Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([OH:15])[C@@H:5]([NH2:14])C1C=CC(F)=C(F)C=1.C(N(CC)C(C)C)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:4]1[O:15][C:27](=[O:29])[NH:14][CH2:5]1)=[O:16]
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccc(F)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CNC(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,3S)-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol) in 250 mL tetrahydrofuran at 0° C. was added N,N-diisopropylethylamine (8.75 mL, 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred at 0° C. for 30 min when it was poured over ethyl acetate (200 mL) and saturated sodium carbonate solution (100 mL). The layers were separated, the organic layer washed with saturated sodium carbonate solution (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow oil. The material svas triturated with 25% ethyl acetate/hexane to provide (4S,5R)-4-(3,4-difluorophen)fl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester. The recovered mother liquor was passed through silica (50% ethyl acetate/hexane) to give additional product.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Yield: 101.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (340 mg, 0.561 mmol) prepared in Example 4b, triethylsilane (0.4 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield the title compound (259 mg, 43%) as a colorless solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11]C=CN=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:13]([N:26]1[CH2:29][CH:28](OS(C)(=O)=O)[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:35][CH2:36][N:37](C(C)C)C(C)C>CC#N>[CH:13]([N:26]1[CH2:29][CH:28]([CH:6]2[CH2:5][NH:4][CH2:3][CH2:2][N:1]2[C:7]2[CH:35]=[CH:36][N:37]=[CH:11][N:12]=2)[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(C3CNCCN3c3ccncn3)C2)cc1

Procedure:
To a solution of 2-piperazin-1-yl-pyrimidine (2.48 g, 15.10 mmol, Alfa) and methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (4 g, 12.6 mmol, Oakwood) in CH3CN (40 mL) was added DIPEA (2.63 mL, 15.10 mmol) at room temperature. The resulting mixture was then refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then pH adjusted with 1N NaOH. The resulting mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by MPLC to yield 2-[4-(1-benzhydryl-azetidin-3-yl-piperazin-1-yl]-pyrimidine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10]C1CCCCO1.[CH3:17][CH2:18][CH2:19]CC>CS(C)=O>[CH2:9]([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:19][C:18]#[CH:17]
Reactant: BrCCCCCCCCOC1CCCCO1
Reactant: CCCCC
Solvent: CS(C)=O
Product: C#CCCCCCCCCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N2, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[NH:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:16](=[O:18])[CH3:17])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:16](=[O:18])[CH3:17])=[CH:27][CH:26]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(Nc3ccc(NC(=O)c4ccc(C(C)=O)cc4)cc3)cc2)cc1

Procedure:
Compound 748 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-acetylbenzoic acid. [M+H]+ calcd for C30H25N3O4: 492.18; found 492.00.
Reaction SMILES: [CH3:1]I.[Mg].[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8](C(OC)=O)[C:6]=1[NH2:7].[Cl-].[NH4+].C([O:20][CH2:21][CH3:22])C>>[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:21]([OH:20])([CH3:22])[CH3:1])[C:6]=1[NH2:7]
Reactant: CCOCC
Reactant: CI
Reactant: COC(=O)c1cccc(C)c1N
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: Cc1cccc(C(C)(C)O)c1N

Procedure:
In this example a solution containing 381.46 g of methyl iodide in 500 ml of ethyl ether was added dropwise to 65.3 g of magnesium submerged in ethyl ether at room temperature and under nitrogen. The mixture was then cooled and then a solution containing 0.67 moles of 2-methyl-6-methoxycarbonylaniline in 500 ml of ethyl ether was dropwise added thereto. The mixture was then refluxed for 21/2 hours, then cooled and 750 ml of saturated aqueous ammonium chloride solution carefully added dropwise. Additional ammonium chloride solution was then added and the resulting mixture filtered through diatomaceous earth. The water layer in the filtrate was decanted from the ether layer and washed with ether. The ether washings were combined with the ether layers washed with water, dried and evaporated to dryness affording the title product.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[CH:29](N)(N)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[C:37]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])(=[O:40])[CH:38]=[CH2:39]>CO>[CH2:29]([O:41][C:37]([CH2:38][CH2:39][N:8]([CH:6]1[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3][C:4]([CH3:27])([CH3:26])[CH2:5]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:39][CH2:38][C:37]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:40])[CH:16]1[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]1)=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCC(N)N
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCN(CCCCCCN(CCC(=O)OCCCCCCCCCCCCCCCCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 12 h

Procedure:
To a 1-liter four-necked flask were added 20 g (50 mmoles) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-hexanediamine and 200 g of methanol, and the hexanediamine was completely dissolved in the methanol. To the resulting solution was added dropwise a solution of 32.4 g (0.1 mole) of octadecyl acrylate in 100 g of methanol at room temperature, after which reaction was continued for 12 hours under reflux. The solvent was removed by evaporation, and FD-MS measurement was carried out. As a result, it was found that N-(2-octadecyloxycarbonylethyl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-hexanediamine was produced in a small amount, but Compound O was not confirmed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
At 0 C., to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1:5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M−t-Bu+2H). (J. Am. Chem. Soc. 2003, 125, 3714.)
Reaction SMILES: [CH2:1]([S:3][S:4][CH2:5][CH3:6])[CH3:2].S(Cl)([Cl:10])(=O)=O.[CH3:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]>N1C=CC=CC=1>[CH2:1]([S:3][Cl:10])[CH3:2].[CH3:12][N:13]([S:4][CH2:5][CH3:6])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSSCC
Reactant: CNC(=O)Nc1ccc(C)c(Cl)c1
Solvent: c1ccncc1
Product: CCSCl
Product: CCSN(C)C(=O)Nc1ccc(C)c(Cl)c1
Temperature: -40 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
Ethane sulfenyl chloride was prepared extemporaneously as in Example 9 from 68 g of diethyl disulfide and 67 g of sulfuryl chloride, cooled to -40° C. and a solution of 51.5 g of N-methyl-N'-(3-chloro-4-methylphenyl)-urea in 800 ml of pyridine were added thereto. The mixture was allowed to come to a temperature of -20° C. and was stirred for 11/2 hours at -20° C. The mixture was poured into a water-ice-hydrochloric acid mixture and was then extracted with methylene chloride. The organic phase was washed with water, dried and concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with a 9-1 benzene-ethyl acetate mixture and the product was dissolved in ethyl ether. The ether solution was treated with activated carbon, filtered, and concentrated to dryness to obtain 19.5 g of N-methyl-N-ethylthio-N'-(3-chloro-4-methylphenyl)-urea melting at <50° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([S:11]([C:14]([CH3:36])([CH3:35])[C:15]([NH:17][C:18]2[O:22][N:21]=[C:20]([C:23]([CH3:34])([C@@H:25]([O:27]C3CCCCO3)[CH3:26])[CH3:24])[CH:19]=2)=[O:16])(=[O:13])=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.O>[OH:27][C@@H:25]([CH3:26])[C:23]([C:20]1[CH:19]=[C:18]([NH:17][C:15](=[O:16])[C:14]([S:11]([CH:8]2[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]2)(=[O:12])=[O:13])([CH3:36])[CH3:35])[O:22][N:21]=1)([CH3:34])[CH3:24]
Reactant: C[C@H](OC1CCCCO1)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCN(S(C)(=O)=O)CC2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCN(S(C)(=O)=O)CC2)on1
Yield: 100 %

Procedure:
A solution of 192 mg (0.35 mmol) of 2-(1-methanesulfonylpiperidine-4-sulfonyl)-2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}propanamide in DCM/methanol (1/1, 4 mL) is treated with 241 mg (1.40 mmol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 18 h. The resin is removed by filtration and washed alternating with DCM and methanol. The combined filtrates are concentrated under reduced pressure and the resulting residue is purified by column chromatography (silica, eluent: heptanes, 50-100% ethyl acetate) to yield 163 mg of N-{3-[(3S)-3-hydroxy-2-methylbutan-2-yl]-1,2-oxazol-5-yl}-2-(1-methanesulfonylpiperidine-4-sulfonyl)-2-methylpropanamide. Yield 78%; ES-MS: m/z 466 [M+H]
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
139 mg (79%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(2,4-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH:27]([NH:29][CH2:30][CH2:31][S:32][C:33]1[N:34]=[CH:35][N:36]2[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][C:37]=12)=[O:28]>>[CH:27]([NH:29][CH2:30][CH2:31][S:32][C:33]1[N:34]=[CH:35][N:36]2[CH:40]=[C:39]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[S:38][C:37]=12)=[O:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNC=O)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCNC=O)c4s3)[C@H](C)[C@H]12
Yield: 48.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 1.06 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.665 g of 7-(2-formylaminoethyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 818 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(2-formylaminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[CH2:12]([S:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([CH2:22][CH2:23][CH3:24])[N:16]=1)[CH3:13]>CN(C=O)C>[CH2:12]([S:14][C:15]1[N:20]=[C:19]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[CH:18]=[C:17]([CH2:22][CH2:23][CH3:24])[N:16]=1)[CH3:13]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCCc1cc(Cl)nc(SCC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(-n2cnc3ccccc32)nc(SCC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (76 mg) in DMF (2 mL) was added benzimidazole, and this was followed by addition of 2-ethylthio4-chloro-6-propylpyrimidine dissolved in DMF (3 mL). The reaction mixture was then placed in a 100° C. oil bath. After 1 h, the reaction was cooled to room temperature, quenched with 5 mL of water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried (anhydrous Na2SO4). Removal of solvent followed by purification on silica gel column (9% acetone/hexane) provided 390 mg of the title compound. Mass spectrum (CI) 298 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H); 8.17 (d, J=7.6 Hz, 1H); 7.88 (d, J=7.8 Hz, 1H); 7.42 (m, 2H); 7.05 (s, 1H); 3.27 (q, J=7.4 Hz, 2H); 2.78 (t, J=7.5 Hz, 2H); 1.85 (m, 2H); 1.49 (t, J=7.3 Hz, 3H); 1.05 (t, J=7.3 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2cnccc2Cl)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc(-c2cnccc2Cl)c1C(=O)O

Procedure:
Combine 3-(4-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (0.90 g, 0.003 mol) with aqueous sodium hydroxide (2N, 7.0 mL, 0.014 mol), ethanol (2 mL), and tetrahydrofuran (2 mL) and stir overnight at ambient temperature. Adjust the aqueous mixture to approx. pH 2.5 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as a light solid (0.78 g, 97%). MS(ES): (M+1)+ 239.0, 241.0 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:22]3[CH2:21][CH2:20][CH:19]([N:18]4[C:17]5[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=5[NH:15][C:14]4=[O:13])[CH2:24][CH2:23]3)[N:10]=2)[CH:7]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 34.8 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1: 0.186 g), 4-(2-keto-1-benzimidazolinyl)piperidine (Aldrich; 0.201 g), triethylamine (0.094 g), and dichloromethane (4 mL) is stirred at 45° C. for 20 h, after which time the mixture is cooled. Dichloromethane and aqueous sodium bicarbonate are added and the solids collected and dried. Additional material is obtained by concentration of the organic layer. Crystallization from methanol/dichloromethane/hexane gives 0.123 g of the title compound; mp 210-211 (decomp)°C; IR (mineral oil) 1695, 1486, 1338, 736, 1074 cm-1. 1H NMR (DMSOd6) δ1.63, 2.19, 2.38, 3.08, 3.66, 4.12, 6.96, 7.23, 7.54, 7.87, 8.80, 10.84.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[CH:9]=[C:8]([F:15])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][C:13](=[S:14])[NH:12][C:10]1[CH:9]=[C:8]([F:15])[CH:7]=[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)([CH3:25])[CH3:24]
Reactant: CC(C)O
Reactant: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Solvent: CCN(CC)CC
Product: CC(C)OC(=S)Nc1cc(F)cc(OC(C)(C)C)c1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a solution of 1-tert-butoxy-3-fluoro-5-isothiocyanatobenzene (460 g, 2.04 mol) in anhydrous isopropyl alcohol (3250 ml) was added triethylamine (315 g, 3.06 mol). The mixture was heated to reflux under N2 atmosphere for 16 h and the temperature was cooled to 40-50° C. After concentration, the resulting dark residue was diluted with n-heptane (1000 ml) and heated to 60° C. The mixture was slowly cooled to 25° C., at the same time seeding was added. A slurry was observed and stirred at 25° C. for 16 h before being cooled slowly to 0-10° C. within 2 h. After filtration and washing with n-heptane (200 ml), the collected solid was dried in oven under vacuum at 40-45° C. for 18 h to give (3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (453.1 g).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CO.C(N(CC)CC)C.[Cl:15][CH:16]([O:20][N:21]=[CH:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:15][CH:16]([O:20][N:21]=[CH:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18]
Reactant: O=C(Cl)C(Cl)ON=Cc1ccccc1Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(Cl)ON=Cc1ccccc1Cl
Reaction time: 1 h

Procedure:
A mixture of 3.0 gm. (0.031 mole) of N,O-dimethylhydroxylamine hydrochloride and 60 ml. of methanol was cooled in ice bath; then 6.3 gm. (0.062 mole) of triethylamine was stirred in. A solution of 4.1 gm. (0.015 mole) of 2,6-dichlorobenzylideneaminooxyacetyl chloride in toluene was added dropwise and with cooling and stirring. After one hour more at ice-bath temperature the reaction mixture was allowed to stand overnight at room temperature; then evaporate to dryness under reduced pressure. The residue was ground under water, separated, extracted with methylene chloride and the extract was treated with decolorizing carbon, then filtered. The filtrate, evaporated to dryness under reduced pressure, gave 3.1 gm. (69.1%) of a solid melting at 62°-72° C. The melt was turbid, however, and the crude product was extracted with hot n-heptane. The hot extract was passed through a Florisil* column; evaporation of the solvent left product melting at 76°-78° C. (clear).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6][OH:7].[H][H].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>C(OC)(C)(C)C.[Pd]>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[NH:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: Cc1ccccc1N=C=O
Agent: [Pd]
Solvent: COC(C)(C)C
Product: COc1cc(CO)ccc1NC(=O)Nc1ccccc1C
Reaction time: 8 h

Procedure:
15 g (81.8 mmol) of 3-methoxy-4-nitrobenzyl alcohol were hydrogenated in 500 mL of methyl tert-butyl ether over 1.3 g of palladium/charcoal (10%; 50% water) while cooling with ice. After the uptake of hydrogen had ceased, the catalyst was filtered off and 10.14 mL (81.8 mmol) of 2-methylphenyl isocyanate were added to the filtrate within 30 minutes while stirring. The reaction mixture was left to stand overnight and the precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 20.5 g (88%).