:33]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: CCCCCCCNCc1ccc(OC(COC)OC)cc1
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(OC(COC)OC)cc1)C(=O)Nc1ccc(OC)cc1OC
Reaction time: 48 h
Yield: 85.1 %

Procedure:
2,4-Dimethoxyphenyl isocyanate (Aldrich, 5.6 g) was added in one portion to a stirred solution of the product from step (c) (10.3 g) in acetonitrile (50 ml). The mixture was stood at room temperature for 2 days and then evaporated in vacuo to give a mobile pale tan oil which was flash chromatographed through a silica column using cyclohexane/ethyl acetate (1:1) as eluant to give the desired product as a colourless oil (13.0 g).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12]O)[CH2:4][CH2:3]1.C(=O)([O-])[O-:15].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1CCC(=NO)c2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CCC(=O)Nc2ccccc21
Temperature: 120 °C
Yield: 84 %

Procedure:
A mixture of 800 mg (4.57 mmol) of 4-methyl-1-tetralone oxime and 4.0 g of polyphosphoric acid was heated at 120° C. in an oil bath for 20 minutes. The dark brown mixture was cooled to 80° C. and poured into ice water. The solution was neutralized by the addition of 10% aqueous sodium carbonate then extracted chloroform (3×50 mL). The combined extracts were washed with water, dried over magnesium sulfate and filtered. Evaporation of the solvent followed by column chromatography on silica gave the product as an off-white solid (670 mg, 84%). 1H NMR (200 MHz, CDCl3): 1.30 (d, 8 Hz, 3H), 1.68 (m, 1H), 2.30 (m, 3H), 3.11 (m, 1H), 6.98 (m, 1H), 7.15-7.30 (m, 3H), 8.55 (br s, 1H). 13C NMR: 18.22, 32.89, 32.98, 37.28, 121.95, 125.67, 125.93, 126.98, 137.69, 137.80, 176.04.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CN(C=O)C>[Br:1][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:3][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: BrBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Reaction time: 0.5 h

Procedure:
A solution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151°; NMR δ (CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 11H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (bs, 1H); M/z (−) 268 (M+), 266, 196, 194.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:24]([O-])=O)=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[CH2:4][CH2:3]1.O.NN.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([S:40]([Cl:43])(=[O:42])=[O:41])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>C1COCC1.[Ni]>[ClH:43].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([S:40]([NH:24][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][C:12]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=[O:41])=[O:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccccc3)c2)CC1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCN(C)CC3)cc2NS(=O)(=O)c2ccccc2)cc1OC
Product: Cl
Reaction time: 1 h
Yield: 45 %

Procedure:
N-[5-(4-Methyl-1-piperazinyl)-2-nitrophenyl]benzenesulfonamide (0.600 g, 1.59 mmol) was dissolved in THF (20 mL) followed by the addition of Raney-Ni (0.322 g, in ethanol) and hydrazine hydrate (0.100 g, 2.0 mmol). The reaction mixture was stirred for 1 h, filtered through Celite and concentrated. The residue was dissolved in pyridine (12 mL) and divided in 12 equal parts. To one part was added 3,4-dimethoxy-benzenesulfonylchloride (47 mg, 0.20 mmol). The reaction mixture was stirred overnight, poured into petroleum ether to form a precipitate that was collected by centrifugation. The precipitate was purified by column chromatography (SiO2, CH2Cl2/MeOH 95:5 to 9:1). The pure product was dissolved in MeOH and treated with HCl/diethyl ether to give 34.5 mg, (45% yield). MS (posES-FIA) m/z=found: 547.4; Calcd: 546.16.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-cyanocyclohexanecarboxylate (996 mg, 5.96 mmol) in THF (37 mL) was added a solution of 0.5 M lithium hydroxide in water (20 mL). The mixture was stirred overnight then the THF was removed in vacuo and the residual aqueous solution acidified to pH 4. The resulting mixture was extracted with ether (2×30 mL), EtOAc (2×30 mL) and CHCl3 (2×30 mL) then the combined extracts, dried over anhydrous sodium sulfate and concentrated in vacuo. This material was taken to the next step without any purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.73 (4H, m), 2.05-2.22 (4H, m) and 2.36-2.59 (2H, m).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)C.C(O)CCC>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCCCO
Product: c1ccc(Cn2ccnc2)nc1

Procedure:
A solution of 2-chloromethylpyridine hydrochloride (16.4 g, 0.1 mol) in ethanol (50 ml) was added dropwise to a stirred, boiling solution of potassium tert-butoxide (22.4 g, 0.2 mol) and imidazole (6.8 g, 0.1 mol) in dry butan-1-ol (100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 5 h. After removal of the solvents under reduced pressure, the resulting oil was dissolved in hydrochloric acid (150 ml, 2 M), and the acid solution was washed with ether (100 ml). The acid solution was then basified with sodium hydroxide solution (10 M), and the basic solution was extracted with chloroform (3×100 ml). The chloroform solutions were combined, dried (MgSO4 ), and the chloroform was then removed under reduced pressure. The residue was purified by using a silica-gel column and by elution with chloroform/methanol (9:1). The resulting solid was recrystallised from ethanol/light petroleum affording 1-(2-pyridylmethyl)imidazole as white cubes, m.p. 79°-80°.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8](O)=O)([O-:3])=[O:2].[NH2:16][NH:17][C:18]([NH2:20])=[S:19].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.O1CCOCC1>[N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([C:8]1[S:19][C:18]([NH2:20])=[N:17][N:16]=1)[CH3:11])([O-:3])=[O:2]
Reactant: CC(Oc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1ccccc1[N+](=O)[O-])c1nnc(N)s1
Reaction time: 0.33 h

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 8.4 grams (0.040 moles) of 2-(2-nitrophenoxy)propanoic acid, (3.6 grams, 0.040 mole) of thiosemicarbazide and 30 ml. of dioxane. The slurry was heated to 90° centigrade and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams, 0.044 mole) was slowly added (for 26 minutes) while maintaining the temperature within 90°-95° C., and then stirred for an additional 20 minutes. It was refluxed for 60 minutes and cooled. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), leaving a viscous gummy residue to which 50 ml. of water was added and the slurry was made basic by adding 50 percent solution of NaOH until the pH of the solution was 10, and a solid precipate formed. The solid precipate was filtered off, washed with water, dried in a vacuum oven at 80 degrees Centigrade to tan crystals, 5-(1-(2-nitrophenoxy) ethyl)-2-amino-1,3,4-thiadiazole. (Melting point 137-142 degrees Centigrade).
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](O)=[O:15]>O1CCCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCc1ccccc1F
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane dimethyl sulfide complex (2M in THF, 27.6 mL) was added dropwise to a solution of 3-(2-fluorophenyl)propanoic acid (3.09 g) in tetrahydrofuran (25 mL) and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction was cautiously quenched with methanol and when bubbling had ceased, evaporated. The residue was purified by flash silica chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient to give the subtitled compound as a clear oil. Yield 2.72 g.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:11]O>>[NH2:2][C@H:3]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: CO
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Agent: Cl
Product: COC(=O)C1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of (1R,3S)-3-aminocyclopentanecarboxylic acid (5.00 g, 38.7 mmol, Peptech) in MeOH (100 mL) for about 15 min to give a tan solution, and the reaction mixture was stirred at ambient temperature for about 24 h. The solvent was removed under reduced pressure to give (3S)-methyl 3-aminocyclopentanecarboxylate (5.5 g, 25.5 mmol, 66%) which was dissolved in DMF (100 mL) and then K2CO3 (17.6 g, 127 mmol) and (bromomethyl)benzene (6.05 mL, 50.9 mmol) were added. The reaction mixture was stirred overnight at ambient temperature. The solid was collected by filtration and washed with DMF (100 mL). The filtrate was concentrated under high vacuum and the crude material was purified by silica gel chromatography eluting with 10% EtOAc in heptane to give (3S)-methyl 3-(dibenzylamino)cyclopentanecarboxylate (7.3 g, 89%) as a yellow oil: LC/MS (Table 2, Method a) Rt=2.97 min; MS m/z: 324 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:20]=2)[N:15]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)[CH:14]=1)[C:6](O)=[O:7].[CH3:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51].Cl.CN(C)CCCN=C=NCC.CC(O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:20]=2)[N:15]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)[CH:14]=1)[C:6]([NH:53][S:50]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[CH3:43])(=[O:52])=[O:51])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(Cc2ccc3ccc(Cl)cc3n2)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(Cc2ccc3ccc(Cl)cc3n2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution the acid from Step 4 (159 mg) and 2-methylbenzenesulfonamide (70 mg) in CH2Cl2 (3 ml) was added successively 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg) and DMAP (50 mg). After stirring at r.t. overnight, HOAc (200 μl) was added and the mixture was concentrated. Chromatography of the residue using EtOAc/hexane (2:3) containing 1% HOAc afforded 172 mg of the title compound.
Reaction SMILES: C[C:2]1([CH3:27])C(C)(C)OB([C:9]2[CH:26]=[CH:25][C:12]([NH:13][C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[S:16](=[O:24])(=[O:23])[N:15]=3)=[CH:11][CH:10]=2)[O:3]1.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[N:30]=1.C(=O)([O-])[O-:53].[Na+].[Na+]>COCCOC.O>[C:2]([OH:53])(=[O:3])[CH3:27].[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([C@H:39]3[CH2:44][CH2:43][C@H:42]([N:45]4[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]4)[CH2:41][CH2:40]3)[N:30]=[C:29]([C:9]3[CH:10]=[CH:11][C:12]([NH:13][C:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[S:16](=[O:23])(=[O:24])[N:15]=4)=[CH:25][CH:26]=3)[C:37]=12
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(NC3=NS(=O)(=O)c4ccccc43)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC5=NS(=O)(=O)c6ccccc65)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]-1H-1λ6-benzo[d]isothiazole-1,1-dione (0.09 g, 0.000234 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.08 g, 0.00018 mol), tetrakis-(triphenylphosphine)palladium (0.013 g, 0.000011 mol) and sodium carbonate (0.048 g, 0.00045 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1H-1λ6-benzo[d]isothiazole-1,1-dione acetate (0.075 g, 0.000119 mol) as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[N:7]=[N:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[C:6]([O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:7][NH:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=C(CO)N=NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
To a suspension of 4-tert-butyl-5-hydroxymethylpyrazol-3-one (6.25 g, 0.037 mol) in dry dichloromethane (200 ml) was added p-toluene sulfonyl chloride (9.8 g, 0.051 mol) followed by triethylamine (6.14 ml, 0.044 mol) dropwise. The solution was stirred at room temperature for 3 days. Dichloromethane (250 ml) was then added to dilute and the solution was washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 0%→30% ethyl acetate/dichloromethane as eluent to give the title compound (7.5 g). Data for the title compound: 1H NMR (400 MHz, DMSO) δ 1.28 (9H, s), 2.43 (3H, s), 4.49 (2H, m), 5.32 (1H, m), 7.47 (2H, m), 7.86 (2H, m), 12.28 (1H, s); MS (ES+) m/e 325 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)=[O:26])[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:8]2)[N:6]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].N1C=CC=CC=1>C(Cl)Cl>[C:43]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)=[O:26])[CH2:11][CH2:10][CH:9]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:16][CH2:17]3)[CH2:8]2)[N:6]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C2(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC(N3CCC(c4ccc(F)cc4)CC3)C2)cs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C2(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC(N3CCC(c4ccc(F)cc4)CC3)C2)cs1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 0.040 g of the compound from EXAMPLE 44, 0.20 g of acetic anhydride and 0.40 g of pyridine in 1.0 mL of CH2Cl2 was stirred overnight, evaporated and dried in vacuo. The residue was purified by preparative TLC (10% [aq. NH4OH/MeOH 1/9]/CH2Cl2). The title compound (0.037 g) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.60-2.24 (m, 9H), 2.27(s, 3H), 2.50 (m, 4H), 2.85 (m, 1H), 3.20 (m, 2H), 4.55 (m, 2H), 6.83 (s, 1H), 6.97-7.20 (m,5H), 7.64 (s,2H), 7.76 (s, 1H), 9.06 (broad, 1H). LC-MS: m/z 657 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(=O)(O)[O-].[Na+:44]>O1CCOCC1.[Pd].O>[CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O-:20])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:44]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC(=O)OCc3ccccc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SCC(=O)OCc3ccccc3)C[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of p-nitrobenzyl 2-benzyloxycarbonylmethylthio-6-(1-hydroxy)ethyl-carbapen-2-em-3-carboxylate (7.1 mg, 0.014 mmol) in dioxane (0.84 ml) is treated with ethanol (0.07 ml), water (0.49 ml) containing sodium bicarbonate (1.4 mg, 0.017 mmol), and 10% palladium on charcoal (7.1 mg) and the mixture is hydrogenated at 40 psi for 30 minutes. The mixture is diluted to 3 ml with water and centrifuged to remove the catalyst which is washed with more water (2×1 ml). The combined aqueous solution is washed with ethylacetate (4×2 ml), filtered through a cotton plug, concentrated in vacuo to ca. 1 ml, and lyophilized to provide the title compound as a powder: UV (0.1 M pH 7 phosphate buffer) 300 nm; electrophoresis (0.05 M pH 7 phosphate buffer, 2 KV, 25 ma, 20 mins) gives a single bioactive zone migrating 3.5 cm toward the anode.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:29]=2[CH:28]=1.C(N(CC)CC)C>CCO>[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[CH:9]=[C:8]([C:10]5[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=5)[C:7]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=5)=[N:6]4)[CH2:36][CH2:35]3)[C:29]=2[CH:28]=1
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Reactant: Cn1c(=O)n(C2CCNCC2)c2cc(Cl)ccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(C2CCN(CC(O)Cn3cc(-c4ccncc4)c(-c4ccc(C(F)(F)F)cc4)n3)CC2)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 21.6 %

Procedure:
To a solution of 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (68 mg, 0.197 mmol) and 5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027 mL, 0.197 mmol). The reaction mixture was heated at 80° C. overnight, concentrated, and purified by column chromatography (silica, 2-10% MeOH/CH2Cl2) to afford the title compound (0.026 g, 22%). MS (electrospray): exact mass calculated for C31H30ClF3N6O2, 611.2 [M+H]+. m/z found, 611.2. 1H NMR (400 MHz, CDCl3): 8.59 (br s, 2H), 8.20 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz, 1H), 4.31 (d, J=14.2, 6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H), 3.18-3.33 (m, 2H), 3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t, J=12.4 Hz, 2H).
Reaction SMILES: [F:1][CH:2]([O:7][CH2:8][CH:9]=[CH2:10])[C:3]([F:6])([F:5])[F:4].[Cl:11][SiH:12]([Cl:14])[Cl:13]>C(Cl)(Cl)Cl>[F:1][CH:2]([O:7][CH2:8][CH2:9][CH2:10][Si:12]([Cl:14])([Cl:13])[Cl:11])[C:3]([F:6])([F:5])[F:4]
Reactant: C=CCOC(F)C(F)(F)F
Reactant: Cl[SiH](Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(OCCC[Si](Cl)(Cl)Cl)C(F)(F)F

Procedure:
Each hour, 1.5 liters (11.3 moles) of tetrafluoroethylallylether, 1.3 liters (12.7 moles) trichlorosilane and 10 ml of a catalyst solution are added to the reactor. The catalyst solution is prepared by dissolving 19.4 g of tetrachlorodioctenediplatinum (II) in 1000 ml of chloroform.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:38])[NH:34][CH2:35][CH2:36][NH2:37])([CH3:31])([CH3:30])[CH3:29]>C1COCC1.CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([NH:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:38])=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)c2nc(NCCNC(=O)OC(C)(C)C)c(F)cc2c1=O
Temperature: 70 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
7-Chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (2.20 g, 7.37 mmol) in THF (20 mL) and MeCN (20 mL) was treated with triethylamine (3.07 mL, 22.0 mmol), followed by (2-amino-ethyl)-carbamic acid tert-butyl ester (1.41 g, 8.80 mmol) and the mixture heated to 70° C. After 26 h (2-amino-ethyl)-carbamic acid tert-butyl ester (300 mg, 1.87 mmol) was added. After a further 15 h the heating was stopped and the solvent removed in vacuo. The residue was taken up in ethyl acetate, washed with water, dried filtered, and concentrated in vacuo to give a residue which was purified by chromatography (silica gel, 30-100% ethyl acetate in petroleum ether (b.p. 40-60° C.)) to give the title compound (2.89 g); ESMS m/z 423 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Cl>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: Oc1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cccc(Oc2cccc(Cl)c2)c1

Procedure:
A mixture of 3-bromobenzaldehyde (6.0g), 3-Chlorophenol (4.8g), sodium hydride (1.3 g of an 80% suspension in oil) and cuprous cloride (1 g) was heated under reflux in pyridine (125 ml) under an atmosphere of nitrogen gas for 16 hours. The mixture was cooled, diluted with water, acidified with hydrochloric acid and extracted with diethyl ether. The etheral extracts were dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:9) to give the title compound as a colourless oil.