Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[Br-].[CH3:6][N:7]([CH3:37])[C:8]1[C:9]([N+:34]([O-:36])=[O:35])=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:38]1([C:44]2[N:45]=[CH:46][N:47]([CH2:49][CH2:50][CH:51]=O)[CH:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N+:34]([C:9]1[C:10]([CH:11]=[CH:51][CH2:50][CH2:49][N:47]2[CH:48]=[C:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:45]=[CH:46]2)=[CH:31][CH:32]=[CH:33][C:8]=1[N:7]([CH3:6])[CH3:37])([O-:36])=[O:35]
Reactant: CN(C)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1[N+](=O)[O-]
Reactant: O=CCCn1cnc(-c2ccccc2)c1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Product: CN(C)c1cccc(C=CCCn2cnc(-c3ccccc3)c2)c1[N+](=O)[O-]
Yield: 142.2 %

Procedure:
An ethanolic solution of 900 mg of sodium ethoxide was dropped into an ethanolic solution containing 6.88 g of 3-dimethylamino-2-nitrobenzyl-triphenylphosphonium bromide and 3.22 g of 3-(4-phenyl-1H-imidazol-1-yl)propionaldehyde. The obtained solution was heated under reflux for 2 hours to conduct a reaction. After the completion of the reaction, the reaction mixture was freed from the solvent by distillation and extracted With 2N NaOH. The aqueous layer was made acidic again with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. The obtained oily substance was purified by silica gel chromatography to give 6.80 g of 2-nitro-3-[4-(4-phenyl-1H-imidazol-1-yl)butenyl]-N,N-dimethylaniline. 680 mg of 10% Pd-C was added to a solution of the product in ethyl acetate to conduct catalytic reduction in a hydrogen stream. Thus, 2-dimethylamino-6-[4-(4-phenyl-1H-imidazol-1-yl) butyl]aniline was obtained as an oily substance. This substance was dissolved in chloroform to give a solution. 1.1 g of butyl isocyanate was dropped into the solution. The obtained mixture was heated under reflux for two hours to conduct a reaction. After the completion of the reaction, the reaction mixture was concentrated to precipitate a crystal. This crystal was recrystallized from an ethyl acetate/hexane mixture. Thus, 4.51 g of the title compound was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([CH:31]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[CH:20].C(N(CC)CC)C.Cl>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.[Cu]I.O1CCCC1>[OH:32][C:24]1[CH:23]=[CH:22][C:21]([C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Cc1cccnc1NS(=O)(=O)c1cccc(I)c1
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2cccc(S(=O)(=O)Nc3ncccc3C)c2)ccc1O

Procedure:
3-Iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol), ethyl 5-ethynyl-2-hydroxybenzoate (9.5 g, 50 mmol), triethylamine (65 ml) and tetrahydrofuran (65 ml) were stirred at 60° C. Dichlorobis(triphenylphosphine)palladium (250 mg, 0.36 mmol) and copper(I)iodide (140 mg, 0.7 mmol) were added with stirring. After 1 h the solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried, treated with activated carbon and the solvent evaporated. The residue was recrystallized from methanol, then from toluene and finally from acetic acid. Yield 12.7 g 58%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:19]CC1C=CC2OC(C3C=CC=C(F)C=3)=NC=2C=1>>[Cl:19][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Reactant: OCc1ccc2oc(-c3ccc(F)cc3)nc2c1
Product: Fc1ccc(-c2nc3cc(CCl)ccc3o2)cc1

Procedure:
Compound 74B was reacted in a manner analogous to Compound 69C to give the title product. 400 MHz 1H NMR (DMSO-d6) δ □ ppm 4.9 (s, 2H) 7.4 (t, J=9.0 Hz, 2H) 7.5 (dd, J=8.4, 1.8 Hz, 1H) 7.7 (d, J=9.0 Hz, 1H) 7.8 (d, J=1.2 Hz, 1H) 8.2 (dd, J=9.0, 5.4 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([SH:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:28]([CH:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:21][C:17](=[O:20])[CH2:18][CH2:19][S:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:16])[CH3:29]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: CC(C)(C)c1cc(S)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCSc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 35 %

Procedure:
The procedure of Example 1 was repeated using 20.0 grams of 2,4-di-tert-butyl-6-mercaptophenol, 15.5 grams of 2-ethylhexyl acrylate, 0.25 ml of triethylamine and 150 mls of toluene. The residue was purified by chromatography on silica gel using toluene/heptane eluent to give 12.4 g (35% yield) of a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(COCCc1ccc2occc2c1)N1CCC(O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1CCN(CCOCCc2ccc3occc3c2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.6 %

Procedure:
1.39 g of 2-(2-(1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone was dissolved in 14.0 ml of tetrahydrofuran. Thereafter, 14.4 ml of a tetrahydrofuran solution containing a 1 mol/l borane-tetrahydrofuran complex was added dropwise to the obtained solution while cooling on ice, and the obtained mixture was then stirred at a room temperature for 17 hours. Thereafter, 8.0 ml of 6 mol/l hydrochloric acid was added to the reaction mixture, and the obtained mixture was heated to reflux for 1 hour. After cooling, water and ethyl acetate were added to the reaction mixture. The pH of the obtained mixture was adjusted to pH 10 by addition of a 2 mol/l aqueous sodium hydroxide solution, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=30:1 to 10:1), so as to obtain 0.96 g of an achromatic oil product, 1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.N1C=CC=CC=1CC(=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Ic1cccnc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc(Oc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 3-iodopyridine (602 mg, 2.94 mmol), 4-bromophenol (560 mg, 3.24 mmol), CuBr (23 mg, 0.16 mmol), 1-(pyridin-2-yl)propan-2-one (53 mg, 0.39 mmol), Cs2CO3 (1.92 g, 5.89 mmol), and DMSO (6 mL) was degassed with three vacuum/N2 cycles, heated at 100° C. for 9 h, and then stirred at rt overnight. The reaction was filtered through Celite with EtOAc. The filtrate was washed with H2O (100 mL) and brine (100 mL). The aqueous wash was back extracted with EtOAc (3×40 mL). The organic extracts were combined, dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (0%-20% EtOAc in hexanes) to give 250 mg of 3-(4-bromophenoxy)pyridine as a clear liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.39-8.42 (m, 2H), 7.58-7.61 (m, 2H), 7.43-7.51 (m, 2H), 7.02-7.07 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](OC=C)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.F[C:20](F)(F)[C:21]([OH:23])=[O:22]>O1CCOCC1>[CH:21]([O:23][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Br:1])([O:22][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11])[CH3:20]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(Br)cc1
Reactant: C=COc1ccc(Br)cc1
Solvent: C1COCCO1
Product: CC(Oc1ccccc1Br)Oc1ccccc1Br
Yield: 165.1 %

Procedure:
Under nitrogen, a 250 milliliter round bottom flask was charged with 1-bromo-4-(vinyloxy)benzene (6.97 grams, 35.0 millimoles, 1.00 equivalent), dioxane (50 milliliters), 4-bromophenol (6.67 grams, 38.5 millimoles, 1.10 equivalent), and a stir bar. Trifluoroacetic acid (1.21 milliliter, 15.75 millimoles, 0.45 equivalent) was added and the flask was equipped with a condenser while maintaining an inert atmosphere. The reaction mixture was heated to reflux overnight, allowed to cool, and quenched with triethylamine (2.00 milliliters). The mixture was separated via automated flash column chromatography using 220 grams Grace normal phase silica column (5% ethyl acetate in hexanes). Concentration gave the product in form of a colorless oil (9.69 grams, 26.0 millimoles, 74%). 1H NMR (400 MHz, CDCl3) δ 7.41-7.32 (m, 4H), 6.91-6.81 (m, 4H), 5.86 (q, J=5.3 Hz, 1H), 1.62 (dd, J=5.3, 0.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 154.71, 132.46, 119.59, 115.19, 98.44, 20.10.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@H:30]([CH3:35])[C:31]([F:32])([F:33])[F:34])=[C:24]([C:25]([N:9]2[CH2:8][CH2:7][C:6]3[N:5]=[C:4]([C:3]([F:2])([F:14])[F:15])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:26])[CH:28]=1)(=[O:19])=[O:18]
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Agent: Cl
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (CA [741736-98-1]; WO2004069162) and 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.3).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([NH2:27])[C:24]3[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)#N.Cl.[OH-:33].[Na+]>O1CCCC1>[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([NH2:27])[C:24]3[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)(=[O:33])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)c4ccccc4)CC3)nc(N)c2cc1OC
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions, a solution of 5.43 g. (0.03 mole) of phenylmagnesium bromide in 100 ml. of tetrahydrofuran is swept with dry nitrogen and a solution of 3.15 g. (0.01 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino 6,7-dimethoxyquinazoline in 75 ml. of the same solvent is added dropwise over 30 minutes at room temperature. When the addition is complete, the reaction mixture is heated at 65° C. for 6 hours, then allowed to stand at room temperature overnight. To the reaction mixture is then added 25 ml. of 2N hydrochloric acid and stirring is continued for an additional 30 minutes. The reaction mixture is then made alkaline with sodium hydroxide solution and the organic layer separated. The aqueous layer is extracted with 2 × 100 ml. of tetrahydrofuran and the combined organic layers are dried over anhydrous magnesium sulfate and evaporated to dryness to obtain the crude title compound which can be further purified by crystallization from ethanol or by column chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](Br)=[CH:7][CH2:8][N+:9]([O-:17])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][N:46]([CH3:50])[CH2:47][C:48]#[CH:49]>[Pd](Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([C:49]#[C:48][CH2:47][N:46]([CH3:50])[CH3:45])=[CH:7][CH2:8][N+:9]([O-:17])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: C#CCN(C)C
Reactant: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2C(Br)=CC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN(C)CC#CC1=CC[N+]([O-])=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.5 g (10 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine-2-oxide, 40 ml of 98% diethylamine, 40 ml of dimethylformamide, 44.3 mg (0.25 mmole) of palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide and 16 ml of 1-dimethylamino-2-propyne was stirred at room temperature under nitrogen for 24 hr. The mixture was concentrated at reduced pressure to dryness. An ether solution of the residue containing petroleum ether was washed with water followed by dilute cold hydrochloric acid. The aqueous solution was separated, made alkaline with dilute cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ether and petroleum ether to give a tan solid, mp 121°-123° C. Recrystallization from ether gave tan prisms, mp 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[ClH:1].[N:13]1([NH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14]1
Reactant: Nn1cccc1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cl
Product: c1ccc2c(Nn3cccc3)ccnc2c1
Yield: 19.3 %

Procedure:
A solution of 4-chloroquinoline (10 g) and 1-aminopyrrole (6 g) in 100 ml isopropanol containing 1 ml saturated ether/HCl was stirred at 80° for thirty minutes, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed successively with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to 12 g of solid, m.p. 165°-168°. Four grams were converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 2.9 g crystals, m.p. 233°-234°.
Reaction SMILES: C([O:4][C@@H:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].Cl>O.C(O)C.C(OCC)(=O)C>[OH:4][C@@H:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)=[O:7]
Reactant: CC(=O)O[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)[C@@H](O)c3ccccc3)C[C@H]12
Yield: 71.4 %

Procedure:
A solution of (3aR,7aR)-2-[(S)-2-acetoxy-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (2 g) in a mixture of water (20 cc) and ethanol (25 cc) is treated with normal sodium hydroxide solution (5 cc) and the mixture is refluxed for 1 hour, then diluted with water (100 cc) and ethyl acetate (50 cc) and neutralized by the addition of normal hydrochloric acid (5 cc). The organic phase is washed with water (50 cc) and with a saturated sodium chloride solution (50 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-2-[(S)-2-hydroxy-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1.3 g) in the form of a white meringue.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:26]([Cl:27])=[C:25]([S:28][CH3:29])[CH:24]=[CH:23][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH3:22])=[O:16]>ClCCl>[Cl:12][C:13]1[C:26]([Cl:27])=[C:25]([S:28]([CH3:29])=[O:9])[CH:24]=[CH:23][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH3:22])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)c2cnoc2C)c(Cl)c1Cl
Solvent: ClCCl
Product: Cc1oncc1C(=O)c1ccc(S(C)=O)c(Cl)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
3-Chloroperbenzoic acid (85%, 0.99 g) was added portionwise to a stirred solution of 4-(2,3-dichloro-4-methylsulphenylbenzoyl)-5-methylisoxazole (1.5 g) in dichloromethane (50 ml) whilst maintaining the temperature below -20° C. The mixture was stirred at -20° C. for 1 hour. Dichloromethane (50 ml) was added and the solid was removed by filtration. The filtrate was evaporated to dryness and the residue was chromatographed on silica eluted with a mixture of ethyl acetate and cyclohexane (1:5) to give 4-(2, 3-dichloro-4-methylsulphinylbenzoyl)-5-methylisoxazole (compound 46, 0.8 g) as a white solid, mp 125°-126.4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:30][CH2:31][CH3:32])[C:12]=1[OH:33])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([CH3:27])=[CH:25][CH:26]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:28]=[CH:29][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:33])[C:13]=2[CH2:30][CH2:31][CH3:32])[CH:21]=1)=[O:5]
Reactant: CCCc1c(OCCCOc2ccc(C)c(N)c2)ccc(C(C)=O)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C)c(NC(=O)C(=O)OC)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 1.9 ml (21 mmol) of chloro-oxalic acid methyl ester in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.5 g (21 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-6-methylaniline and 3.0 g (21 mmol) of triethylamine in 60 ml of methylene chloride. The reaction mixture is stirred for 90 minutes at room temperature, is poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-6-methylphenyl}-oxamic acid methyl ester having a melting point of 125°-127°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2cccnc2)cc1

Procedure:
A mixture of 4-carboxybenzeneboronic acid (0.5 g, 2.9 mmol), 3-bromopyridine (0.46 g, 2.9 mmol), sodium carbonate (1.37 g), and tetrakis(triphenylphosphine)palladium(0) (0.1 g) in 50% aqueous 1,2-dimethoxyethane (70 mL) was heated to reflux for 16 h, cooled, acidified, and extracted with dichloromethane. The organic phase was dried and concentrated in vacuo to yield the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][Br:11])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(C#N)c1
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)ccc1F
Yield: 63.1 %

Procedure:
A solution of 3-Cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and catalytic 2,2i-azobisisobutyronitrile (AIBN) in benzene was heated to reflux for 16 hours, evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane to provide 1.0 g of 3-cyano-4-fluorobenzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12].[C-:17]#[N:18].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:17]#[N:18])=[CH:8][C:7]1=[O:12]
Reactant: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1=CC(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 90 °C

Procedure:
A suspension of 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (10 g, 42 mmol) and KCN (8:0 g, 120 mmol) in DMF (400 mL) and water (100 mL) was warmed to 90° C. for 48 hours. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (250 mL) and water (100 mL). The organic phase was separated and the aqueous phase was extracted with more EtOAc (2×100 mL). The organic phases were combined and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting with 2:1:0.01 EtOAc:hexanes:MeOH. Fractions containing product were concentrated under reduced pressure to give the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (dd, J=6.8, 2.0 Hz, 1H), 7.1-7.2 (m, 2H), 4.55 (AB quartet, J=17 Hz, 2H), 3.46 (ddd, J=13, 7.1, 6.5 Hz, 1H); 3.28 (ddd, J=13, 7.1, 6.5 Hz, 1H), 3.10 (m, 1H), 2.78 (ABX, J 17, 6.4 Hz, 2H), 2.2-2.2 (m, 2H); HPLC RT=2.36 min (Method A); ES MS M+1=267.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C@@H:13]2[CH2:17][C@H:16]([S:18][C:19]3[C@H:20]([CH3:43])[C@@H:21]4[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]4[C:23]=3[C:24]([O:26]CC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH2:15][N:14]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:12])[CH2:6][CH2:5]1.[ClH:57]>O1CCCC1.O>[ClH:57].[F:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C@@H:13]2[CH2:17][C@H:16]([S:18][C:19]3[C@H:20]([CH3:43])[C@@H:21]4[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]4[C:23]=3[C:24]([OH:26])=[O:25])[CH2:15][NH:14]2)=[O:12])[CH2:6][CH2:5]1
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)N4CCCN(CCF)CC4)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)N4CCCN(CCF)CC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[4-(2-fluoroethyl)-1-homopiperazinylcarbonyl]-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 12 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.62 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 500 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 15(b), to give 96 mg of the title compound, as a powder.