Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:28])=[N:22][C:23](Cl)=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:37])[F:36])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1.FC(F)(F)C(O)=O>O1CCCC1.[Cl-].[NH4+].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[N:24][C:23]([CH:1]([CH3:3])[CH3:2])=[N:22][C:21]=4[CH3:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:36])[F:37])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1
Reactant: CC(C)[Mg]Cl
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(C)C)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
i-Propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.76 mL, 0.760 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (189 mg, 0.381 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.7 mg, 0.0381 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (19.1 mg, 0.0379 mmol, 10%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:16]([CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][NH2:7])[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1CCC(Cc2ccccc2)CC1

Procedure:
[2-(4-Benzyl-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (1.34 g, 4.2 mmol) is dissolved in CHCl3 (3 mL) and treated with TFA (3 mL) for 2 h at 20° C. The solvent is evaporated, the residue dissolved CH2Cl2 (100 mL) and washed with 1M aqueous NaOH (2×30 mL). The organic layer is dried (Na2SO4), filtered and concentrated to provide the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.O[CH:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22]1>O1CCCC1.C(O)C>[OH:32][CH:29]1[CH2:30][CH2:31][C:24]2([CH2:25][CH2:26][CH:21]([C:17]#[N:18])[CH2:22][CH2:23]2)[CH2:27][CH2:28]1
Reactant: O=C1CCC2(CC1)CCC(O)CC2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC1CCC2(CCC(O)CC2)CC1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Potassium tert-butylate (1.44 g) was added in small portions, at 0° C. under nitrogen atmosphere, to a solution of 1.40 g of tosylmethylisocyanide and 1.00 g of 3-hydroxy-9-oxo-spiro[5.5]undecane (II-a, Prep. 1) dissolved in 7 ml of anhydrous tetrahydrofuran and 0.53 ml of absolute ethanol. After 0.5 hrs at room temperature, the mixture was filtered on an alumina cake. The cake was washed with dichloromethane and the filtrates, dried over anhydrous sodium sulfate, were evaporated under reduced pressure to give 0.52 g of crude 9-hydroxy-3-cyano-spiro[5.5]undecane as a light oil. [TLC: Rf=0.52 (SiO2 plates, diethylether). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.63 (1H, hept), 2.57 (1H, m), 1.90-1.05 (16H, m)].
Reaction SMILES: [Li].[C:2]([O:7][CH3:8])(=[O:6])[CH:3]([CH3:5])[CH3:4].[CH2:9](Br)[CH:10]=C.O.[CH2:14]1COCC1>>[CH3:4][C:3]([CH3:14])([CH2:5][CH:9]=[CH2:10])[C:2]([O:7][CH3:8])=[O:6]
Reactant: C=CCBr
Reactant: C1CCOC1
Reactant: COC(=O)C(C)C
Agent: [Li]
Solvent: O
Product: C=CCC(C)(C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropilamide (7.6 ml) in THF (12 ml) was added drop by drop n-butil lithium (2.5M in hexane, 21.6 ml) at −78° C. After stirring the reaction mixture at −78° C. for 30 minutes, a solution of methyl isobutyrate (5 g) in THF (12 ml) was added in 10 minutes and the mixture stirred at −78° C. for 1 h. A solution of allyl bromide (4.7 ml) in THF (12 ml) was dropped into the mixture reaction and it was stirred at −78° C. for 1 h. After adding some drop of water, volatiles were evaporated in vacuo, the crude dissolved in ethyl acetate, washed with water and dried over Na2SO4. After filtration volatiles were evaporated in vacuo to give 1.8 g of the title compound as a yellow pale liquid, which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([Mg]Br)[CH2:17][CH:18]=[CH2:19].C(O)(=O)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([OH:15])[CH2:19][CH2:18][CH:17]=[CH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC[Mg]Br
Reactant: O=CCCOCCCCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCCC(O)CCOCCCCc1ccccc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of Intermediate 13 (0.55 g, 2.66 mmol) in THF (5 mL) was cooled to −30° C. To this solution a 0.5 M solution of 3-butenylmagnesium bromide (5.8 mL, 2.92 mmol) in THF was added, and the resulting mixture was stirred 2 hours at −30° C. The reaction was allowed to reach room temperature; acetic acid (0.1 mL) was added and concentrated. Purification by column chromatography with silica gel and methylene chloride/acetone (20:1) as eluent afforded the title compound (410 mg, 54%) as oil.
Reaction SMILES: F[C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19][CH2:20][OH:21]>>[CH2:20]([O:21][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([CH3:9])[CH3:8])[CH3:19]
Reactant: CC(C)(F)C(=O)CC#N
Reactant: CCO
Reactant: NNc1ccccc1
Agent: Cl
Product: CCOC(C)(C)c1cc(N)n(-c2ccccc2)n1
Yield: 24 %

Procedure:
Using the procedure described in Example 161B Step 2, using 4-fluoro-4-methyl-3-oxopentanenitrile (0.77 g, 6 mmol) and phenylhydrazine hydrochloride (0.954 g, 6.6 mmol) in EtOH at 95° C. for 3 hours, which was purified by silica gel chromatography with 10-35% EtOAc/hexane to afford 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-amine as solid (0.315 g, 24%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 2H), 7.43 (m, 2H), 7.27 (m, 1H), 5.60 (s, 1H), 3.83 (br, 2H), 3.35 (q, 2H), 1.63 (s, 6H), 1.15 (t, 3H); LC-MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12]Br)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH2:12][N:15]([C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cc(Br)ccc1CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2cc(Br)ccc2CN1[C@@H]1CCCC[C@H]1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (0.50 g) in DMF (5.00 mL) were added trans-2-aminocyclohexanol hydrochloride (0.37 g) and N-ethyldiisopropylamine (1.42 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added 5% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.22 g).
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C)C=O>[Br-:8].[CH2:1]([N+:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccn1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: ONCc1cccc[n+]1Cc1ccccc1
Product: [Br-]
Reaction time: 168 h
Yield: 91 %

Procedure:
A mixture of 25.7 grams (115 mmoles) benzyl bromide and 16.7 grams (137 mmoles) 2-hydroxyiminomethyl-pyridine in dimethyl formamide (70 ml) was stored 7 days at room temperature. The precipitate was filtered off and washed with ethanol and ether. Recrystallization from 96% ethanol yielded 30.9 gram (77%) of the compound 1 in the form of white crystals. (a) In case (hetero)arylmethyl chlorides were used instead of bromides or iodides the reaction mixture was heated at 60°-90° C. for 3 to 4 hours. (b) Cyclohexylmethyl iodide alkylated 2-hydroxyiminomethylpyridine with great difficulty. After reaction at 100° C. for 10 hours a product was precipitated with ether. Recrystallisation yielded a mixture of compound 30 and of the hydroiodide of 2-hydroxyiminomethyl-pyridine from which the compound 30 could be recovered by washing with water.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH3:2].[NH3:12]>C(O)C>[CH2:1]([NH:3][C:4]1[C:5]([NH2:12])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH3:2]
Reactant: CCNc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CCO
Product: CCNc1c(N)ncnc1Cl
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of ethyl(4,6-dichloropyrimidin-5-yl)amine (0.31 g, 1.61 mmol) and concentrated aqueous ammonia (10 mL) in ethanol (3 mL) was heated to 100° C. in a sealed tube for 16 hours. The solution was cooled and evaporated to dryness. The residue was partitioned between ethyl acetate (20 mL) and dilute brine (10 mL). The organic layer was dried, filtered and concentrated to give N5-ethyl-6-chloropyrimidine-4,5-diamine (0.214 g, 1.24 mmol, 77%) as a waxy solid. LC-MS (LCT2) m/z 173, 175 [M+H+], Rt 3.97.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 144.6 %

Procedure:
To a mixture of 2-(morpholin-4-yl)ethanol (197 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL), washed with 2 M aqueous NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel to give 4-[2-(4-bromophenoxy)ethyl]morpholine (480 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, 2H), δ 6.70 (d, 2H), 4.07 (t, 2H), 3.74-3.71 (m, 4H), 2.78 (t, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCNCC3)ccnc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCN(Cc4ccccc4)CC3)ccnc21
Temperature: 0 °C
Yield: 47.6 %

Procedure:
A solution of N-(1-tert-butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide (500 mg), benzyl bromide (370 mg) and potassium carbonate (300 mg) in dimethylformamide (10 ml) was stirred at 80° C. for 4 hours. The reaction mixture was poured into ice-water and extracted with chloroform. The residue obtained by water washing, drying and then concentration under reduced pressure was purified by silica gel column chromatography to give 300 mg of N-(1-tert-butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-benzyl-4-piperidinecarboxamide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19](Br)=[CH:18][C:17]([O:21][C:22](=[O:24])[CH3:23])=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.CC1C=CC(C)=CC=1>C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:22]([O:21][C:17]1[CH:18]=[C:19]([CH:26]=[CH2:27])[C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([F:25])[CH:7]=3)=[N:15][C:14]=2[CH:16]=1)(=[O:24])[CH3:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: Cc1ccc(C)cc1
Product: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (46 mg, 0.06 mmol) was added into a mixture 4-[5-(acetyloxy)-7-bromo-1,3-benzoxazol-2-yl]-2-fluorophenyl acetate (0.8 g, 1.98 mmol), tributyl(vinyl)tin (0.9 g, 2.8 mmol) and p-xylene (9 mL). The reaction mixture was stirred at 130° C. for 5 h, cooled to room temperature, diluted with ethyl ether (10 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (0.4 g, 56% yield, m.p. 154–156° C.); MS m/e 356 (M+H)+.
Reaction SMILES: Cl.O.C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH2:16][CH2:17][OH:18])[C:8]=1[F:19]>[Fe].C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:16][CH2:17][OH:18])[C:8]=1[F:19]
Reactant: O=[N+]([O-])c1ccc(Cl)c(F)c1CCO
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(F)c1CCO
Yield: 79.6 %

Procedure:
4.8 g of iron powder and 0.45 ml of concentrated hydrochloric acid were added to a mixture solvent of 50 ml of water and 10 ml of ethanol, and the solution was heated at 80°-90° C. 6.69 g (31 mmol) of 4-chloro-3-fluoro-2-(2-hydroxyethyl)nitrobenzene was added to the solution through 10 minutes, and the solution was heated for 1 hour as was. After air-cooling, 100 ml of ethyl acetate was added to the solution, and insoluble matter was filtered. The organic layer was separated and was washed with aqueous 10% sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solvent was removed by distillation to obtain 4.68 g of the subject compound (126) in a 80% yield.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2>C(O)C.CCCCCC>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:32][CH2:33][N:34]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]4[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=4)=[CH:16][CH:15]=3)[CH2:35][CH2:36]1)(=[O:29])=[O:30])[CH:22]=[CH:21]2
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)c[nH]1
Yield: 85 %

Procedure:
By an exactly analogous method to that described in Example 1, starting from 4-(2-methylimidazol-4-yl)benzoic acid hydrochloride and 1-(6-bromonaphth-2-ylsulphonyl)piperazine was prepared 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-methylimidazol-4-yl)benzoyl]piperazine (423 mg, 85% yield), m.p. 215-216° C. (from ethanol/hexane), 1H NMR (d6DMSO) 2.3 ppm (s,3H), 3.0-3.2 ppm (broad s,4H), 3.4-3.7 ppm (broad s,4H), 7.2 ppm (d,2H), 7.5 ppm (s,1H), 7.7 ppm (d,2H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.4 ppm (s,1H), 8.45 ppm (s,1H), 11.8 ppm (broad s,1H), the spectrum also contained signals due to ethanol (˜0.33 mol eq.); microanalysis, found: C, 55.4; H, 4.8; N, 9.9; S, 5.8%; C25H23N4O3BrS requires: C, 55.6; H, 4.5; N, 10.1; S, 5.8%; MS (M+H)+ 539/541.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([NH2:13])[CH2:6][CH2:5]2.[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]=[C:14]=[S:15])[CH2:6][CH2:5]2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC1CCc2cc(F)c(F)cc2C1
Solvent: CCOC(C)=O
Product: Fc1cc2c(cc1F)CC(N=C=S)CC2
Yield: 79.1 %

Procedure:
A mixture of (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.56 g, 3.06 mmol), prepared as in Example 8, and 1,1'-thiocarbonyldiimidazole (0.82 g, 4.59 mmol) in 15 mL of ethyl acetate was stirred until the reaction was complete. The solvent was removed by evaporation. Purification of the residue by column chromatography on silica gel (solution: 5% acetone/methylene chloride) gave (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.55 g, 2.42 mmol). [α]D25 -15.5° (c=1.0, CH3OH)
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:5]=1[NH:6][CH2:7][CH:8]1[O:12][CH2:11][CH2:10][CH2:9]1>[Zn]>[ClH:3].[Cl:3][C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:5]=1[NH:6][CH2:7][CH:8]1[O:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(NCC2CCCO2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Cl
Product: Nc1ccc(NCC2CCCO2)c(Cl)c1

Procedure:
3.0 g of ammonium chloride and 50 g of zinc powder are added to 150 ml of an aqueous-alcoholic solution (85% of alcohol and 15% of water). This mixture is heated to the reflux temperature, whilst stirring, and 0.1 mol (25.7 g) of 2-chloro-4-nitro-N-tetrahydrofurfurylaniline is then added gradually. When the addition has ended and the reaction mixture is decolorised, the latter is filtered and the filtrate is collected in 20 ml of ice-cooled hydrochloric acid. After cooling, the expected hydrochloride precipitates in the form of crystals. It is filtered off, washed with a small amount of ice-cooled absolute alcohol and dried in vacuo. It melts at about 170° C. with decomposition.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.C([N:50]1CC[O:53][CH2:52][CH2:51]1)C.NCCO.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:50][CH2:51][CH2:52][OH:53])=[O:20])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: NCCO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 8 %

Procedure:
A solution of 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) in DMF (2 mL) was treated with EDC (48.5 mg, 0.253 mmol), HOBT hydrochloride (38.8 mg, 0.253 mmol) and N-ethylmorpholine (0.080 mL, 0.633 mmol) and after 3 min with 2-aminoethanol (0.025 mL, 0.422 mmol)). The resulting mixture was stirred at room temperature for 5 h then EDC (48.5 mg, 0.253 mmol), N-ethyl morpholine (0.080 mL, 0.633 mmol), HOBT (38.8 mg, 0.253 mmol) and further 2-aminoethanol (0.025 mL, 0.422 mmol) were added and the corresponding mixture was stirred for 16 h then concentrated in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)benzamide (8 mg, 8%) as a white solid. LCMS (HpH, 2 min), Rt=0.78 min, MH+=470.
Reaction SMILES: ClCC(C)(C)C([NH-])=O.Cl[CH2:10][C:11]([CH3:24])([CH3:23])[C:12]([NH:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:13].[H-].[Na+].CCOCC>CN(C=O)C.C(Cl)Cl>[CH2:20]([O:19][C:17]([CH2:16][C:15]([N:14]1[CH2:10][C:11]([CH3:24])([CH3:23])[C:12]1=[O:13])=[CH2:22])=[O:18])[CH3:21]
Reactant: CCOC(=O)/C=C(/C)NC(=O)C(C)(C)CCl
Agent: CC(C)(CCl)C([NH-])=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(CC(=O)OCC)N1CC(C)(C)C1=O

Procedure:
The β-chloropivaloyl amide cyclization to the title β-lactam compound was accomplished by treatment of 209 mg (0.84 mmole) of the amide with 64.5 mg (1.3 mmole) of NaH in 5 mL of DMF-CH2Cl2 (1:4) for 3 hours at room temperature. The reaction mixture was poured into 75 mL of ether and washed with two 25 mL portions of water, 25 mL of brine, dried over MgSO4, filtered and evaporated to yield 177 mg (0.84 mmole, 100%) of the β-lactam title compound as an oil. IR (neat) 1770, 1705 cm-1 ; 1H NMR δ 1.16-1.33 (9H, m), 2.63 (3H, s), 3.26 (2H, s), 4.03-4.26 (2H, q), 5.2 (1H, s).