Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-]([S+](C)C)(F)(F)F.C[O:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[CH:25]=[CH:26][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:24][CH:23]=1.[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[CH:25]=[CH:26][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1
Agent: C[S+](C)[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reaction time: 5 h

Procedure:
Boron fluoride-dimethyl sulfide complex [CAS: 353-43-5] (15.64 ml, 148.67 mmol) was added dropwise to a stirred solution of methyl 4-(4′-methoxyphenoxy)benzoate [CAS: 38342-84-6] (1.28 g, 4.9 mmol) in DCM (100 ml) cooled in an ice-water bath under nitrogen atmosphere. The resulting mixture was stirred for 5 hours. The reaction mixture was washed with water and then extracted with DCM. The organic layer was separated and dried (Na2SO4) and the solvent was evaporated till dryness. The residue was purified by column chromatography (silica gel; 0-10% EtOAc/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D24 (0.89 g, 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=C(O)C=CC=1.[C:24]1([CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[C:32]2=[O:41])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([C:33]2([OH:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]([CH:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]2=[O:41])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 4-(benzyloxy)phenol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (76%): 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 7.46-7.40 (m, 1H), 7.38-7.21 (m, 15H), 7.13-7.06 (m, 2H), 6.97 (d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.86 (dd, J=8.8, 3.0 Hz, 1H), 6.52-6.45 (m, 2H), 4.85 (s, 2H), 4.53 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].Cl.Cl[C:20](Cl)(Cl)[CH:21]([OH:23])O.Cl.[NH2:27][OH:28]>O>[OH:28][N:27]=[CH:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:23]
Reactant: NO
Reactant: CC(C)c1ccccc1N
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccccc1NC(=O)C=NO
Temperature: 85 °C
Yield: 60.4 %

Procedure:
A mixture of 2-isopropylaniline (4.7 g, 35 mmol), Na2SO4 (30.0 g), concentrated hydrochloride (3 mL), chloral hydrate (6.5 g), hydroxylamine hydrochloride (8.00 g) in water (150 mL) was heated at 85° C. for 40 minutes. After cooling to room temperature, it was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 4.357 g (54%) of the title compound as solid.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:32])[C@@H:24]([NH:25][C:26](=[S:31])[CH2:27][CH:28]([F:30])[F:29])[C@H:21]3[S:20][CH2:19][C:18]=2[S:33][CH2:34][S:35][C:36]2[N:37]=[N:38][NH:39][CH:40]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[F:29][CH:28]([CH2:27][C:26]([NH:25][C@@H:24]1[C:23](=[O:32])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:33][CH2:34][S:35][C:36]3[N:37]=[N:38][NH:39][CH:40]=3)[CH2:19][S:20][C@H:21]12)=[S:31])[F:30]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2[C@H](NC(=S)CC(F)F)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(O)C1=C(SCSc2c[nH]nn2)CS[C@@H]2[C@H](NC(=S)CC(F)F)C(=O)N12
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 7β-difluoromethylthioacetamido-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (451 mg: 0.710 mMol.) in a mixture of dichloromethane (3 ml) and anisole (1.2 ml) under ice cooling is added trifluoroacetic acid (3 ml), and the mixture is stirred under ice cooling for 1 hour. The reaction mixture is concentrated to dryness and the residue is pulverized with ether, washed, and dried to give 7β-difluoromethylthioacetamido-3-(1,2,3- triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (257 mg) white powder. Yield: 77%.
Reaction SMILES: COC([C:5]1([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:9][CH:8]=[C:7]([OH:10])[C:6]1=[O:11])=O.O1CCOCC1.Cl>O>[OH:11][C:6]1[C:7](=[O:10])[CH2:8][CH2:9][C:5]=1[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: COC(=O)C1(Cc2ccc3ccccc3c2)CC=C(O)C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC(Cc2ccc3ccccc3c2)=C1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
Step b) A mixture of 3-hydroxy-1-naphthalen-2-ylmethyl-2-oxo-cyclopent-3-enecarboxylic acid methyl ester (3.0 g, 10.71 mmol), dioxane (50 ml), and HCl (10N, 50 ml) was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature, poured into H2O and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether gave a brown solid (1.75 g, 69%): m.p. 120°-122° C.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN1CCOCC1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCCC1
Yield: 75 %

Procedure:
4.0 g (17.3 mmol) N-BOC-L-hydroxy-proline in 150 ml CH2Cl2 were treated with 1.71 ml (17.3 mmol) piperidine, 1.9 ml (17.2 mmol) NMM and 6.16 g (20.7 mmol) TPTU at RT over night. The mixture was washed with 1M KHSO4, water, 5% aq. NaHCO3 solution, water and brine, dried over Na2SO4 and was concentrated. Column chromatography yielded 3.87 g (75%) (2S,4R)-4-Hydroxy-2-(piperidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid, MS: 298 (M).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].CON(C)[C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[O:14]>C(OCC)C>[CH3:8][CH:7]([CH3:9])[CH2:6][CH2:5][C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[O:14]
Reactant: CC(C)CCBr
Reactant: CON(C)C(=O)c1ccsc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
Magnesium powder (1.49 g, 61.3 mmol) was added to dry diethyl ether (100 ml) under nitrogen atmosphere. One iodine crystal (catalytic) was added, followed by 1-bromo-3-methylbutane (6.3 ml, 52.6 mmol). The reaction was initiated by sonication at 30° C. and was allowed to spontaneously reflux. Once the exothermic reaction had subsided, the mixture was added by cannulation to a solution of thiophene-3-carboxylic acid methoxy-methyl-amide (7.50 g, 43.8 mmol) in dry diethyl ether (10 ml). Once addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with saturated ammonium chloride (2×150 ml), dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by silica gel chromatography to yield the title compound as a colourless oil (1.55 g, 19%). δH (d6 DMSO): 0.88 (6H, d), 1.49 (2H, q), 1.56 (1H, m), 2.90 (2H, t), 7.49 (1H, d), 7.59 (1H, d), 8.50 (1H, s).
Reaction SMILES: Cl.Cl.Cl.[C:4]1([CH:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])[N:28]=4)[N:25]=3)[CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:37]1([CH:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])[N:28]=4)[N:25]=3)[CH2:15][CH2:16]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 51.4 %

Procedure:
1.08 g of ethyl 2-[6-[3-[4-(diphenylmethyl)-1-piperazinyl]propyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate trihydrochloride was dissolved in 8 ml of ethanol; 8.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 4.5 by the addition of 1 N hydrochloric acid. The mixture was crystallized by the addition of acetone, washed with water-acetone (2:1) and dried to yield 435 mg of the title compound.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH2:36]OS(C)(=O)=O)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C)C=O>[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])[C@H:20]([CH2:36][S:3][C:4]2[N:8]([CH3:9])[N:7]=[N:6][N:5]=2)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnnc1SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of sodium hydride (62.8% suspension in oil) (0.38 g) in N,N-dimethylformamide (12 ml) was added 5-mercapto-1-methyl-1H-tetrazole (1.14 g) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. This solution was added dropwise to a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.0 g) in N,N-dimethylformamide (60 ml) under ice-cooling. The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into ice-water (200 ml) and extracted 3 times with ethyl acetate (100 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (40:1, V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(1-methyl-1H-tetrazol- 5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.68 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[NH:12][C:13]([CH:14]=1)=[C:9]23)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([NH:39][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[NH:12][C:13]([CH:14]=1)=[C:9]23)=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: Cn1cc(-c2[nH]c3cc(NC(=O)CCl)cc4c3c2C=NNC4=O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2[nH]c3cc(NC(=O)CNCc4ccccc4)cc4c3c2C=NNC4=O)cn1
Temperature: 50 °C
Yield: 12.5 %

Procedure:
To a solution of 2-Chloro-N-[2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamide 270(a) (100 mg, 0.28 mmol) in DMF (1.5 mL) was added Cs2CO3 (˜5 eq.) followed by benzyl amine (33 mg, 0.3 mmol.). The resulting mixture was heated at 50° C. overnight. Excess Cs2CO3 was filtered and the clear dark solution was purified by reverse phase HPLC to afford 15 mg of desired product as yellow solids.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].OC1C2N=N[NH:22]C=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:42]1[CH:47]=[CH:46][C:45]([C:48]2[S:52]SC(=S)C=2)=[CH:44][CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:2]([O:1][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[S:52])[NH2:22])=[CH:44][CH:43]=2)=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(C)C(=O)Oc2ccc(C(N)=S)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To the solution of 1 (ibuprofen, 3.87 g, 18.8 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (2.8 g, 20.7 mmol) and DCC (4.27 g, 20.7 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (2, 3.9 g, 28 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 3 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(4-isobutylphenyl)propanoate (3) was obtained (2.48 g, 40% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:6]([O:27][CH3:28])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:26]=2)[CH:22]=[N:23]1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCOCC1

Procedure:
The title compound was prepared by the procedure of Example 167 using 0.616 g of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.094 g of sodium iodide and 2.03 ml of morpholine to give after purification by chromatography (Silica Gel: ethyl acetate, ethyl acetate/methyl alcohol/triethyl amine 6:4:0.1) 0.196 g (28%) of the desired product. MP 133-135° C. :mass spectrum (electrospray m/e): M+H=445.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(N(CC)CC)C.[CH3:20][C:21]1([C:26](ON2C(=O)CCC2=O)=[O:27])[CH2:25][S:24][S:23][CH2:22]1>CC1OCCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:26]([C:21]2([CH3:20])[CH2:25][S:24][S:23][CH2:22]2)=[O:27])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(CN)ccc1O
Reactant: CC1(C(=O)ON2C(=O)CCC2=O)CSSC1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)C2(C)CSSC2)ccc1O
Reaction time: 8 h

Procedure:
24.3 mmol of N-hydroxysuccinimide are added to 24.3 mmol of dithiolane acid dissolved in 60 ml of dichloromethane cooled to 0° C. (on an ice bath). The reaction medium is stirred for 30 minutes at 0° C. A solution of 24.3 mmol of DCC in 50 ml of dichloromethane is added and the mixture is then stirred at 20° C. for 4 hours. The reaction medium is filtered and washed, and the filtrate is then evaporated to dryness on a rotavapor at 40° C. under vacuum to give 1-{[(4-methyl-1,2-dithiolan-4-yl)carbonyl]oxy}pyrrolidine-2,5-dione (m=7 g, quantitative yield). 10 ml of MeTHF, 3.16 mmol of 4-(aminomethyl)-2-methoxyphenol hydrochloride and 3.16 mmol of triethylamine are added to 1.58 mmol of 1-{[(4-methyl-1,2-dithiolan-4-yl)carbonyl]oxy}pyrrolidine-2,5-dione. After stirring overnight, the mixture is filtered, rinsed with MeTHF and then evaporated. Flash chromatography, eluting with 98/2 dichloromethane/methanol, gives Compound 16 in the form of a yellow oil (84% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:11]2[CH:12]=[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Cn1cccc1C=O
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3cccn3C)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
In ethanol (10 ml), 1-methylpyrrole-2-carbaldehyde (0.33 ml, 3.09 mmol) and methyl 4-amino-3-hydroxyphenylacetate (559 mg, 3.09 mmol) were stirred for 4 hours at room temperature. Iodobenzene diacetate (1.19 g, 3.70 mmol) was added to the reaction mixture. After stirring at room temperature for 30 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (3:1, v/v) eluate fractions, methyl (2-(1-methyl-2-pyrrolyl)-6-benzoxazolyl)acetate (228 mg, 27%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([S:30]([N:33]=CN(C)C)(=O)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7]2[C:13](Cl)=[C:12]([CH:15]=[O:16])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:38]([OH:40])[CH3:39].Cl.[OH-:42].[Na+]>O>[NH2:33][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:6]2[C:7]3[CH:13]=[C:12]([C:15]([O:40][CH2:38][CH3:39])=[O:16])[CH2:11][S:10][C:8]=3[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:22]=1)(=[O:31])=[O:42]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3S(=O)(=O)N=CN(C)C)cc1)C(Cl)=C(C=O)CS2
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3S(N)(=O)=O)cc1)C=C(C(=O)OCC)CS2
Temperature: 25 °C

Procedure:
100.1 mg of the product of Example 15, 2 ml of ethanol and 0.1 ml of concentrated hydrochloric acid were refluxed for 4 hours 30 minutes and the mixture was cooled to ambient temperature, poured into 20 ml of water, neutralized with 2N sodium hydroxide and extracted with dichloromethane. The extracts were washed with water, dried,the solvent eliminated under reduced pressure and after chromatography on silica (eluant: AcOEt-cyclohexane 5-5), 34 mg of the expected product were obtained.
Reaction SMILES: [N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[N:13]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1)[S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Nc1nc2cccc3c2n1CCO3)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(C(F)(F)F)cc1)c1nc2cccc3c2n1CCO3
Temperature: 120 °C

Procedure:
To a solution of N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide (125 mg, 0.40 mmol) in DMF (2.5 mL) was added 1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) and potassium carbonate (55 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h. The resulting mixture was then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide as a crude residue (1st compound to elute off the column) The residue was purified by HPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing 0.05% trifluoroacetic acid) to yield N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide as its corresponding TFA salt. MS 474 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH3:16][CH:17]([CH3:22])[CH2:18][CH2:19]CO>>[CH3:16][CH:17]([CH3:22])[CH2:18][CH2:19][CH2:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1
Reactant: CC(C)CCCO
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Product: CC(C)CCCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and 4-methylpentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.70 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[NH2:10].[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#N.Cl.[OH-:25].[Na+]>ClCCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:11]([C:16](=[O:25])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:13]=1[O:14][CH3:15])[NH2:10]
Reactant: COc1ccc(N)cc1OC
Reactant: [OH-]
Reactant: N#Cc1ccncc1
Agent: Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(N)c(C(=O)c2ccncc2)cc1OC
Reaction time: 0.25 h

Procedure:
To 1,2-dichloroethane (150 ml) is added boron chloride (25 g) under ice-cooling, and the mixture is stirred for 15 minutes. To the reaction mixture is added dropwise a solution of 3,4-dimethoxyaniline (36.3 g) in 1,2-dichloroethane (150 ml), and thereto is added 4-cyanopyridine (27.1 g). The reaction mixture is heated under reflux overnight, and thereto is added 2 M hydrochloric acid (160 ml). The mixture is heated with stirring at 80° C. for two hours, and thereto is added a 2 M aqueous sodium hydroxide solution (450 ml) under ice-cooling. The mixture is separated to collect the 1,2-dichloroethane layer, and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed, dried and concentrated. The residue is crystallized from ether to give 3,4-dimethoxy-6-isonicotinoylaniline (13.1 g).