Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([N:13]=[C:14]=[O:15])([CH3:12])[CH2:10]I)[CH:3]=1.C([OH:20])(C)(C)C>CN(C)C=O.F[B-](F)(F)F.[Ag+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]2([CH3:12])[CH2:10][O:20][C:14](=[O:15])[NH:13]2)[CH:3]=1
Reactant: CC(CI)(N=C=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(c2cc(Br)ccc2F)COC(=O)N1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of the crude (RS)-4-bromo-1-fluoro-2-(2-iodo-1-isocyanato-1-methyl-ethyl)-benzene (10.01 g, 26 mmol) in N,N-dimethyl-formamide (90 ml) was treated at room temperature with silver tetrafluoroborate (5.58 g, 29 mmol) and tert-butanol (3.86 g, 52 mmol). The yellow suspension was stirred at 80° C. overnight. For the workup, the reaction mixture was evaporated at reduced pressure, the residue triturated in ethyl acetate then filtered. The solution was concentrated at reduced pressure and the crude product purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 40/60 as the eluent. The (RS)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one was obtained as a white solid (4.33 g, 61% of theory). MS (ISP): m/z=274.2 [M+H]+, 276.2 [M+2+H]+.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)[CH3:2].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:11][CH:15]=[CH:14]2)[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CCSCc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSCc1cccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 7.40 g (37.5 mmol) of the compound from Example 3A in 195 ml of tetrahydrofuran was added dropwise to 134 ml (93.8 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran under argon at −78° C., and the mixture was stirred at −78° C. for 2 h. The reaction mixture was then slowly added to an ice-cold, saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9/1) to result in 4.98 g (69% of theory) of the title compound.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>CC(C)=O>[I:1][C:2]1[C:3]([S:12]([NH:15][C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])(=[O:14])=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1I
Reactant: CCCCN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc(C(=O)OC)c1I
Temperature: 25 °C

Procedure:
27.3 g of 2-iodo-3-methoxycarbonylbenzenesulfonamide and 9.0 ml of n-butyl isocyanate in 300 ml of absolute acetone are treated with 12 ml of DBU at room temperature and heated at the boil for 3 hours. The reaction solution is cooled to room temperature, concentrated to approximately 1/3 of its volume and poured into 1 l of water. The aqueous phase is acidified with concentrated hydrochloric acid to a pH of 1-2, and the precipitate obtained is filtered off with suction. 31.3 g of methyl 2-iodo-[[[(n-butylamino)carbonyl]amino]sulfonyl]benzoate of melting point 163°-7° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[Br:25][C:26]1[CH:27]=[C:28]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:25][C:26]1[CH:27]=[C:28]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][N:8]1[C:9]2[S:15][C:14]([CH2:16][CH3:17])=[CH:13][C:10]=2[C:11](=[O:12])[N:6]([CH2:5][C:4]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=2[O:2][CH3:1])[C:7]1=[O:18]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3Br)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.4 g), 3′-bromo-4′-(bromomethyl)biphenyl-2-carbonitrile (3.8 g), potassium carbonate (2.7 g) and acetonitrile (200 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (4.92 g, 81%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19](O)[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:24])[N:12]=1)[CH3:2].O=S(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][CH:19]([C:14]1[C:15]([O:17][CH3:18])=[N:16][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[N:12][C:13]=1[CH3:24])[CH2:20][CH2:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Solvent: ClCCl
Product: CCCC(Cl)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]butan-1-ol (1 g, 3 mmol) [prepared as described in Example 10] in dry DCM (20 mL) is added SOCl2 (7 mL 0.015 mol) dropwise under nitrogen. The solution is then allowed to stir at room temperature for 1 h. The reaction mixture is concentrated and azeotroped with toluene twice to obtain 5-(1-chloro-butyl)-2-(2,6-diethyl-phenyl)-4-methoxy-6-methyl-pyrimidine which is used in standard nucleophilic displacement reactions to obtain a variety of compounds including the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:16]1[C:15]([OH:17])=[N:14][N:13]2[C:12]=1[CH:11]=[N:10][N:9]=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrBr
Reactant: Oc1cc2cnnc(-c3ccccc3F)n2n1
Solvent: CC(=O)O
Solvent: O
Product: Oc1nn2c(-c3ccccc3F)nncc2c1Br
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.2508 g, 1.09 mmol) in glacial acetic acid (5 ml) was added dropwise bromine (62 μl, 1.20 mmol) and the mixture was stirred at room temperature for 2.25 h. Water (20 ml) was then added and the resulting solid was collected by filtration, washed with water, and dried under vacuum at 50° C. to yield 0.3054 g (91%) of the title compound as a buff solid; 1H NMR (360 MHz, d6-DMSO) δ 7.43-7.50 (2H, m), 7.72 (1H, m), 7.80 (1H, m), 9.40 (1H, s), 12.67 (1H, s).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:24][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:24][O:18][C:14]1[CH2:13][CH:12]([C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:17][CH2:16][N:15]=1
Reactant: O=C1CC(c2nc(-c3ccccc3)no2)CCN1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCC(c2nc(-c3ccccc3)no2)C1
Temperature: 0 °C
Yield: 90.8 %

Procedure:
Add 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-2-one (1.0 g, 4.11 mmol) to a solution of trimethyloxonium tetrafluoroborate (1.06 g, 6.99 mmol) in dichloromethane (8.2 mL) at 0° C. Stir the reaction overnight at room temperature and pour into an ice cold solution of saturated aqueous sodium bicarbonate. Separate and extract the aqueous layer with additional dichloromethane. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound as a crystalline white solid (0.96 g). 1H NMR (CDCl3) δ 1.9 (m, 1H), 2.17 (m, 1H), 2.65-2.72 (m, 2H), 3.43 (m, 1H), 3.58 (m, 1H), 3.7 (s, 3H), 3.75 (m, 1H), 7.43-7.53 (m, 3H), 8.0-8.1 (m, 2H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][CH2:10][N:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:12](=[O:16])[CH2:13][S:14][CH3:15])[CH3:8]>O.C(O)C>[CH2:7]([O:9][CH2:10][N:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:12](=[O:16])[CH2:13][S:14]([CH3:15])=[O:2])[CH3:8]
Reactant: CCOCN(C(=O)CSC)c1cccc(C(F)(F)F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCN(C(=O)CS(C)=O)c1cccc(C(F)(F)F)c1
Reaction time: 24 h

Procedure:
A solution of sodium periodate (20.5 g) in water (190 ml) was added dropwise to a stirred solution of crude product of Step 2 in ethanol (850 ml) at 5° C. The mixture was allowed to reach 20° C. gradually and stirred for 24 hours, then concentrated under reduced pressure. The concentrate was extracted with dichloromethane (500 ml), the extract dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product as a brown oil (27.5 g). 1H NMR (CDCl3l ): δ 1.24(3 H,t); 2.76(3 H,s); 3.56(2 H,s); 3.67(2 H, 5.12(2 H,s); 7.51-7.69(4 H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18]([O:20]CC)=O)[C:5]2=[O:23].[H-].[Na+].[CH2:26]([Mg]Br)[CH2:27][CH:28]=[CH2:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7]([OH:17])=[C:6]([C:18](=[O:20])[CH2:29][CH2:28][CH:27]=[CH2:26])[C:5]2=[O:23]
Reactant: CCOC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Reactant: C=CCC[Mg]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
A mixture of ethyl 6-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (2.53 g, 8 mmol, Example 1 A-C) in 20 mL THF was stirred at room temperature and treated with sodium hydride (0.6 g, 15 mmol, 60% in oil). The resulting mixture was stirred for 10 minutes. The mixture was then treated with 3-butenylmagnesium bromide (15 mL, 8 mmol). After 5 minutes, the mixture was warmed to 60° C., and the reaction was stirred for another 0.5 hours. The mixture was cooled to 0° C., quenched with 20 mL saturated NH4Cl, and 100 mL EtOAc was added. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 2.17 g white solid. MS m/e: 347 (M+H)+.
Reaction SMILES: CCN(CC)CC.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[N:9]1([C:18]([C:17]2[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][CH:16]=2)=[O:19])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Et3N (2.00 mL, 14.3 mmol) and azetidine hydrochloride (462 mg, 4.94 mmol) were added to a solution of 4-bromobenzoyl chloride (1.07 g, 4.88 mmol) in CH2Cl2 (20 mL). The mixture was stirred at room temperature for 2 hr, diluted with CH2Cl2 (100 mL), and washed with 1N aqueous HCl (100 mL), H2O (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 and concentrated to give a colorless oil (1.10 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (ddd, J=17.43, 6.57, 2.27 Hz, 4 H) 4.21-4.32 (m, 4 H) 2.32-2.40 (m, 2 H); ); LCMS for C10H10BrNO m/z 241.00 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([OH:18])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:19]([N:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:18])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:11])=[CH:9][C:2]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([N:21]([CH2:19][CH3:20])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])#[N:5]
Reactant: CCN(C(=O)c1cccc(O)c1)c1ccccc1
Reactant: Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(C(=O)c1cccc(Oc2cc(C(C)(O)c3cncn3C)ccc2C#N)c1)c1ccccc1
Temperature: 60 °C

Procedure:
2-Fluoro-4-[1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile (0.054 g, 0.220 mmol), N-ethyl-3-hydroxy-N-phenyl-benzamide (0.053 g, 0.220 mmol) and Cs2CO3 (0.143 g, 0.440 mmol) were dissolved in anhydrous DMF (5 mL) and heated at 60° C. under Ar for 4 days. The reaction was diluted with EtOAc, washed with satd. NaHCO3 solution, water, and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2) to give the title compound. FAB MS (M+1)=467.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[Br:8][C:7]1[C:2]([NH:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:3][CH:4]=[C:5]([Br:9])[N:6]=1
Reactant: CCOC(=O)CCl
Reactant: Nc1ncc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ncc(Br)nc1Br
Temperature: 25 °C

Procedure:
Amino-3,5-dibromopyrazine (1 equiv) in dimethylformamide was cooled to 0° C. and treated with cesium carbonate (1.3 equiv) and ethyl chloroacetate (1.2 equiv). The solution was warmed to 25° C. and further heated to 65° C. The reaction mixture was cooled to 25° C., filtered, and the solid was washed with dimethylformamide. The filtrate was added to ice-water and the slurry was agitated. The resulting solid was isolated, washed with water, and dried. The crude product was dissolved in methyl t-butyl ether with heating, cooled to rt, and concentrated to dryness. The solid was dissolved in ethyl acetate and concentrated to a thick slurry. The product was triturated with 2% ethyl acetate in heptane, filtered, washed with heptane, and dried to afford the title compound as a solid. MS (ESI) m/z 337.8 [M−1]+, 339.8 [M+1]+, 341.8 [M+3]+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:1]1([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C1CNCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCNCC2)cc1
Yield: 56.2 %

Procedure:
Alternatively, a mixture of hexahydro-1H-1,4-diazepine (17.47 g, 174.4 mmol) and methyl 4-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was heated with triethylamine (24 mL, 174.4 mmol) in tetrahydrofuran (872 mL) to reflux for three hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 3.04 g of methyl 4-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]benzoate, 1H NMR (300 MHz, CDCl3) δ7.98 (d, 2H), 7.42 (d, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.67 (m, 2H), 2.66 (m, 2H), 1.77 (m, 2H)
Reaction SMILES: [CH3:1][N:2]([C@H:49]1[CH2:53][CH2:52][N:51](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:50]1)[C:3]([C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:12]([CH3:35])[C@@H:13]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]3[C:15]=2[C:16]([O:18]CC2C=CC([N+]([O-])=O)=CC=2)=[O:17])[CH2:7][N:6]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:4].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][N:2]([C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)[C:3]([C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:12]([CH3:35])[C@@H:13]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH2:7][NH:6]1)=[O:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)[C@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N(C)[C@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-{N-methyl-N-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]carbamoyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.45 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 700 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 30 mg of the title compound as a powder.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[NH:10])[CH:3]([CH3:5])[CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C(O)(=O)C>C(O)C>[O:18]=[C:19]1[NH:11][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[N:10][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O

Procedure:
To a stirred sodium (3.15 g., 0.137 g-atom) in ethanol (250 ml.) was added 2-isobutoxybenzamidine (26.3 g., 0.137 mole) followed by diethyl ethoxymethylenemalonate (29.6 g., 0.137 mole). The mixture was heated under reflux for 3 hours. The cooled mixture was added to icewater (300 ml.) which was then acidified to pH 5 with glacial acetic acid. The crystalline product (36.4 g., 85%) m.p. 89°-91°, which formed on cooling was collected and a portion recrystallized from 50% aqueous ethanol to give the title compound, m.p. 92°-93°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1.O[CH2:12][C@@H:13]([N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=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>[Br:1][C:2]1[S:6][C:5]([N:7]([CH2:12][C@@H:13]([N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ncc(Br)s1
Reaction time: 0.25 h
Yield: 17 %

Procedure:
N-(5-Bromo-thiazol-2-yl)-acetamide) (442.0 mg, 2.0 mmol), (S)-2-(1-hydroxy-3-phenylpropan-2-yl)isoindoline-1,3-dione (281.0 mg, 1.0 mmol), triphenylphosphine (303.0 mg, 1.5 mmol) and THF (15.0 mL) were charged into a 100 mL round bottom flask. The resulting reaction mixture was a suspension. The flask was immersed in an ice-water bath. After stirring for 15 minutes under nitrogen, a solution of DIAD (421.5 mg, 1.5 mmol) in 3.0 mL THF was slowly added to the flask through a syringe. The reaction mixture became a clear solution after the addition was complete. After 10 minutes, the reaction mixture was brought to room temperature by removing the ice water bath and the stirring was continued for 16 hours. THF was evaporated off, and the residue was diluted with 40 mL saturated sodium bicarbonate and extracted with DCM (75 mL×2). The residue was subjected to a silica gel column chromatography purification with hexane-EtOAc (7:3) as the eluant to afford a compound as a white solid (S)-N-(5-bromothiazol-2-yl)-N-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropyl)acetamide (20 mg, yield 17%). LCMS (API-ES) m/z (%): 484.0 (100%, M++H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].S(Cl)(Cl)=O.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[CH2:21]([NH:24][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])[CH2:22][CH3:23]
Reactant: CCCN
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, thionyl chloride and propylamine in a manner as previously described for example 9d. 1H NMR (300 MHz, CDCl3) δ 7.55 (1H, d, J=8.6 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 5.87 (1H, bs), 3.87 (3H, s), 3.63 (3H, s), 3.45 (2H, m), 2.69 (3H, s), 1.67 (2H, m), 1.02 (3H, t, J=7.4 Hz). LCMS (ESI+) [M+H]/z Calc'd 261. found 261.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:35])[NH:26][O:27]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:35])[NH:26][OH:27])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 90.6 %

Procedure:
Palladium on BaSO4 (5%, 4.0 g) was added to a degassed solution of the benzyl hydroxamate 7 (4.6 g) in MeOH (200 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 8 (3.5 g, 93%). 1H NMR (DMSO-d6): 10.37 (s, 1H), 8.71 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.54 (ddd, J=14.8, 8.8, and 6.0 Hz, 1H), 2.91 (s, 3H), 2.70-2.87 (m, 7H), 2.24 (t, J=7.2 Hz, 2H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:27][CH:28]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1cccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 3.3 %

Procedure:
2 g (84 mmole) 5-(4-[2-(3-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated in 200 ml ethyl acetate and 10 ml acetic acid in the presence of Pd/C (10%) at atmospheric pressure over night. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was crystallized in ethanol to give 1.18 g (yield 59%) of the desired product.