Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1>C(O)(C)C>[CH3:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=1)=[N:3][CH:4]=[CH:5]2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Solvent: CC(C)O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1[N+](=O)[O-]
Temperature: 180 °C
Yield: 81.1 %

Procedure:
1-Chloro-6-methyl-5-nitroisoquinoline (0.25 g, 1.1 mmol) and 3-(trifluoromethyl)benzenamine (0.17 mL, 1.3 mmol) were added to a microwave tube containing 3 mL of isopropanol. The tube was capped and heated at 180° C. for 1500 seconds. The volatiles were removed in vacuo. The residue was taken up in DCM and washed with saturated NaHCO3. The organic layer was dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 10 to 40% of ethyl acetate in hexanes to give the product as an orange solid (0.31 g, 79%). MS (M+H)+ 348.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].Cl[CH2:13][CH:14]=O>O>[CH3:10][C:8]1[N:9]2[CH:13]=[CH:14][N:1]=[C:2]2[C:3]([C:4]#[N:5])=[C:6]([CH3:11])[CH:7]=1
Reactant: O=CCCl
Reactant: Cc1cc(C)c(C#N)c(N)n1
Solvent: O
Product: Cc1cc(C)n2ccnc2c1C#N
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of compound 2-amino-4,6-dimethylnicotinonitrile (1 equiv.) in water was added chloroacetaldehyde (55% aq. solution) (1.2 equiv.) and reaction was heated at 80° C. for 16 h. On completion, it was quenched by 1N NaOH till pH 8. Solid precipitated was filtered and vacuum dried to afford the title compound (75% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[NH2:18][CH2:19][C:20]1[C:21](=[N:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[C:22]([NH2:25])=[N:23][N:24]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([NH:18][CH2:19][C:20]1[C:21](=[N:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[C:22]([NH2:25])=[N:23][N:24]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)OCc1ccccc1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Agent: N=C=N
Solvent: CN(C)C=O
Product: NC1=NN=C(CNC(=O)CC(=O)OCc2ccccc2)C1=NNc1cccc(F)c1
Reaction time: 16 h

Procedure:
A solution of malonic acid monobenzyl ester (1.5 eq, 0.26 mmol) in anhydrous DMF (3 mL) was added to a 10 mL reaction vessel containing PS-carbodiimide (2 eq, 380 mg). The reaction mixture was stirred at ambient temperature under argon for 10 minutes before a solution of 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg, 0.17 mmol) in anhydrous DMF (3 mL) was added. The mixture was further stirred for approximately 16 hours before it was filtered, washed with DMF (3×3 mL) and concentrated under reduced pressure. The title compound was obtained in a yield of 38 mg (55%) as a yellow powder with no further purification. MS (m/z, ES+): 411 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.40 (brs, 1H, N—H pyrazole), 8.45 (s, 1H, N—H amide), 7.40-7.60 (m, 3H, Ar—H), 7.28-7.35 (m, 5H, Ar—H), 7.05-7.15 (t, 1H, F—Ar—H), 5.15 (s, 2H, benzyl CH2), 4.47 (s, 1H, CHaHb amide), 4.43 (s, 1H, CHaHb amide), 3.35 (2H, CH2 pyrazole-overlap with H2O).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14](C(Cl)(Cl)Cl)[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].O>CS(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:33][CH:30]([CH3:32])[CH3:31])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(NC(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 83.3 %

Procedure:
To a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (600 mg, 1.03 mmol) in DMSO (6 mL) was added isopropyl amine (1.2 mL). The reaction was heated to 90° C. in a sealed tube for 12 h then cooled to RT. The mixture was treated with water and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with basic alumina column chromatography (eluent: 35% EtOAc in petroleum ether) to give 3-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (450 mg, 83.3%) as an off brown solid. MS (ESI, pos. ion) m/z: 523.0 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 9.44 (d, J=7.6 Hz, 1H), 8.18 (s, 1H), 8.09-8.07 (m, 1H), 7.96-7.93 (m, 3H), 7.83 (d, J=1.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 3.88-3.83 (m, 1H), 2.32 (s, 3H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14].ClCCl.CO>C(O)C>[CH2:1]([C@H:8]([CH2:13][CH2:12][OH:11])[C:9]([NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCC[C@H]1Cc1ccccc1
Reactant: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: NC(=O)[C@@H](CCO)Cc1ccccc1
Yield: 63.8 %

Procedure:
(R)-2-benzylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (R)-2-benzyl-4-hydroxybutyramide.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH:10]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[H][H]>[Pd].C(O)C>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH:10]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11]2)=[O:8])=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1

Procedure:
A solution of 20 g. (0.067 mole) of 4-cyano-N-(1-cyclohexyl-3-pyrrolidinyl)benzamide in 400 ml. of 95% ethanol and 19.24 g. (0.202 mole) of concentrated hydrochloric acid containing 2.0 g. of palladium on charcoal (10%) was shaken at room temperature in three atmospheres of hydrogen for five hours. The filtered mixture was concentrated at reduced pressure and the residue was partitioned between dilute sodium hydroxide and chloroform. The dried chloroform solution was concentrated at reduced pressure and the residue was recrystallized from ethyl acetate to give 8.0 g. (40%) of product which melted at 125°-129° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.O.[OH-].[K+]>C(O)C.[C].[Pd]>[C:13]([CH2:12][O:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[C:7]=1[C:8](=[O:10])[CH:9]=[CH:24][CH:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH2:19][CH2:18][OH:17])[CH2:22]1)([OH:15])=[O:14]
Reactant: O=Cc1cccc(OCCO)c1
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cccc(O)c1C(=O)C=CC1C=CC=C(OCCO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a suspension of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (1 g) and 3-(2-hydroxyethoxy)benzaldehyde (0.74 g) in ethanol (12 mL) were added water (3 mL) and potassium hydroxide (3 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was dissolved in water, and the solution was washed with diethyl ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid, and the resulting mixture was extracted with ethyl acetate twice. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was treated with diethyl ether, and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure to give the title compound (1.6 g).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:20])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
2.78 g of 4-octyloxybenzoic acid was added to 10 ml of benzene, and under stirring at room temperature, 2.36 g of PCl5 was added little by little. The mixture was then heated under reflux for 4 hours. Thereafter, the solvent was distilled off to obtain 4-octyloxybenzoic acid chloride.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
3-(2-Bromo-ethyl)-indole (3.00 g, 13.39 mmol) was initially introduced into abs. CHCl3 (25 ml), and 1-methylpiperazine (2.68 g, 26.8 mmol) was added. The mixture was stirred at a bath temperature of 75° C. for 5 h and at RT overnight. The mixture was extracted dilute sulfuric acid (2×30 ml), the acidic aqueous phase was rendered alkaline with 5N NaOH, while cooling with ice, and the mixture was extracted with ether (3×30 ml). The organic phase was dried over Na2SO4 and concentrated i. vac. Yield: 1.45 g (Ind-68, 45%)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][C:24]1=[O:29].N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:23]4[CH2:28][CH2:27][S:26][CH2:25][C:24]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: O=C1CSCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(NCc1cn(-c2ccc(N3CCSCC3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 110 °C
Yield: 25.9 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (230 mg, 0.518 mmol), 3-thiomorpholinone (121 mg, 1.03 mmol), 1,2-trans-diaminocyclohexane (26 μL, 0.21 mmol) and K3PO4 (220 mg, 1.04 mmol) in dioxane (2 mL) was degassed with Ar before being charged with CuI (40 mg, 0.21 mmol). The mixture in a sealed tube was heated at 110° C. overnight. It was then purified by HPLC to give the title compound (58 mg). MS 433.1 and 435.0 (M+H, Cl pattern).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:28]1([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH:41]=[CH:42][CH:43]=[O:44])[CH2:37][CH2:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.C1CCCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[CH:12]=[C:11]2[C:42](=[CH:41][CH:38]2[CH2:37][CH2:36][N:35]([CH2:34][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:40][CH2:39]2)[CH2:43][OH:44])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc2cc(C(=CC3CCN(Cc4ccccc4)CC3)CO)n(S(=O)(=O)c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A solution of N-phenylsulfonyl-6-methyl indole (1.18 g, 4.34 mmol) in 30 ml of dry THF was cooled to -78° C. and treated with 3.5 ml (5.2 mmol) of 1.5 M lithium diisopropylamide in cyclohexane at -78° C. After stirring at -78° C. for 1 hour, a solution of 3-[1-(phenylmethyl)-4-piperidinyl]-2-propenal (1.0 g, 4.36 mmol) in 5 ml of dry THF was added at -78° C. and stirred at that temperature for 40 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 2.23 g of an orange oil. The oil was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 1.0 g of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:42])[NH:18][C:19](=[O:41])[N:20]([CH2:22][CH2:23][O:24][C:25]4[C:26]([C:37]([O:39]C)=[O:38])=[C:27]([CH:34]=[CH:35][CH:36]=4)[O:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:30]([CH2:29][O:28][C:27]1[CH:34]=[CH:35][CH:36]=[C:25]([O:24][CH2:23][CH2:22][N:20]2[CH:21]=[C:16]([CH:6]3[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH:9]=[CH:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=4)[C:17](=[S:42])[NH:18][C:19]2=[O:41])[C:26]=1[C:37]([OH:39])=[O:38])([OH:32])=[O:31]
Reactant: COC(=O)COc1cccc(OCCn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cccc(OCCn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)c1C(=O)O
Temperature: 60 °C

Procedure:
A mixture of the product from step (vi) (0.073 g) and sodium hydroxide (1 g) in methanol (20 ml) and water (20 ml) was heated at 60° C. overnight. The mixture was acidified with 2M HCl and extracted with ethyl acetate. The extract was evaporated and the residue purified by reverse phase chromatography. Yield 0.04 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])[C:10]2([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(O)c2ccc(F)c(Cl)c2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 77 (194.9 mg, 0.560 mmol) and THF (5.6 mL) cooled to 0° C. was added phthalimide (90.70 mg, 0.616 mmol) and Ph3P (191.1 mg, 0.729 mmol). The reaction mixture was then treated with DEAD (331.8 μL, 0.729 mmol) and warmed to RT and stirred for 16 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 Biotage chromatography eluting with hexanes/acetone to afford 238.5 mg (89.2%) of tert-butyl 3-((3-chloro-4-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)-3-fluoropyrrolidine-1-carboxylate (79): LC/MS: [M+1-100] m/z 377.0, 379.0.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH3:9][O:10][C:11]1[C:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[I:28])(=[O:21])=[O:20])=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=1.C(N(CC)CC)C.Cl>ClCCl.N1C=CC=CC=1>[CH2:5]([O:4][C:2]([N:18]([C:12]1[C:11]([O:10][CH3:9])=[N:16][C:15]([CH3:17])=[CH:14][N:13]=1)[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[I:28])(=[O:21])=[O:20])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Reaction time: 2 h

Procedure:
Isobutyl chloroformate (0.58 ml) was added dropwise to a stirred solution of N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (1.65 g), triethylamine (0.57 ml) and pyridine (0.16 ml) in dichloromethane (30 ml) under an atmosphere of argon. The mixture was stirred for 2 hours and then 2M hydrochloric acid (20 ml) was added. The organic layer was separated, washed with water (20 ml) and saturated sodium chloride solution (20 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v), to give N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (2.0 g) as a gum; 1H NMR (d6 -DMSO): 0.7 (d,2H), 1.6-1.8 (m,1H), 2.5 (s,3H), 3.9 (d,2H), 4.0 (s,3H), 7.4 (dt,1H), 7.7 (dt,1H), 8.15 (s,1H), 8.2 (dd,1H), 8.35 (dd,1H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
In a 250 mL oven-dried flask capped with a rubber septum and placed under a nitrogen atmosphere was charged ethyl 2-methyl-2-(4-nitrophenyl)propanoate (5.0 g, 21 mmol), anhydrous tetrahydrofuran (42 mL) and the flask was cooled to 0° C. To this was added via an addition funnel diisobutylaluminum hydride solution (63 mL, 1M in tetrahydrofuran) and the flask was allowed to warm to ambient temperature and stirred for 16 h. The reaction was quenched with Rochelle's salt, stirred for 30 min and filtered over Celite®. The solution was extracted three times with ethyl acetate and the combined organics were washed once each with Rochelle's salt, water, and brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-methyl-2-(4-nitrophenyl)propan-1-ol (4.1 g, 99%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
2-Phenylbenzofuran (7.81 g., 0.040 mol.) was acylated with 7.0 g. (0.041 mol.) of anisoyl chloride according to the procedure described in Example 10 to give 2-phenyl-3-(4'-methoxybenzoyl)benzofuran.
Reaction SMILES: Cl[C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[C-:16]#[N:17].[Na+]>C(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:16]([C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1)#[N:17]
Reactant: O=c1cc(Cl)sn1CCc1ccccc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(=O)n(CCc2ccccc2)s1

Procedure:
A mixture of 4.8 g. (0.02 mole) of 5-chloro-2-phenethyl-4-isothiazolin-3-one in 25 ml of CHCl3, 1.0 g. (0.02 mole) of sodium cyanide in 5 ml of water and 0.015 g of tetrabutyl ammonium bromide was heated under reflux for 1 hour, while stirring. The mixture was then washed with water, dried, and concentrated to give a gummy brown residue, which was recrystallized from 300 ml of ethanol to give 0.15 g. of the named product, mp 228°-230 (softened at 210°).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cnccc1Br
Product: N#Cc1cnccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
4-Bromonicotinonitrile (1.0 g, 5.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.9 g, 7.1 mmol) using the method in Example 51. Purification by chromatography on silica gel eluting with dichloromethane gave 4-(2-fluoro-5-nitrophenyl)nicotinonitrile as a white solid: δH (400 MHz, CDCl3) 7.44-7.52 (2H, m), 8.38-8.47 (2H, m), 8.95 (1H, d, J 5), 9.06 (1H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([OH:20])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C=O)C.O>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:30][C:29]([O:28][CH3:27])=[O:32])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[(trans-4-hydroxycyclohexyl)amino]-7-methylquinazolin-8-ol (20 g, 0.073 mol) in DMF (160 mL) was added K2CO3 (10.6 g, 0.077 mol) in one portion at room temperature. Then a solution of bromoacetic acid methyl ester (11.5 g, 0.075 mol) in DMF (40 mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (150 mL), dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product. The crude product was re-crystallized from EtOH (150 mL) to give the title compound (13 g, 51.4%) as an off-white solid.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:21]([CH3:41])[N:22]=[C:23]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)[C:24](=[O:26])[N:25]=2)[C:8]=1[CH3:42])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:18])(=[O:19])[CH:9]([C:20]2[N:21]([CH3:41])[N:22]=[C:23]([OH:27])[C:24](=[O:26])[N:25]=2)[C:8]=1[CH3:42])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nc(=O)c(O)nn3C)S(=O)(=O)[C@H]12
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
179 mg of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(2-methyl-5-oxo-6-benzhydryloxy-2,5-dihydro-1,2,4-triazin-3-yl)thio-3-cephem 1,1-dioxide, prepared following the experimental procedure described in Example 3, was dissolved in dichloromethane (2 ml) and anisole (0.018 ml) and trifluoroacetic acid (1 ml) were added. After 15 min, TFA was completey removed in vacuo and the residue taken up in dichloromethane (1 ml). Addition of isopropyl ether afforded the title compound (125 mg) as a white powder.