Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzaldehyde (1.0 g, 5.91 mmol), phenol (0.557 g, 5.91 mmol), and K2CO3 (1.635 g, 11.83 mmol) in dioxane (6 mL) was heated at 70° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (60 mL). The solution was washed with water (2×30 mL) and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give the title compound (1.43 g, 99% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[N:9]=[C:10]([CH2:14][O:15][C:33](=[O:35])[CH3:34])[CH:11]=[CH:12][CH:13]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
(6-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.85 g, 3.79 mmol) was dissolved in dichloromethane (30.00 ml) and triethylamine (1.32 ml) and treated with dimethylaminopyridine (0.09 g, 0.76 mmol) and acetic anhydride (0.43 g, 4.17 mmol). The mixture was stirred at room temperature for 10 min, then partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate) to yield acetic acid 6-tert-butoxycarbonylamino-pyridin-2-ylmethyl ester (0.85 g, 84%) as a white solid, MS (ISP): m/e=267.1 (M+H+).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C[Si](C)(C)O[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH2:42][CH2:41][CH2:40][CH2:39]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1.CC1C=CC(O)=CC=1>>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)Oc1ccc2c(c1)CCCC2
Reactant: CCCCCCCCCCCCC
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccc(O)cc1
Agent: Cc1ccccc1-c1ccccc1C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (36.6 mg, 0.0530 mmol), PCy3 (35.0 mg, 0.125 mmol), tridecane (166.7 mg, 0.904 mmol, as an internal standard), and 6-trimethylsiloxy-1,2,3,4-tetrahydronaphthalene (211.4 mg, 0.957 mmol). The solvent in the Grignard reagent (1 M in ether, 3.0 mmol) was exchanged with t-AmOMe (6.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 60° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The resulting aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (0.637 mmol, 67% yield) and bitoluene (0.407 mmol) and p-methylphenol (0.223 mmol) in the reaction mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15]OS(C)(=O)=O)[CH2:12][CH2:11][N:10]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[F:8].[F-:31].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][F:31])[CH2:12][CH2:11][N:10]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)OC[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2ccc(F)c(F)c2)C1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@H](CF)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A mixture of (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (200 mg, 0.46 mmol), and cesium fluoride (190 mg, 1.3 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100° C. for 18 hours. The reaction mixture was cooled and purified directly by silica gel chromatography (5% to 25% ethyl acetate in hexanes gradient) to give (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(fluoromethyl)piperidine-1-carboxylate (85 mg, 51% yield). MS (EI) for C20H20F3NO2: 364 (MH+).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:1](=[O:8])[CH2:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6])=[CH:13][CH:12]=1
Reactant: CCC1CCC(=O)O1
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Product: CCC(O)CCC(=O)NCc1ccc(OC)cc1
Temperature: 82.5 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
Gamma-caprolactone (28.745 Kg, 251.8 moles) and 4-methoxybenzylamine (38.0 Kg, 277 moles) were placed in a 100 gallon glass lined tank. The solution was heated to 80-85° C. and held at that temperature for 16 hours. TLC on silica gel plates showed the reaction was complete. The TLC system comprised: ethyl acetate with detection at 254 nm. Ethyl acetate (18 gal, 68 L) was slowly charged to the reaction pot after cooling to 60° C. Hexanes (a total of 18 gal, 68 L) were added until a haze was achieved. After ½ hour, to allow crystallization to start, the remainder of the hexanes was added. The slurry was cooled to 25° C. and granulated for 3 hours. The solid was collected by filtration and washed with a 1:1 mixture of ethyl acetate and hexanes. The wet cake was vacuum dried with no additional heat to produce 46.05 Kg (72.8%) of the desired amide; mp 81-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Cl)c(Cl)c1
Temperature: 4 °C
Yield: 52.7 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3,4-dichlorobenzoic acid (15.3 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product obtained by precipitation in water (17.6 g; m.p. 228° C.) is dissolved in boiling ethanol (900 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with isopropyl ether (2×30 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4-dichlorobenzamide (9.2 g), m.p. 230° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20]>>[ClH:18].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:7]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc2cc(Br)ccc2c1NCCCCCl
Reactant: CCOCC(=O)Cl
Product: CCOCC(=O)Nc1cnc2cc(Br)ccc2c1NCCCCCl
Product: Cl
Reaction time: 1 h

Procedure:
A modification of the method described in Part C of Examples 125–135 was used to treat 7-bromo-N4-(4-chlorobutyl)quinoline-3,4-diamine (7.25 g, 22.1 mmol) with ethoxyacetyl chloride (2.76 mL, 24.3 mmol). After the reaction was stirred for one hour, it was concentrated under reduced pressure to provide N-[7-bromo-4-(4-chlorobutylamino)quinolin-3-yl]-2-ethoxyacetamide hydrochloride as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:19][CH2:18]2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Yield: 70.3 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.068 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.099 mmol) to afford the desired product (24.3 mg, 71%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.79 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.06-7.96 (m, 2H), 7.53-7.49 (m, 1H), 7.42 (dd, J=11.7, 2.2 Hz, 1H), 3.53 (d, J=12.8 Hz, 2H), 3.28-3.15 (m, 6H), 3.09 (d, J=7.0 Hz, 2H), 2.62-2.54 (m, 1H), 2.14-2.02 (m, 5H), 1.99 (d, J=12.5 Hz, 2H), 1.77-1.63 (m, 2H), 1.36-1.28 (m, 2H), 1.28-1.17 (m, 2H); ESI MS m/z 508 [C29H31ClFN3O2+H]+; HPLC 98.1% (AUC), tR=10.69 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid (2.7 g, 0.010 mol), 4-fluoro-benzene-sulfonyl chloride (2.0 g, 0.010 mol), and sodium carbonate (2.2 g, 0.020 mol) in a mixture of tetra-hydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with saturated sodium chloride solution, dried (MgSO4), and rotary-evaporated under reduced pressure to give an oil. The oil was chromatographed on silica gel (445 g, 230-400 mesh) eluting with dichloromethane-methanol (20:1), and the fractions containing product were rotary-evaporated to give a solid. The solid was recrystallized from toluene to give the title compound as a light yellow solid; yield 0.22 g (5%), mp=138-139° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)[Br:10].O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CCOCC.CC(C)=O>[Br:10][CH2:9][C:11]([CH2:12][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: BrCC1CO1
Reactant: Br[Mg]c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: O=C(CBr)Cc1ccccc1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a suspension of CuBr (0.143 g, 0.997 mmol) in 25 mL dry ether was slowly added 1M phenylmagnesium bromide (10 mL, 10 mmol). Epibromohydrin (0.87 mL, 10.5 mmol) was then added dropwise. The reaction mixture was allowed to stir at −78° C. to room temperature overnight, poured into H2O and extracted with ether. The extracts were washed with H2O and brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude alcohol thus obtained was dissolved in acetone (400 mL) and chilled in ice, and to this solution was added dropwise 6 mL of Jones reagent (prepared by dissolution of 2.67 g CrO3 in 2.5 mL H2SO4, followed by dilution with H2O to 10 mL). The reaction mixture was stirred at 0° C. for 15 min and was then evaporated in vacuo. The residue was taken up in ethyl acetate, washed repeatedly with water and once with brine, dried over Na2SO4, filtered and evaporated to afford the ketone product as a brown oil (1.6 g, 75%). 1H NMR (DMSO-d6) δ 7.17-7.35 (m, 5H), 4.45 (s, 2H), 3.94 (s, 2H); MS (DCI+) m/z 230 (M+NH4+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.O[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]3)=[CH:22][CH:23]=2)=[N:26][CH:27]=1
Reactant: Cc1ccc(O)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1
Temperature: 55 °C

Procedure:
tert-Butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (1.44 g), 2-hydroxy-5-methylpyridine (0.737 g), tri-n-butylphosphine (1.76 mL), 1,1′-(azodicarbonyl)-dipiperidine (1.70 g), and THF (16.5 mL) were mixed in a 20 mL process vial. The vial was sealed, and the reaction mixture was heated with microwaves to 55 ° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt =10/1 to 3/10) to give tert-butyl 4-(4-{2-[(5-methylpyridin-2-yl)oxy]ethyl}benzyl)piperazine-1-carboxylate as a pale yellow amorphous (1.01 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[N+:26]([C:29]1[CH:63]=[CH:62][C:32]([CH2:33][O:34][C:35]([NH:37][CH2:38][CH2:39][S:40][C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=23)=[O:36])=[CH:31][CH:30]=1)([O-:28])=[O:27]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:8]([C:47]3[S:46][C:45]4=[C:41]([S:40][CH2:39][CH2:38][NH:37][C:35]([O:34][CH2:33][C:32]5[CH:62]=[CH:63][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=5)=[O:36])[N:42]=[CH:43][N:44]4[CH:48]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCNC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)C[C@H]12
Yield: 48.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 201 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 424 mg of 7-[2-(4-nitrobenzyloxycarbonyl)aminoethyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 200 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[2-(4-nitrobenzyloxycarbonyl)aminoethyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C@H:4]13.C1C(=O)N([Br:30])C(=O)C1.O.CCOC(C)=O>CN(C=O)C>[Br:30][C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:10][CH2:11][N:5]3[C@@H:4]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:3]23)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl(±)-cis-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.576 g, 1.92 mmol) in DMF (4 mL) at 0° C., freshly recrystalized NBS (0.375 g, 2.1 mmol) was added as a solution in DMF (4 mL). The reaction was stirred at 0° C. for 20 min, after which it was warmed to RT. The reaction was stirred at RT for 0.5 h. Water (10 mL) and EtOAc (10 mL) were added. The layers were separated, and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried. Concentration afforded a crude brown oil. The crude product was purified by column chromatography (MeOH/CH2Cl2). Tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (550 mg, 75%) was isolated as a brown amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.06 (s, 1H), 7.02 (s, 1H), 3.70–3.90 (m, 1H), 3.50–3.70 (m, 1H), 3.00–3.45 (m, 6H), 2.70–2.90 (m, 2H), 1.70–1.90 (m, 2H), 1.48 (s, 9H) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:32][CH:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=1)([CH3:27])[CH3:26].[O:36]1[C:41]2([CH2:46][CH2:45][N:44]([CH2:47][C:48]3[C:49]([F:57])=[C:50]([CH2:54][CH2:55][OH:56])[CH:51]=[CH:52][CH:53]=3)[CH2:43][CH2:42]2)[CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C=O)C>[F:57][C:49]1[C:50]([CH2:54][CH2:55][OH:56])=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][N:44]1[CH2:45][CH2:46][C:41]2([O:36][CH2:37][CH2:38][N:39]([C:33]([C:30]3[CH:29]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:32][CH:31]=3)=[O:35])[CH2:40]2)[CH2:42][CH2:43]1
Reactant: CC(C)c1cc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.183 g) was added in one portion to a stirred solution at 0° C. of 5-isopropylthiophene-3-carboxylic acid (0.063 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.114 g) and triethylamine (0.155 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.100 g.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O.C1COCC1>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
A 250 mL flask was charged with ethyl 4-oxocyclohexanecarboxylate (5 g, 28.5 mmol, Alfa Aesar) and THF (75 mL). The solution was cooled to about 0° C. and AcOH (2.28 mL, 39.9 mmol) and dibenzylamine (6.18 g, 31.3 mmol) (TCI) were added dropwise, resulting in formation of a thick suspension. Na(OAc)3BH (14.3 g, 64.1 mmol) was added portionwise and the reaction mixture was stirred at ambient temperature for about 72 h. The reaction mixture was cooled to about 10° C. Water (25 mL) was added and the reaction mixture was stirred for about 15 min. Heptanes (50 mL) were added. The layers were separated and the organic layer was washed with 10% aqueous AcOH solution (25 mL) and then with water (10 mL). The organic layer was extracted with 4% HCl solution twice (40 mL and 20 mL). The combined aqueous layer was washed with heptanes (20 mL). To the aqueous layer was slowly added 30% aqueous K2CO3 solution (30 g) to adjust the pH to 10. The aqueous solution was extracted with heptane twice (75 mL and 15 mL). The combined organic layer was washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concd under reduced pressure to give ethyl 4-(dibenzylamino)cyclohexanecarboxylate (7.2 g, 72%) as an oil which solidified upon standing: LC/MS (Table 1, Method a) Rt=3.18 and 3.23 min; MS m/z: 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:18][C:19]([CH2:21]Cl)=[CH2:20].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:21][C:19]([Cl:18])=[CH2:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: C=C(Cl)CCl
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC(C#N)(C#N)Cc1ccc(Cl)cc1
Yield: 27 %

Procedure:
First, 0.50 g of (4-chlorobenzyl)malononitrile was dissolved in 10 ml of N,N-dimethylformamide, to which 0.16 g of sodium hydride (60% in oil) was added under ice cooling. After the evolution of hydrogen gas ceased, while stirring under ice cooling, 0.48 ml of 2,3-dichloropropene was added dropwise, followed by stirring at room temperature for 5 hours. Then, 10% hydrochloric acid was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 2-(4-chlorobenzyl)-2-(2-chloro-2-propenyl)malononitrile (the present compound (1)).