Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[C:11]([CH3:13])[CH3:12].C[S-].[Na+].Cl>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[C:11]([CH3:12])[CH3:13]
Reactant: COc1ccccc1C(O)(C=C(C)C)c1ccccn1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CC(O)(c1ccccn1)c1ccccc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.1 %

Procedure:
36.6 g of 1-(2-methoxyphenyl)-3-methyl-1-(2-pyridyl)-2-buten-1-ol were heated at 70° C. in 200 ml of dimethylformamide with 28.6 g of sodium methanethiolate. After 10 hours the mixture was allowed to cool to room temperature, poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 28.5 g of 1-(2-hydroxyphenyl)-3-methyl-1-(2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:9]=[N:8][NH:7][C:6](=[O:10])[C:5]=2[N:11]=1.N([O-])=O.[Na+].O.[ClH:17]>>[Cl:17][C:2]1[S:3][C:4]2[CH:9]=[N:8][NH:7][C:6](=[O:10])[C:5]=2[N:11]=1
Reactant: Nc1nc2c(=O)[nH]ncc2s1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2sc(Cl)nc12
Temperature: 25 °C

Procedure:
The compound (688 mg) obtained in Step 4 was suspended in 6N aqueous hydrochloric acid solution (10 ml), and sodium nitrite (1.41 g) was added in several portions with stirring at room temperature, and the mixture was further stirred at room temperature for 1 hr. Water was added, with stirring at room temperature, and the solid was collected by filtration, washed with water, and dried to give the title compound (571 mg).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](OCC)=[O:27].[H-].[Na+].[K+].[Br-]>C1COCC1>[O:27]=[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1)[CH2:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccccn1
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Cc1nc2ccccc2c(=O)n1-c1ccc(Br)cc1)c1ccccn1

Procedure:
Treatment of 3.15 g (10 mmol) of 2-methyl-3-p-bromophenyl-4(3H)-quinazolinone and 1.81 g (12 mmol) of ethyl picolinate with 1.92 g (40 mmol) of sodium hydride (50%) in 160 ml of THF for a reaction period of 2.5 hours resulted in a yellow-brown reaction slurry which was processed using Method B. The crude yellow product was recrystallized from dimethyl sulfoxide-acetone to yield 4.06 g (96%) of yellow microcrystals, mp 312°-313° (dec): 1H NMR (CDCl3 with 3 drops CF3CO2H) δ 8.96-7.11 (m, 12H, aromatic) and 5.50 ppm (s, 1H, vinyl); ir (KBr) 1685 cm-1C=O).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:16])[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C.C=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[C:6]1[I:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1cc(-c2ccccc2)nc1I
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c(I)nc(-c2ccccc2)c1CO
Temperature: 115 °C
Reaction time: 10 h

Procedure:
To a 60 ml sealed flask is added 1-butyl-2-iodo-4-phenylimidazole (3.26 g, 10 mmol) followed by the addition of 5.5 ml of acetic acid, 16 ml of 37% formaldehyde and 7 g of sodium acetate. The resulting mixture is stirred at 115° C. for 10 h, cooled to room temperature and diluted 50 ml of water. The reaction mixture is adjusted to pH=9, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 2:1) affords 3.24 of 1-butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.59 (2H, dd, J=1.6, 6.8 Hz), 7.39 (2H, m), 7.31 (1H, m), 4.78 (2H, s), 4.00 (2H, t, J=8.0 Hz), 1.78 (2H, m), 1.46 (2H, m), 1.00 (3H, t, J=7.2 Hz); MS (+VE) m/z 357(M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH3:24])[CH:17]=3)=[CH:12][CH:11]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]3[N:7]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]3)=[CH:11][CH:12]=2)[CH:21]=[CH:20][CH:19]=1)[CH3:24]
Reactant: CCOc1cccc(-c2ccc(C3CC(C(=O)OC)=NN3c3ccccc3F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cccc(-c2ccc(C3CC(C(=O)O)=NN3c3ccccc3F)cc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
5-(3′-Ethoxy-biphenyl-4-yl)-1-(2-fluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (250.0 mg, 0.60 mmol) prepared in Step 1 and a solution of potassium hydroxide (67.0 mg, 1.19 mmol) in distilled water (4.0 mL) were added to methanol (4.0 mL). The reaction mixture was stirred at 70° C. for 2 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 200.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])N)[N:3]=1.[CH3:11][CH:12]1[CH2:17][C:16](=O)[CH2:15][CH2:14][N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CCO.O.C(O)(C)C>[Br:1][C:2]1[N:3]=[C:4]2[N:8]([CH3:10])[C:16]3[CH2:17][CH:12]([CH3:11])[N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:15]=3[C:5]2=[CH:6][CH:7]=1
Reactant: CN(N)c1cccc(Br)n1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
2-Bromo-6-(1-methylhydrazinyl)pyridine (1.60 g, 7.98 mmol) and tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (enantiomer B) (1.70 g, 7.98 mmol) were heated in EtOH (10 mL) at reflux for 16 h and then the mixture was concentrated to provide a white foam. This foam was combined with para-toluenesulphonic acid (3.18 g, 16.7 mmol) and heated to 160° C. for 10 minutes. The mixture was allowed to cool and isopropanol (20 mL), water (8 mL), potassium carbonate (5.00 g, 36.2 mmol), and di-tert-butyl dicarbonate (2.55 g, 11.7 mmol) were added. After stirring for 16 h, the mixture was partitioned between methylene chloride and water, and the organic layer was removed, dried, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1:4) to provide the title compound (360 mg, 11%) as a white solid: ESI MS m/z 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH3:3].[CH3:18][O:19][C:20](=[O:28])[C@H:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH2:22]>>[CH3:17][C:2]([CH3:1])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:22][C@H:21]([C:20]([O:19][CH3:18])=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:16])[N:12]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Product: COC(=O)C[C@H](NC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)OC

Procedure:
The subtitle compound was prepared from 2-[1,1-dimethylethoxycarbonylamino]thiazol-4-ylacetic acid (Chem. Pharm. Bull. 1993, 41, 758) (1.0 g) and L-aspartic acid dimethyl ester (1.15 g) according to the method of example 10 step (i). Yield 1.36 g. Used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([NH:37]CCO)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:19]1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[NH2:37][CH2:18][CH2:19][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14]
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 182.5 %

Procedure:
Compound 2 (1.26 g, 5.08 mmol), 2-(tritylamino)ethanol (2.00 g, 6.60 mmol) and triphenylphosphine (1.80 g, 6.86 mmol) were dissolved in 51 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (1.3 mL, 6.60 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford 3 (75.0%, 2.71 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[C:5](OC)=[O:6].C([Si](C)(C)Cl)(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH2:5][OH:6]
Reactant: C=CCc1cc(C(=O)OC)cc(Cl)c1O
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: C=CCc1cc(CO)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a stirred solution of 10.00 g (44.1 mmol) of the product of Step A in 100 mL methylene chloride was added 6.468 g (52,9 mmol) of 4-dimethyl-aminopyridine, 7.980 g (52.9 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between methylene chloride and water, the organic layer was separated washed with 1.0N HCl, 5% NaHCO3, dried (MgSO4), filtered and evaporated. The residue was dissolved in 35 mL of anhydous THF, magnetically stirred at 0° C., and then treated with 100 mL of a 1.0M solution of lithium triethylborohydride under a nitrogen atmosphere. The reaction was allowed to warm to room temperature, and treated with several mL water until hydrogen evolution ceased. The reaction mixture was evaporated in vacuo, redissolved in methylene chloride, dried (MgSO4), filtered and reevaporated in vacuo. The residue was finally redisolved in 30 mL THF and treated with 45 mL of a 1.0M solution of tetrabutylammonium fluoride in THF while stirring for 12 hours at room temperature. The reaction mixture was then evaporated to an oil and purified on a silica gel flash chromatography column eluted with methylene chloride to afford 4.992 g (57%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[C:14]([NH:13][C@H:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[CH3:12])=[O:15])[CH2:21][CH2:22]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(C(=O)OC(C)(C)C)CC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2NCC3)cc1
Reaction time: 1 h

Procedure:
tert-butyl 7-[({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}amino)carbonyl]indoline-1-carboxylate (510 mg, 1.2 mmol) was dissolved in CH2Cl2 (5 ml) and TFA (5 ml) was added, the solution was stirred for 1 hour. The solvent was removed. NaHCO3 (sat.) was added and extracted 3× with EtOAc. The combined organic layers were washed with water and brine, then dried over MgSO4. 1H NMR (500 MHz, DMSO-d6): δ 8.50 (d, 1H), 7.90 (d, 2H), 7.55 (m, 3H), 7.10 (d, 1H), 6.50 (m, 2H), 5.15 (m, 1H), 3.85 (s, 3H), 3.50 (m, 2H), 2.90 (m, 2H), 1.40 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.Cl.Cl.[O:19]([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][N:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:31]=3)[CH2:33][CH2:34]2)[N:3]=1
Reactant: c1ccc(Oc2nccc(N3CCNCC3)n2)cc1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4ccnc(Oc5ccccc5)n4)CC3)nc(N)c2cc1OC
Yield: 9.2 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.8 g, 3.3 mmole) and 2-phenoxy-4-piperazinopyrimidine dihydrochloride (1.2 g, 3.6 mmole) were heated under reflux in n-butanol (50 ml) overnight. The mixture was then evaporated in vacuo and the residue partitioned between chloroform/methanol/saturated aqueous sodium carbonate solution (300 ml:100 ml:50 ml). The chloroform/methanol layer was separated, dried (Na2SO4), evaporated in vacuo then the residue (1 g) chromatographed on silica gel (85 g). The column was eluted with chloroform, then chloroform containing 2.5% methanol by volume, appropriate fractions combined, evaporated in vacuo and the residue recrystallized from ethanol to give the title compound, (0.14 g) m.p. 253°-254° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].OO>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
Into a 100-mL three neck round-bottom flask, was placed a solution of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (compound 244.1, 3.47 g, 12.2 mmol) in tetrahydrofuran (35 mL). Sodium hydroxide (980 mg, 24.5 mmol) was added and then the mixture was cooled to 0° C. Hydrogen peroxide (2.51 mL, 24.4 mmol) was carefully added drop-wise and the resulting mixture was stirred for 2 h at room temperature. The reaction was carefully quenched with aqueous Na2S2O3(sat.) (20 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with brine (2×150 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish the title compound as a white solid (1.64 g, 77%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[C:4]([F:17])[CH:3]=1.[C:18]([C:20]1[N:24]([CH3:25])[C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([C:20]1[N:24]([CH3:25])[C:23]([C:2]2[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH2:13][CH:14]3[CH2:16][CH2:15]3)(=[O:11])=[O:10])=[C:4]([F:17])[CH:3]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NCC1CC1)c1cc(F)c(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1cc(F)c(S(=O)(=O)NCC2CC2)cc1F
Reaction time: 16 h
Yield: 26.8 %

Procedure:
According to general procedure B, 4-bromo-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide (150 mg, 0.5 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.3 mL) was added. Tri-t-butylphosphine (75 μL, 0.026 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide (47 mg). HPLC purity 98.2% at 210-370 nm, 9.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C16H15F2N3O2S−H+, 350.07803; found (ESI-FTMS, [M−H]1−), 350.07826
Reaction SMILES: Br[C@@H:2]1[C@@H:7]([OH:8])[CH2:6][C@H:5]2[C@H:9]3[C@H:19]([C@H:20]([N:22]([CH3:24])[CH3:23])[CH2:21][C@:3]12[CH3:4])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:28])[C@@H:15]([O:25][CH2:26][CH3:27])[CH2:16]1)[CH2:11][CH2:10]3.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:24][N:22]([C@@H:20]1[CH2:21][C@@:3]2([CH3:4])[C@@H:5]([CH2:6][C@@H:7]3[O:8][C@@H:2]32)[C@H:9]2[C@H:19]1[C@:17]1([CH3:18])[C@@H:12]([CH2:11][CH2:10]2)[CH2:13][C@H:14]([OH:28])[C@@H:15]([O:25][CH2:26][CH3:27])[CH2:16]1)[CH3:23]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)[C@H](Br)[C@@H](O)C[C@@H]32)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@@]2(C)[C@H]3C[C@@H]3O[C@@H]32)C[C@@H]1O
Yield: 45.8 %

Procedure:
A solution of 17α-bromo-11α-N,N-dimethylamino-2β-ethoxy-5α-androstane-3α,16β-diol (212 mg) in methanol (33 ml) containing water (1.2 ml) was treated with a 40% solution of potassium carbonate (0.66 ml) and the mixture was refluxed. After 1 hour most of the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The washed and dried (Na2SO4) organic layer was evaporated and the residue was purified by preparative thin layer chromatography over silica (ethyl acetate--petroleum ether 1:1) and crystallization from aqueous methanol to give the title compound (80 mg) m.p. 149°-151°, [α]D +6.7°.
Reaction SMILES: [H-].[Na+].C1COCC1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33]Cl)=[CH:27][CH:26]=3)=[O:24])=[C:21]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:20][C:19]=2[CH:41]=1>O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:27][CH:26]=3)=[O:24])=[C:21]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:20][C:19]=2[CH:41]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCCl)cc3)c(C3CCCCC3)sc2c1
Reactant: C1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)cc3)c(C3CCCCC3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
49 mg of sodium hydride is added to a THF solution of 0.2 mL of pyrrolidine, and this mixture is agitated for one hour at room temperature. To this is added 54 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2 -chloroethoxy)phenyl]methanone, and this mixture is heated and refluxed for ten hours. Water is added and extracted with ethyl acetate, and this extract is refined by TLC (developing solvent was chloroform:methanol=19:1), which gives 12 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]methanone.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]2([CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=3)[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[O:18]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]2([CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([O:30][CH2:3][CH:2]=[CH2:1])=[C:25]([F:31])[CH:24]=3)[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[O:18]2)[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1c(F)cc(C2=CC3(CCN(Cc4ccccc4)CC3)Oc3ccccc32)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1c(F)cc(C2=CC3(CCN(Cc4ccccc4)CC3)Oc3ccccc32)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Allyl bromide (1.1 mole equiv.) was added dropwise to a mixture of N-benzyl-4-(3,5-difluoro-4-hydroxyphenyl)spiro[2H-1-benzopyran-2,4′-piperidine] (750 mg, 1.79 mmol; prepared according to the procedures outlined in Examples 1 and 42), cesium carbonate (1.1 mole equiv.) and anhydrous N,N-dimethylformamide (15 cm3). After stirring for 2 h at room temperature no starting material remained. The reaction mixture was diluted with ethyl acetate (50 cm3) and treated with water (100 cm3) the aqueous layer was separated and re-extracted with ethyl acetate (2×25 cm3). The combined organic extracts were washed with water (4×100 cm3) before being dried (Na2SO4) and the volatile materials were removed in vacuo to afford the desired material in high purity (60%).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[O:8]([CH2:15][C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[CH:22]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C:23](=[CH2:27])[CH2:24][S:25](=O)[C@H:20]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(=O)C.C(OCC)(=O)C>[O:8]([CH2:15][C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[CH:22]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C:23]([CH2:27][O:4][C:1](=[O:3])[CH3:2])=[CH:24][S:25][C@H:20]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 5 ml. of fresh acetic anhydride were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting mixture was added one drop of acetyl chloride. The mixture was refluxed at 130°--140° C. for 2.75 hours and then was cooled. Ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate and then with water. The resulting organic layer was separated and evaporated to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate as a foam.