Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([C:13]4([CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)O1.[CH:24]1([NH:27][C:28]2[C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[C:36](I)[C:31]=3[O:30][N:29]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH:24]1([NH:27][C:28]2[C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[C:36]([C:9]4[CH:17]=[C:16]5[C:12]([C:13]6([CH2:19][CH2:20][CH2:21][CH2:22]6)[C:14](=[O:18])[NH:15]5)=[CH:11][CH:10]=4)[C:31]=3[O:30][N:29]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C32CCCC2)OC1(C)C
Reactant: Cc1ccc2c(NC3CC3)noc2c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc2c(NC3CC3)noc2c1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 105 °C
Reaction time: 20 h
Yield: 24 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopentane-1,3′-indolin]-2′-one (preparation 4, 0.060 g, 0.19 mmol), N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (WO2006094187, 0.090 g, 0.29 mmol), 1,4-dioxane (1.2 mL) and a 2M aqueous caesium carbonate solution (0.29 mL, 0.58 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.015 g, 0.02 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100-110° C. After 20 hours, the mixture was cooled and partitioned between water and ethyl acetate. The organic extract was dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (98:2 dichloromethane/methanol) gave the title compound (0.017 g, 28%) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C@@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[F:31][C:32]1[CH:33]=[C:34]([CH2:39][C:40](O)=[O:41])[CH:35]=[C:36]([F:38])[CH:37]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][C:40]([NH:1][C@@H:2]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([NH:5][C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][C@@H:7]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:4])=[O:41])[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a stirred solution of (2S)-2-amino-2-(4-fluorophenyl)-N-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]acetamide (65b) (81 mg, 0.199 mmol) in dichloromethane (2mL) under nitrogen was added 3,5-difluorophenylacetic acid (40 mg, 0.232 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (50 mg, 0.261 mmol). The mixture was stirred 5 h at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, 1N aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane:ethyl acetate (TLC Rf=0.42) to afford the title compound (85 mg, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) δ3.54 (s, 2H), 5.08 (t, 1H, J=7.0 Hz), 5.19 (d, 1H, J=6.5 Hz), 5.79 (d, 1H, J=7.0 Hz), 6.16 (br d, 1H, J=6.5 Hz), 6.62 (br d, 1H, J=7.0 Hz), 6.66-6.86 (m, 3H), 6.87-7.04 (m, 3H), 7.08-7.39 (m, 10H), 7.50 (br s, 1H). MS APCI, m/z=560 (M+1). LC/MS: 2.61 min.
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][C:9]([NH2:11])=[NH:10].C([O:14][C:15](=O)[CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=2)[C:19](=[O:30])[N:18]1[CH2:31][C:32]([F:35])([F:34])[F:33])C>C([O-])(O)=O.[Na+]>[CH3:29][S:26]([C:23]1[CH:24]=[C:25]2[C:20]([C:19](=[O:30])[N:18]([CH2:31][C:32]([F:34])([F:35])[F:33])[C@H:17]2[CH2:16][C:15]([NH:10][C:9]([NH2:11])=[NH:8])=[O:14])=[CH:21][CH:22]=1)(=[O:27])=[O:28]
Reactant: CCOC(=O)CC1c2cc(S(C)(=O)=O)ccc2C(=O)N1CC(F)(F)F
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Product: CS(=O)(=O)c1ccc2c(c1)[C@H](CC(=O)NC(=N)N)N(CC(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
1.6 g of KOtBu were dissolved using 22 ml of DMF(anhydrous). This solution was added to a solution prepared of 1.5 g guanidine-hydrochloride using 15 ml of DMF(anhydrous). The mixture was stirred for 30 minutes at ambient temperature. Then, a solution prepared of 1.1 g [6-methanesulfonyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-1H-isoindol-1-yl]-acetic acid ethyl ester using 15 ml DMF(anhydrous) was added. The reaction mixture was stirred at ambient temperature for 22 h. Afterwards, the mixture was taken up in 500 ml of semisaturated aqueous NaHCO3 solution and extracted twice using 200 ml of ethyl acetate each time. The EA layer was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using EA/MeOH 3:1 yielded 0.28 g of an amorphous solid (Rf(EA/MeOH 3:1)=0.15; MS (ES+): 393 (M+1)+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)=[CH:13][C:12]=1[N+:28]([O-])=O)C(OCC)=O)C.Cl>CCO>[NH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([C:14]1[CH:13]=[C:12]2[C:11]([CH2:5][C:4](=[O:3])[NH:28]2)=[CH:16][CH:15]=1)=[O:27]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
[2-Nitro-4-(3-nitro-benzoyl)-phenyl]-malonic acid diethyl ester (2.00 g, 4.65 mmol) was dissolved in EtOH (11.5 mL) after which Sn powder (4.42 g, 37.2 mmol) was added followed by dropwise addition of concentrated HCl(aq) (13 mL). The mixture was allowed to reflux for 3 hours, filtered while hot and then allowed to cool to room temperature. The mixture was diluted with CHCl3 (200 mL) and then extracted once with H2O (200 mL). The aqueous layer was then neutralized with NaHCO3 (pH=7) and then the aqueous layer was extracted with a 95% EtOAc/5% i-prOH solution (3×200 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solution was then concentrated in vacuo affording the 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one in 44% yield (0.516 g, 2.05 mmol).
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[S:7])[CH:2]=1.[CH:13]1([CH2:19]N)[CH2:18][CH2:17][CH2:16]CC1>C(Cl)(Cl)Cl>[CH:10]1([CH2:9][NH:8][C:6]([NH:3][CH2:2][CH:1]2[CH2:16][CH2:17][CH2:18][CH2:13][CH2:19]2)=[S:7])[CH2:19][CH2:13][CH2:18][CH2:17][CH2:16]1
Reactant: NCC1CCCCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: S=C(NCC1CCCCC1)NCC1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 720.9 %

Procedure:
A solution of N,N'-thiocarbonyldiimidazole (Aldrich, 90%, 3.64 g, 18.4 mmol) in chloroform (20 mL) was added dropwise to a solution of cyclohexanemethylamine (Aldrich, 98%, 5.00 g, 4.33 mmol) in chloroform (10 mL). The reaction mixture was then stirred at 50° C. for 2 h, cooled to ambient temperature, and washed with hydrochloric acid (0.1N, 3×50 mL) and water (50 mL). The organic layer was dried (magnesium sulfate), and concentrated under vacuum to a yellow solid, which was recrystallized from ethanol. The mother liquor from this crystallization was concentrated, and the resulting solid was recrystallized from toluene. The two crops of crystals were combined and dried under vacuum to provide 1,3-bis(cyclohexylmethyl)thiourea as a pale yellow powder (4.19 g, 85%), m.p. 124°-125° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]2[C@@H:8]([C@H:9]2[C:11]([O:13]C(C)(C)C)=[O:12])[C@:7]([NH:25]C(OC(C)(C)C)=O)([C:18]([O:20]C(C)(C)C)=[O:19])[C@@H:6]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)(=[O:3])[CH3:2].C(O)(=O)C>O>[C:1]([NH:4][C@H:5]1[C@@H:10]2[C@@H:8]([C@H:9]2[C:11]([OH:13])=[O:12])[C@:7]([NH2:25])([C:18]([OH:20])=[O:19])[C@@H:6]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)O)[C@H]2[C@](N)(C(=O)O)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
Di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-(acetylamino)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.40 g, 3.81 mmol) is added to acetic acid (7.99 g, 7.62 mL, 133.05 mmol,) and water (3.81 mL, 3.81 g, 211.60 mmol) and heated in a microwave to 140° C. After 15 minutes, cool to room temperature, dilute with water and filter to collect the solids. Sequentially wash the solids with water (2×50 mL) and diethyl ether (2×50 mL), and then dry in a vacuum oven giving the title compound (1.23 g, 2.95 mmol, 77%): MS (m/z): 417/419 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2[CH2:14][S:15][CH2:16][C:3]1=2.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1c2ccccc2NC(=O)c2cscc21

Procedure:
To a suspension of 3.8 g. of 1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 15 ml. of dry pyridine is added, in portions, a total of 2.18 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid is collected and recrystallized from methanol, to give a tan solid, m.p. 224°-225° C. (dec.).
Reaction SMILES: S1C=CC2C(=O)CCCCC1=2.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH:22]C=O)[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2.C(N)=O.[ClH:28]>>[ClH:28].[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2
Reactant: O=CNC1CCCCc2sccc21
Agent: Cl
Agent: O=C1CCCCc2sccc21
Solvent: NC=O
Product: NC1CCCCc2sccc21

Procedure:
5,6,7,8-Tetrahydro-4H-cyclohepta[b]thiophen-4-one is converted to N-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)formamide, m.p. 164°-166° C., by the method of Kloetzel et al., Journal of Organic Chemistry 18, 1511 (1953). Hydrolysis of the formamide is accomplished by refluxing for one hour in 1N hydrochloric acid and evaporating to dryness to afford 5,6,7,8-tetrahydro-4H-cyclohepta[ b]thiophen-4-amine hydrochloride, m.p. 233°-236° C. dec. The amine hydrochloride is then allowed to react with methyl isocyanate in dry tetrahydrofuran as solvent in the presence of a stoichiometric equivalent of triethylamine to afford 1-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea, m.p. 220°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)=O>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:14]=[C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13][N:12]3[CH:16]=2)=[CH:20][C:21]=1[N+:26]([O-:28])=[O:27]
Reactant: Nc1ccc(-c2ccccc2F)nn1
Reactant: O=C(CBr)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3nc(-c4ccccc4F)ccc3n2)ccc1Br
Yield: 37.9 %

Procedure:
A stirred solution of 6-(2-fluorophenyl)pyridazin-3-amine (2.22 g, 11.7 mmol) and 2-bromo-1-(4-bromo-3-nitrophenyl)ethanone (3.78 g, 11.7 mmol) in acetonitrile (100 mL) is heated at 80° C. for 12 hours. The mixture is concentrated to dryness and then purified via chromatography using CH2Cl2 to afford the title compound (1.83 g, 37%) as a yellow solid: Rf 0.46 (CH2Cl2); LCMS (m/z)=413.3, 415.3 [M+H]+, tR=3.19 min.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[CH2:12]([S:28]([O-:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+]>C(O)C>[CH2:12]([S:28]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11])(=[O:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C1Cc2ccccc2C1Br
Reactant: CCCCCCCCCCCCCCCCS(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCS(=O)(=O)C1C(=O)Cc2ccccc21
Reaction time: 0.5 h

Procedure:
16.6 g of 1-bromo-2-indanone are added with stirring to a hot solution of 26.0 g of potassium hexadecylsulphinate in 100 ml of ethanol. The mixture is stirred for a further 30 minutes without further heating and then precipitated with 100 ml of water. The resulting precipitate is recrystallised from 200 ml of methanol.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)Nc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)Nc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-phenylaminocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.O.C(OO)(=[O:24])C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: CC(=O)OO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1ncc(O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
To a solution of 3-chloro-2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 5, 297.6 g, 897.9 mmol) in acetic acid:water (2.2 L:1.0 L) at 0° C. was added peracetic acid (191 mL; 1.077 mol) and the reaction was allowed to warm gradually to room temperature. After 4 hours the reaction was complete and was quenched with 0.5 M aqueous solution of sodium thiosulfate (225 mL). The resulting dark solution was evaporated to dryness and the residue was passed through a plug of silica eluting with heptanes:ethyl acetate 1:0 to 10:1 to afford a pale yellow viscous oil which contained 8% of the 4-isomer. Further silica gel column chromatography was performed eluting with EtOAc:heptane 1:4 to afford a pale yellow solid which was triturated with heptanes and dried under suction to afford the title compound as a white solid (110 g, 65% over two steps).
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:24])=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH2:1][C@@H:3]3[CH2:4][O:5]3)=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OC[C@@H]1CO1
Temperature: 25 °C

Procedure:
(R)-(−)Epichlorhydrin (1.93 g; 0.021 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (1.92 g; 0.007 mol) and potassium carbonate (1.44 g; 0.011 mol) in acetonitrile (5 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzene sulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone as a white solid (1.456 g; 63%). A sample was recrystallized from diethyl ether-hexane: M. p. 115.1-116.8° C. Similarly, but replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin, 1-(5-benzene sulfonyl-2-(R)-oxiranylmethoxy-phenyl)-ethanone was prepared. M. p. 111.9-113.5° C. Similarly, but replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone, the above procedure gave 1-[5-(3-fluoro-benzenesulfonyl)-2-(S)-oxiranylmethoxy-phenyl]-ethanone: M. p. 112.7-114.9° C. Replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-Fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone and replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin gave 1-[5-(3-Fluoro-benzenesulfonyl)-2-(R)-oxiranylmethoxy-phenyl]-ethanone. M. p. 118.3-120.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:12])[NH:7]2.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:12])[N:7]2[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(OB(O)O)cc1
Reactant: CCOC(=O)c1nc2c(Cl)cccc2[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2c(Cl)cccc2n(-c2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.7 %

Procedure:
To a slurry containing 5.7 g (22.6 mmol) of ethyl 5-chloro-2-oxo-1,2-dihydroquinoxaline-3-carboxylate, 6.9 g (45.4 mmol) of 4-methoxyphenylboric acid, 8.2 g (45.1 mmol) of anhydrous copper (II) acetate and chloroform (200 ml), 3.6 g (45.5 mmol) of pyridine and 4.6 g (45.5 mmol) of triethylamine were added dropwise, and the mixture was stirred for 72 hours at room temperature. The reaction mixture was washed with 10% hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was isolated by silica gel chromatography (developing solvent: ethyl acetate:hexane=2:3), and the isolated solid was washed with diisopropyl ether, to obtain 6.3 g (yield: 78%) of ethyl 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a pale yellow powder.
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH3:33])/[C:28]([OH:30])=O)[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[C:48]1([CH:54]([O:61][C:62]([C:64]2[N:69]3[C:70](=[O:73])[C@@H:71]([NH2:72])[C@H:68]3[S:67][CH2:66][C:65]=2[S:74][CH2:75][C:76]2[C:77](=[O:81])[O:78][CH2:79][CH:80]=2)=[O:63])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C)C=O.C(OCC)(=O)C.O.N1C=CC=CC=1>[O:81]=[C:77]1[C:76]([CH2:75][S:74][C:65]2[CH2:66][S:67][C@@H:68]3[C@H:71]([NH:72][C:28](=[O:30])/[C:27](/[C:25]4[N:26]=[C:22]([NH:21][C:2]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[S:23][CH:24]=4)=[N:31]\[O:32][CH3:33])[C:70](=[O:73])[N:69]3[C:64]=2[C:62]([O:61][CH:54]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])=[CH:80][CH2:79][O:78]1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CCOC3=O)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CCOC3=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
A stirred solution of 2-(2-Tritylaminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid hydrochloride (287 mg) and diisopropylethylamine (0.208 ml) in dry dimethylformamide (5 ml) was cooled to -50° C. under an inert atmosphere. Treatment with methanesulfonyl chloride (0.047 ml) was followed by stirring at -50° C. for 45 min. Pyridine (0.048 ml) and a solution of diphenylmethyl-7β-amino-3-(2,5-dihydro-2-oxofuran-3-ylmethylthio)ceph-3-em-4-carboxylate (298 mg) in dimethylformamide (3 ml) were then added and the reaction allowed to warm to 0° C. The reaction was stirred at 0° C. for 90 min. before pouring into ethyl acetate/water. The ethyl acetate was separated and washed three times with water, saturated sodium bicarbonate solution, and brine before drying over magnesium sulphate. Evaporation of solvent and chromatography of the residue on silica gel(Keiselgel 7:3 ethyl acetate:hexane) gave the title compound (364 mg). υmax (CH2Cl2) 3400, 1780, and 1760cm-1 ; δH (CDCl3) 3.50 (1H, d, J 17.4Hz), 3.53 (2H, s), 3.67 (1H, d, J 17.4Hz), 4.08 (3H, s), 4.72 (2H, s), 5.08 (1H, d, J 4.7Hz), 5.88 (1H, dd, J 8.6Hz, 4.7Hz), 6.76 (1H, s), 6.83 (1H, d, J 8.8Hz), 6.90 (1H, s), 6.95 (1H, s), 7.16-7.46 (26H, m). [mass spectrum: +ve ion (3NOBA, Na+) MNa+ 942].
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[C:13](=[O:14])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 4-[2-(2-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.57 g) in methanol (3 mL) and tetrahydrofuran (8 mL) was treated with 1N sodium hydroxide (1.7 mL) and a white precipitate formed after 1 minutes. After 5 minutes, the reaction mixture was concentrated, the residue was acidified with excess hydrochloric acid and partitioned between dichloromethane (100 mL) and water (10 mL). The organic layer was dried (MgSO4) and concentrated. The resulting residue was crystallized from ethyl acetate-hexane-tetrahydrofuran to give 0.343 of 4-[2-(2-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 167°-170° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)[CH:3]=1>C(O)C.O1CCCC1.[Pd]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)=[CH:9][C:10]=1[NH2:16]
Reactant: COc1ccc(-c2cc(C)ccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C)ccn2)cc1N
Yield: 99.9 %

Procedure:
A suspension of 4-(4-methylpyridin-2-yl)-2-nitro anisole (347 mg) in ethanol (3.5 ml) and tetrahydrofuran (3.5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 120 mg) under a hydrogen atmosphere for 1 hour. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2-methoxy-5-(4-methylpyridin-2-yl)aniline (304 mg).