Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CI)C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNCC2OCCN(C(=O)OC(C)(C)C)CC2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (1.4 g) in DMF (5 mL) were added potassium carbonate (1.2 g) and 4-methoxybenzylamine (0.79 g), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][O:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C(Cl)Cl>C1(C)C=CC=CC=1>[C:11]1([C:10]2[C:6]([CH2:4][OH:3])=[CH:7][O:8][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cocc1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1cocc1-c1ccccc1
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Prepare a solution of 4-phenylfuran-3-carboxylic acid ethyl ester (3.9 g, 18.1 mmol) in toluene (20 mL) under nitrogen at −78° C. Add a 1.0 M solution of Diisobutyl aluminium hydride in methylene chloride (35 mL, 35.0 mmol). Stir the reaction mixture for 1 hour, quench with water, and pour into 10% Rochelle's salt (200 mL). Extract the aqueous phase with ethyl acetate (2×200 mL). Wash the organic phase with brine (100 mL), dry (Na2SO4), filter, and concentrate. Flash chromatography on silica gel eluting with 4:1 Hex/ethyl acetate to afford 2.3 g of (4-phenylfuran-3-yl)methanol. 1H NMR (CDCl3) δ 7.51-7.58 (m, 4H), 7.30-7.45 (m, 3H), 4.67 (d, J=5 Hz, 2H).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: CC(=O)C(Cl)=NNc1ccc(C)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccc(C)cc1)Sc1ccc(Cl)cc1

Procedure:
The reaction of 4.07(0.0193 mol) g of 1-chloro-1-[(4-methylphenyl-)hydrazono]-2-propanone, 3.43 g of 4-chlorothiophenol and 3.36 ml of triethylamine in 40 ml of ethanol as in Example 11 yielded 5.55 g of 1-[(4-chlorophenyl)thio]-1-[(4-methylphenyl)hydrazono]-2-propanone, mp 133°-135.5° C.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)=[C:4]([F:16])[CH:3]=1.[CH3:17][N:18](C)C=O>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:4]([F:16])=[CH:3][C:2]=1[C:17]#[N:18]
Reactant: CN1CC=C(c2cc(F)c(Br)cc2F)CC1
Reactant: CN(C)C=O
Product: CN1CC=C(c2cc(F)c(C#N)cc2F)CC1

Procedure:
A mixture of 2.88 g (10 mmoles) of 4-(4-bromo-2,5-difluorophenyl)-1,2,3,6-tetrahydro-1-methylpyridine and 0.90 g (10 mmoles) of cuprous cyanide in 30 ml of dimethylformamide was refluxed overnight. The solvent was evaporated, the residue treated with ammonium hydroxide, and the solution extracted with dichloromethane. Evaporation of the organic phase afforded the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:36][C:37](=[O:39])[CH3:38])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.O.NN>C(#N)C>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:36][C:37](=[O:39])[CH3:38])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: NN
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(CCCN)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{4-(4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl)acetamide (53.2 mg) in acetonitrile (0.5 ml) was added hydrazine monohydrate (46.1 μl), and the mixture was stirred at 50° C. for 30 min. The volatiles were evaporated. To the mixture was added chloroform (1 ml), and an insoluble material was removed by filtration. The filtrate was purified by preparative thin-layer chromatography over NH silica gel with chloroform/methanol (10:1) as an eluent to give N-{4-[4-(3-aminopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:12](N(CC)CC)[CH3:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(O)C>[Cl:11][C:3]1[C:2]([CH:12]=[CH2:13])=[CH:9][CH:8]=[C:7]([F:10])[C:4]=1[C:5]#[N:6]
Reactant: CCN(CC)CC
Reactant: N#Cc1c(F)ccc(Br)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1Cl

Procedure:
3-Bromo-2-chloro-6-fluorobenzonitrile (15.4 g, 65.6 mmol), potassium vinyl trifluoroborate (17.6 g, 131 mmol), triethylamine (18.3 mL, 131 mmol) and PdCl2(dppf)-CH2Cl2 adduct (2.68 g, 3.28 mmol) were added to ethanol (75 mL) then degassed and heated at reflux for 3 h. The reaction was diluted with ethyl acetate and washed with brine, dried and evaporated to dryness. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10% ethyl acetate/hexane solvent system to yield 2-chloro-6-fluoro-3-vinylbenzonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:17]O.Cl>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:17])=[O:9])=[O:5]
Reactant: COc1ccc(O)c(C(=O)CCC(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)c1cc(OC)ccc1O

Procedure:
3-(2-Hydroxy-5-methoxybenzoyl)propionic acid was esterified with methanol-hydrogen chloride, in a similar manner to the procedure described in Example 1 (i), to give methyl 3-(2-hydroxy-5-methoxybenzoyl)propionate as an oil.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[N+:20]([C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])([O-:22])=[O:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([N:19]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[N+:20]([O-:22])=[O:21])[C:26]2=[O:27])[CH2:17][CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
15 ml of a chloroform solution containing 500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 540 mg of 3-nitrophthalic anhydride was refluxed for 1 hour. After cooling, 756 mg of carbonyldiimidazole was added to the mixture and the resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain 900 mg of N-tert-butoxycarbonyl-trans-4-(1,3-dioxo-4-nitro-2-isoindolinyl)-cyclohexylamine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][C:19]([NH2:21])=[O:20].Cl>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([CH2:18][C:19]([NH2:21])=[O:20])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Reactant: NC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CN1CC(=O)N(c2cccc(I)c2)C1=O
Yield: 53.7 %

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (1 g) in DMF (20 ml) was treated with sodium hydride (60% oil dispersion, 158 mg) and 2-bromoacetamide (1.36 g) at 20° C. After 2 h the reaction mixture was treated with aqueous 2M HCl, extracted with EtOAc and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography on Biotage (40 g) eluting with EtOAc to give the title compound (638 mg). LCMS RT=2.32 min.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[CH:13][S:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[Cl:17])[CH:14]=[CH:13][S:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CSc2cn3ccsc3n2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(SCc2ccccc2)nc2sccn12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
6-Benzylthioimidazo[2,1-b]thiazole (2.0 g) is dissolved in a mixture of 8 ml of dichloromethane and 40 ml of carbon tetrachloride. N-Chlorosuccinimide (1.2 g) is added to the solution during 10 minutes and stirred for an hour at room temperature. The insoluble product is filtered off and the filtrate is purified by silica gel chromatography (eluent: ethylacetate) to give 2.0 g of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[O:18][CH2:19][O:20][CH3:21].[Li]CCCC.[I:27]I.S([O-])(O)=O.[Na+]>C1COCC1.CC(OC)(C)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]([I:27])[C:3]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: CCCCCC1CCc2cc(OCOC)c(F)c(F)c2O1
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCCC1CCc2c(I)c(OCOC)c(F)c(F)c2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17.7 g (58.9 mmol) of 7,8-difluoro-6-methoxymethoxy-2-pentylchroman are initially introduced in 370 ml of THF, and 47.7 ml (75.9 mmol) of n-BuLi (15% soln. in hexane) are added dropwise at −78° C. When the addition is complete, the mixture is stirred at this temperature for 30 min and subsequently at room temperature for 1 h. The solution is re-cooled to −78° C., and a solution of 17.9 g (70.7 mol) of iodine in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 90 min and subsequently diluted with MTBE. Sat. sodium hydrogensulfite soln. is added to the mixture, which is subsequently washed with water and sat. sodium chloride soln. The crude product remaining after drying using sodium sulfate and removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=3:1), giving 7,8-difluoro-5-iodo-6-methoxymethoxy-2-pentylchroman as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:12][CH2:11][CH2:10][S:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCBr
Reactant: OCCSCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCOCCSCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
A mixture of 2-[(2-phenylethyl)thio]ethanol (1.0 g), 1,4-dibromobutane (3.79 g), TAB (0.6 g) and 50% aqueous sodium hydroxide (12 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with water (100 ml), extracted with diethyl ether (2×100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with cyclohexane followed by System B (5:95) gave the title compound (1.34 g) as a colourless oil. T.l.c. (System F 3:1) Rf 0.62.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CN(C=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([C:27]3[S:31][C:30]([C:32](N(OC)C)=[O:33])=[C:29]([CH3:38])[C:28]=3[CH3:39])[CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])C>C1COCC1>[CH3:39][C:28]1[C:29]([CH3:38])=[C:30]([C:32](=[O:33])[CH2:1][CH3:2])[S:31][C:27]=1[C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([S:10]([NH2:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)[CH:20]=1
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)c(C)c2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1sc(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)c(C)c1C
Temperature: 72.5 °C

Procedure:
Ethyl magnesium bromide (0.14 g, 1.1 ml, 1.06 mmol) was added drop wise to a solution of 5-(4′-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[1,1′-biphenyl]-3-yl)-N-methoxy-N,3,4-trimethylthiophene-2-carboxamide (Step 7, 0.11 g, 0.21 mmol) in anhydrous THF (10 ml) at 25° C. under stirring. The reaction mixture was then heated to 70-75° C. for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 0° C. The cooled reaction mixture was then quenched with a saturated solution of ammonium chloride (10 ml). The resultant mixture was then extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography using 35% ethyl acetate in hexane as an eluent to obtain the title compound 9 (0.03 g, 33.0%).
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:28][C:29]([C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=1[Cl:38])=[O:30])[C:6]([C:8]1[CH:9]=[N:10][N:11]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:12]=1[C:13]([F:16])([F:15])[F:14])=[O:7].C[C:44]([N:46](C)C)=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:44]([C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:28][C:29]([C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=1[Cl:38])=[O:30])[C:6]([C:8]1[CH:9]=[N:10][N:11]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:12]=1[C:13]([F:16])([F:15])[F:14])=[O:7])#[N:46]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3ccccc3Br)c2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3ccccc3C#N)c2C(F)(F)F)CC1
Temperature: 100 °C

Procedure:
A mixture of compound 22-3 (100 mg, 0.14 mmol) and Zn(CN)2 (34 mg, 0.28 mmol) in DMA (8 mL) was purged with argon for 10 min. Pd(PPh3)4 (33.4 mg, 0.02 mmol) was added and the mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane) to provide compound 22-4 (27 mg, 29%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:9][C:10]([O:12][CH2:13][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:11])=[C:6]([CH3:8])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC(=O)OCc1ccccc1
Yield: 161.1 %

Procedure:
0.36 g of 2-(4-hydroxy-2,6-dimethylphenyl)acetic acid was treated with 184 mg of a 60% dispersion of sodium hydride in mineral oil and 0.72 g of benzyl bromide in 10 ml of dry dimethylformamide. The solvent was removed by evaporation and the residue was partitioned between water and methylene chloride. The organic layer was evaporated to give 0.63 g of crude product of melting point 54°-57° C. Recrystallization from aqueous methanol gave 0.58 g of pure benzyl 2-(4-benzyloxy-2.6-dimethylphenyl)acetate of melting point 62°-64° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(C)C=CC=CC=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCCC1
Temperature: 145 °C
Reaction time: 20 h
Yield: 285.5 %

Procedure:
2-fluoro-4-nitrophenol (36.73 g, 0.234 mol) was added to a dried chlorobenzene (5v/w, 250 mL). The mixture was heated to 145° C. Intermediate VII (12.5 g, 0.039 mol) was added to the reaction solution. The reaction was conducted at this temperature for 20 h. After completion of the reaction, the solvent was evaporated off to produce a grey solid. This solid was dissolved in CH2Cl2, and washed with a satureated saturated K2CO3 solution several times. The organic layer was collected. The solvent was dried off to produce a solid, which is recrystallized with ethanol to produce a yellow solid (49.16 g) in a yield of 71.4%.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][C:28]1[O:32][C:31](=[O:33])[O:30][C:29]=1[CH2:34]Br>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:34][C:29]3[O:30][C:31](=[O:33])[O:32][C:28]=3[CH3:27])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: Cc1oc(=O)oc1CBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: Cc1oc(=O)oc1COC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.7 %

Procedure:
In the same manner as in Example 81, 156 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 122 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)=[CH:11][C:10]=2[C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:11][C:10]=2[C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)c1cc(OC[C@@H]2CCCN2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 1,1-dimethylethyl (2S)-2-[({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)methyl]-1-pyrrolidinecarboxylate (may be prepared as described in Description 74; 0.6 g, 1.19 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (2.0 ml, 26 mmol) dropwise. After stirred at 25° C. for 2 h, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7 min, 35%-50%; 7-14 min, 95%; RT=7.0 min) to yield the title compound as a light yellow solid. 150 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>O1CCCC1.[Ni]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(O)c(Cl)c1

Procedure:
A solution of 86.8 g of 2-chloro-4-nitrophenol in 200 ml of tetrahydrofuran containing 2 g of Raney nickel catalyst was hydrogenated in a Parr shaker at 50 p.s.i. hydrogen pressure. The mixture was filtered and the solvent was evaporated from the filtrate. The residue was recrystallized from ether to give 4-amino-2-chlorophenol (1A), as a tan solid, mp: 144°-147° C.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([NH:22][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH3:1])[CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1cccc(OCc2ccccc2)c1

Procedure:
10 g of phenacyl bromide and 11 g of 3-benzyloxyaniline are stirred at 60° C. for 2 h in 100 ml of ethanol in the presence of 11.7 g of powdered Na2CO3. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated. The residue is slurried with ether and the crystals are filtered off, 2'-(3-benzyloxyphenylamino)acetophenone being obtained.