Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[F:27].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[C:21]([F:27])=[CH:20][CH:25]=[CH:24][C:23]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1cccc(Br)c1F
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 1H-indole (3.78 g, 15.5 mmol), and 1-bromo-2,3-difluorobenzene (3 g, 15.5 mmol) in THF (55 mL) were added Palladium catalyst Pd(PPh3)4 (0.54 g, 0.47 mmol) and the freshly prepared sodium hydroxide solution (1.865 g, 47 mmol in 22 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.92 g (82%) of 4-(2,3-difluoro-phenyl)-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH:24]([CH3:28])[NH:23]1>CN(C)C=O.C(OCC)C>[CH3:21][CH:22]1[NH:23][CH:24]([CH3:28])[CH2:25][N:26]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:27]1
Reactant: CC1CNCC(C)N1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Yield: 70.9 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (98.7 mg) and 2,6-dimethylpiperazine (77.2 mg) in dimethylformamide (1 mL) was heated at 100° C. for 5 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 1:98.5:0.5 methanol-methylene chloride-triethylamine) to give the title compound as a white solid (97.3 mg), m.p. 61° C.-62° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14]>C1COCC1>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: NCCCO
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Product: OCCCNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A solution of phenyl isothiocyanate (200 mg) in abs. THF (2 ml) was added dropwise under argon and with stirring to a solution of 3-amino-1-propanol (114.5 mg) in abs. THF (2 ml). The reaction mixture was stirred at room temperature for two hours. After removing the solvent, the residue was dissolved in aqueous HCl and washed with ether. Subsequently, the aqueous phase was basified with potassium carbonate and extracted three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative chromatography, and the product-containing fractions were combined, freed of acetonitrile, basified and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. After removing the solvent, 114 mg of the desired product were obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.ClCCl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16][C:17]=1[C:24]([F:25])([F:26])[F:27])[CH3:23]
Reactant: CCOc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F

Procedure:
N-Boc-(R)-2-(4-ethoxy-3-trifluoromethylbenzyl)morpholine, intermediate (a), was dissolved in TFA, (20% v/v solution in dichloromethane, 1.2 mL total) over 3 hrs. The reaction mixture was poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine, example 10 as a yellow oil (17 mg, 85%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[C:11]=2/[CH:20]=[CH:21]/[CH:22]([OH:31])[CH2:23][CH:24]([OH:30])[CH2:25][C:26]([O:28]C)=[O:27])=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:18])([CH3:19])[C:11]=2/[CH:20]=[CH:21]/[CH:22]([OH:31])[CH2:23][CH:24]([OH:30])[CH2:25][C:26]([OH:28])=[O:27])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC(C)(C)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)C1
Reaction time: 0.17 h

Procedure:
A 1N NaOH solution (30 ml, 30 mmoles) was added to a solution of the 3,5-dihydroxyester prepared in Step 9 (9.70 g, 24 mmoles) and 60 ml of ethanol. After stirring for 10 minutes, the ethanol was evaporated in vacuo. The residue was redissolved in H2O and extracted twice with ether. The aqueous layer was acidified with 33 ml of 1N HCl and extracted twice with H2CCl2. The H2CCl2 was removed in vacuo.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1)[CH3:2].[CH3:12][C:13]1([CH3:20])[C:17]([CH3:19])([CH3:18])[O:16][BH:15][O:14]1.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([B:15]2[O:16][C:17]([CH3:19])([CH3:18])[C:13]([CH3:20])([CH3:12])[O:14]2)=[C:6]([CH3:11])[CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(Br)c(C)c1
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCSc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 85 °C

Procedure:
A mixture of the product from step (i) (6.6 g), 4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (1.94 ml), triethylamine (2.4 ml), palladium acetate (0.06 g) and 2-(dicyclohexylphosphino) biphenyl (0.3 g) in dioxane (20 ml) was heated at 85° C. for 2 h. The mixture was quenched with aqueous ammonium chloride solution, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50% isohexane/DCM. Yield 0.7 g
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[O:27]CC1C=CC=CC=1)=[O:5])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1O
Reaction time: 7 h
Yield: 101.7 %

Procedure:
A mixture of 7-benzyloxy-2-phenyl-4-piperidin-1-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (47 mg, 0.10 mmole) and 10% Pd/C (20 mg) in a mixture of ethanol and ethyl acetate (3 ml, 1:5) was hydrogenated at room temperature for 7 h before it was filtered, washed with ethyl acetate and concentrated in vacuo to give the title compound as a yellow oil (39 mg). MS: (+) m/z 384.34 (M+1), MS: (−) m/z 382.37 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Yield: 20 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (398 mmol) and 2-nitroaniline (362 mmol) yielded 21.6 g (100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C1(C)C=CC=CC=1>[C:10]([C:3]1[C:4]([O:7][CH2:8][CH3:9])=[N:5][S:6][C:2]=1[NH:1][C:13](=[O:14])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1nsc(N)c1C#N
Solvent: Cc1ccccc1
Product: CCOc1nsc(NC(=O)Oc2ccccc2)c1C#N
Reaction time: 24 h
Yield: 40.5 %

Procedure:
A solution of 16.6 g of 5-amino-4-cyano-3-ethoxyisothiazole and 30.7 g of phenyl chloroformate in 100 ml of toluene under nitrogen atmosphere was stirred and heated at 100° for about 16 hours. After this time, thin-layer chromatography indicated that the reaction was 50% complete. An additional 15 ml of phenyl chloroformate was added and heating (100°) continued for an additional 24 hours; at this time thin-layer chromatography indicated 80% reaction. After an additional 6 hours, 90% reaction was indicated. The mixture was allowed to cool to 5° and filtered. The solid filter cake was washed with toluene and recrystallized from acetic acid, then ethanol, to give 11.5 g of phenyl (4-cyano-3-ethoxy-5-isothiazolyl)carbamate, m.p. 252°-253°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[NH:25]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCOC(C)=O>[CH:20]1([NH:23][C:24]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:11]=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[O:41])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: Clc1ccc(-c2nccc(N3CCOCC3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(-c2nccc(N3CCOCC3)n2)cc1)NC1CC1
Temperature: 140 °C
Yield: 46 %

Procedure:
4-(2-(4-chlorophenyl)pyrimidin-4-yl)morpholine (100 mg 0.5 mmol), (4-(3-cyclopropylureido)phenyl)boronic acid pinacol ester (181 mg, 0.6 mmol), Cs2CO3 (326 mg, 1.0 mmol) and Pd(PPh3)2Cl2 (18 mg, 0.025 mmol) were combined in dioxane (3 ml) and water 0.7 ml). The reaction mixture was then heated by microwave at 140° C. for 20 min. The reaction mixture was portioned between EtOAc and water. The organic layer was passed through a PTFE hydrophobic frit and the solvent removed in vacuo. The solid residue was triturated with EtOAc, collected by filtration and dried in vacuo to afford the title compound (78 mg, 46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([OH:17])[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)O.N1C=CC=N1>C(O)C.CO.C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([OH:17])[C:10]1[CH:15]=[CH:14][C:13]([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(O)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Temperature: 85 °C
Reaction time: 6.5 h
Yield: 58.1 %

Procedure:
[2-(4-Chloro-phenyl)-2-hydroxy-2-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (5 g, 10.6 mmol) was combined with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (4.1 g, 21.11 mmol) and potassium phosphate (tribasic, 7.88 g, 37.10 mmol) in a round-bottomed flask. The solids were then dissolved in a solvent mixture of 1:1:1:1 ethanol, methanol, toluene and water (33 mL of each solvent). The solution was degassed with nitrogen and tetrakistriphenylphosphine palladium (0) (0.612 g, 0.53 mmol) was added. The mixture was degassed with nitrogen and then heated at 85° C. under nitrogen for 2 hours. The reaction mixture was then allowed to cool to room temperature. Additional batches of reagents were then added: potassium phosphate (7.88 g, 37.10 mmol) and pyrazole boronate (4.1 g, 21.11 mmol). The reaction mixture was degassed with nitrogen and a further batch of tetrakistriphenylphosphine palladium (0) (0.101 g, 0.087 mmol) was added. The reaction mixture was degassed and then heated at 85° C. under nitrogen for 17 hours. Additional batches of reagents were added again (refer to quantities above) and heating was continued at 85° C. under nitrogen for a further 6.5 hours. The reaction mixture was then allowed to cool to room temperature and was evaporated in vacuo to remove the organic solvent. The residual aqueous layer was diluted with aqueous 2N NaOH solution (150 mL) then extracted with ethyl acetate (150 mL). The organic layer was separated off and washed with aqueous 2N NaOH solution (150 mL) followed by brine (150 mL). The organic layer was separated off, dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether. The solid was filtered in vacuo then dried to afford the title compound as a white solid (2.55 g, 58%). LC/MS: (PS-B5) Rt 3.05 [M+H]+ 414.18. 1H NMR (Me-d3-OD) 7.95 (2H, br s), 7.55 (2H, d), 7.48-7.41 (4H, m), 7.31 (2H, d), 3.87 (2H, q), 1.35 (9H, s).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:23][CH3:24])=[C:5]([NH:16]C(=O)C(F)(F)F)[C:6]([F:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:16][C:5]1[C:4]([O:23][CH3:24])=[C:3]([C:1]#[N:2])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[F:15]
Reactant: COc1c(C#N)cc(-c2ccccc2)c(F)c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(C#N)cc(-c2ccccc2)c(F)c1N
Temperature: 70 °C
Reaction time: 38 h
Yield: 92 %

Procedure:
N-(5-Cyano-2-fluoro-4-methoxybiphenyl-3-yl)-2,2,2-trifluoroacetamide 233) (2.78 g, 8.22 mmol) was dissolved in methanol (31.8 ml), and at room temperature, aqueous 15 wt. % potassium carbonate solution (31.8 ml, 34.5 mmol) was added. This was stirred at 70° C. for 38 hours. After cooling to room temperature, methanol was evaporated away under reduced pressure, and the resulting residue was extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was again extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=4:1) to obtain the entitled compound (1.833 g, 92%) as a colorless gel substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11](Cl)[CH2:12]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CC1(c2ccc(Br)cc2)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-bromophenylacetonitrile (1 eq), 1,2-bromochloroethane (1.5 eq), benzyltriethylammonium chloride (0.14 eq) in NaOH 50% (4M) was heated to 50° C. for 18 h. The mixture was cooled to rt, quenched with HCl 5% and diluted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 95:5) afforded the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCCCc1ccccc1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a mechanically stirred solution of oxalyl chloride (21.6 g; 170 mmol) in dry CH2Cl2 (400 mL) at -78° C. is added DMSO (22.3 g; 360 mmol) dropwise over 45 minutes. After stirring 15 minutes 5-phenylpentanol (25 g; 150 mmol) is added and the internal temperature is allowed to warm to -55° C. After stirring at this temperature for 30 minutes the reaction is cooled to -78° C. and triethylamine (104 mL; 750 mmol) is added slowly over 20 minutes. After stirring 15 minutes the reaction bath is removed and the temperature is allowed to warm to 20° C. over 40 minutes. The reaction mixture is then washed with 500 mL water. The water layer is then back-extracted with CH2Cl2 (2×50 mL). The combined organic fractions are washed with 300 mL 2 N HCl, 100 mL water, 200 mL NaHCO3, 100 mL brine and dried (MgSO4). The solution is concentrated in vacuo to obtain 5-phenylpentanal (25 g) which is used directly in Step B.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]([C:21](=[O:22])[CH2:20][C:13]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=2[F:11])[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)Cc2cc(F)c(F)cc2F)C(=O)O1
Yield: 95.9 %

Procedure:
2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69 g, 39.5 mmol) was dissolved in 400 mL of dichloromethane under stirring, followed by addition of (2,4,5-trifluorophenyl)-acetic acid 1a (7.15 g, 37.6 mmol) and 4-dimethylaminopyridine (7.35 g, 60.2 mmol) in an ice-water bath. Then a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.28 g, 43.2 mmol) in 250 mL of dichloromethane was added dropwise slowly. After stirring at room temperature for 36 hours, the reaction mixture was washed with the solution of 5% potassium bisulfate (250 mL×7) and saturated brine (250 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2,2-dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (11.4 g, yield 96%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:45])[C:7]([S:18][C@@H:19]1[CH2:23][N:22](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:21]([CH2:37][N:38]3[CH2:42][CH:41]([CH3:43])[NH:40][C:39]3=[O:44])[CH2:20]1)=[C:8]2[C:12]([O:14]CC=C)=[O:13])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)CCCCC.[Na].P(=O)(O)(O)O.[H][H]>O1CCCC1.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.[OH-].[OH-].[Pd+2]>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:45])[C:7]([S:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([CH2:37][N:38]3[CH2:42][CH:41]([CH3:43])[NH:40][C:39]3=[O:44])[CH2:20]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: [H][H]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CN3CC(C)NC3=O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P(O)(O)O
Solvent: CCCCCC(=O)OCC
Solvent: C1CCOC1
Product: CC1CN(C[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C(=O)N1
Temperature: 25 °C
Yield: 17.9 %

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{(2S,4S)-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.45 g) in tetrahydrofuran (50 ml) were added triphenylphosphine (0.50 g), sodium 2-ethyl hexanoate (0.70 g) and tetrakis(triphenylphosphine)palladium(0) (0.22 g) successively with stirring at ambient temperature. After stirring at the same temperature for 1 hour, the reaction mixture was evaporated in vacuo to give a residue. A mixture of the residue, 20% palladium hydroxide on carbon (0.5 g), 0.1M phosphoric acid buffer (pH=6.0, 80 ml) and tetrahydrofuran (80 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin, "Diaion HP-20" (trademark, made by Mitsubishi Chemical Industries) (30 ml) eluting in turn with water (90 ml) and 5% aqueous acetone (100 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-(4-methyl-2-oxoimidazolidin-1-yl)methylpyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.29 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](O)=[CH:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][C:5]=2[O:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:9]1[CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=[C:5]2[O:4][N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: Cc1noc2nc(-c3ccccc3)cc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1noc2nc(-c3ccccc3)cc(Cl)c12

Procedure:
6.8 g. of 3-methyl-6-phenylisoxazolo[5,4-b]pyridin-4-ol (0.03 mol.) are refluxed in 60 ml. of phosphorous oxychloride for 3 hours. the excess phosphorous oxychloride is removed in vacuo and the oily residue is treated with ice water. The compound becomes solid. The compound is extracted with chloroform, washed with an aqueous sodium carbonate solution (10%) and again with water. Evaporation of the dried (Na2SO4) and charcoal treated chloroform extract provides 6.3 g. (86%) of 4-chloro-3-methyl-6-phenylisoxazolo[5,4-b]-pyridine which is recrystallized from ligroin and melts at 130°-131°.
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8]>C(O)C>[NH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8]
Reactant: N
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(CBr)c1
Solvent: CCO
Product: NCc1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
An aqueous solution of 25% w/v ammonia (100 mL) was treated with EtOH (200 mL) and cooled to −78° C. The mixture was slowly treated with a cooled (−78° C.) solution of the benzylbromide (2.58 g, 10.0 mmol) in ethanol (100 mL). The mixture was then allowed to come to room temperature and stirred for 48 h. The mixtures were evaporated under reduced pressure and the residue solid was washed with CH2Cl2 to afford 3-(aminomethyl)-4-nitrobenzoic acid (1.7 g, 87% yield).