Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)[CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:3])[CH3:2]>COC(OC)N(C)C>[C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:20])[F:21])[O:16][N:15]=2)[CH:11]=[CH:10][C:6]=1[C:7]([NH:9][CH:14]=[N:15][O:16][CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: COC(OC)N(C)C
Product: CON=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
A mixture of 0.21 g of 2-acetylamino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid amide and 10 mL of N,N-dimethylformamide dimethylacetal was stirred at room temperature for 1.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 3 mL of 1,4-dioxane, a solution of 0.025 g of methoxyamine hydrochloride in 3 mL of water was added dropwise. After the completion of the addition dropwise, it was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, 5 mL of water was added in the residue, and extracted with ethyl acetate (10 mL×1). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:2) to obtain 0.07 g of the aimed product as colorless resinous substance.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20](C(=O)C)[CH2:19][C:18]=3[CH:27]=2)=[O:13])[CH2:6][CH2:5]1)(=O)C.[ClH:28]>>[ClH:28].[ClH:28].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][NH:20][CH2:19][C:18]=3[CH:27]=2)=[O:13])[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CN(C(C)=O)CCO3)CC1
Agent: Cl
Product: O=C(CCC1CCNCC1)c1ccc2c(c1)CNCCO2
Reaction time: 16 h

Procedure:
3-(1-Acetylpiperidin-4-yl)-1-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1-propanone (1.5 g) obtained in Example 1 was dissolved in 30 ml of conc. hydrochloric acid, and the mixture was stirred for 16 hours under reflux. Excess volume of the conc. hydrochloric acid was distilled off under reduced pressure and ethanol was added to the residue. The resultant crystals were collected by filtration, and washed with ethanol. The crystals were dried under reduced pressure to give 1.4 g of the title compound as colorless scaly crystals, m.p. >300° C.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[C:18](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[CH2:4]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:3][C:2]#[CH:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (0.874 g, 3.62 mmol) in methanol (15 mL) was added with potassium carbonate (1.00 g, 7.24 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with dimethyl (1-diazo-2-oxopropyl)phosphonate (0.692 g, 3.62 mmol), and the mixture was stirred at room temperature for additional 3 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(but-3-ynyl)piperidine-1-carboxylate (0.670 g, 78%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:19]([O:20]C(=O)C)[C@H:18]([O:24][C@H:25]2[O:42][C@H:41]([CH2:43][O:44]C(=O)C)[C@@H:36]([O:37]C(=O)C)[C@H:31]([O:32]C(=O)C)[C@H:26]2[O:27]C(=O)C)[C@@H:17]([CH2:48][O:49]C(=O)C)[O:16][C@H:6]1[S:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[OH:15])(=O)C.[Na]>CO>[C@H:25]1([O:24][C@@H:18]2[C@@H:17]([CH2:48][OH:49])[O:16][C@@H:6]([S:7][C:8]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=3[OH:15])[C@H:5]([OH:4])[C@H:19]2[OH:20])[O:42][C@H:41]([CH2:43][OH:44])[C@@H:36]([OH:37])[C@H:31]([OH:32])[C@H:26]1[OH:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2cc(O)ccc2O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Sc3cc(O)ccc3O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To a solution of 14.0 g of 2,5-dihydroxyphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 100 ml of absolute methanol under argon at 5° C. was added 0.6 g of sodium spheres in oil. The reaction was stirred at room temperature for one hour, then 20 ml of a strongly acidic sulfonic acid cation exchanger, for example, Dowex® 50WX8 (H+) resin (Dow), was added, the mixture was stirred 10 minutes then filtered and concentrated in vacuo, giving 9.19 g of the desired intermediate as a dark brown solid, [α]D26 =+52°±2° (0.51% methanol).
Reaction SMILES: [N+:1](=[C:3]([C:10]([CH3:12])=[O:11])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2].[I-].[Na+].C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C(#N)C>[N+:1](=[C:3]([C:10]([O:11][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH2:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=[N+]=[N-])C(=C)O[Si](C)(C)C
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Into 5 ml of dry acetonitrile were added 167 mg (1 millimole) of allyl 2-diazoacetoacetate and 210 mg (1.4 millimoles) of sodium iodide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating under an argon atmosphere at a room temperature. After the resultant was agitated at a room temperature for an hour, it was concentrated under a reduced pressure. To the residue was added 10 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Isoluble materials were removed by filtration and the hexane solution was concentrated to dryness under a reduced pressure to give 176 mg (yield 78.8%) of the desired compound in an oily state.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>ClCCCl.[Cl-].[Zn+2].[Cl-]>[Cl:13][C:11]1[CH:12]=[C:7]([O:6][CH3:5])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: COc1ccc(CC(=O)c2c(Cl)cc(OC)cc2OC)cc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To 1,2-dichloroethane (500 mL) were added anhydrous aluminum chloride (50.5 g) and zinc chloride (5.72 g), followed by stirring for 15 min. Under ice-cooling, a solution of 1,3-dimethoxy-5-chlorobenzene (55 g) in 1,2-dichloroethane (140 mL) was added. The mixture was cooled to −25° C. and 4-methoxyphenylacetyl chloride (53.9 mL) in 1,2-dichloroethane (250 mL) was added drop-wise. The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was cooled to 0° C., quenched with 1.0 N HCl (300 mL), and the resulting suspension was filtered through Celite and silica gel using ethyl acetate. Chromatography on silica gel (eluant: 10–40% ethyl acetate/hexane) provided the title compound (39 g). 1H NMR (DMSO-d6): 7.07 (d, 2H, J=8.77 Hz), 6.85 (d, 2H, J=8.77 Hz), 6.62 (m, 2H), 3.94 (s, 2H), 3.80 (s, 6H), 3.72 (s, 3H); MS: 321 (MH+).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[CH:7][S:8][CH:9]=2)[NH:5][C:4](=[O:11])[C:3]=1[C:12]#[N:13].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:10]3[C:6](=[CH:7][S:8][CH:9]=3)[NH:5][C:4](=[O:11])[C:3]=2[C:12]#[N:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)[nH]c3cscc23)CC1

Procedure:
Compounds of structure (II) with R2 as carbonitrile, and R1 and R3 as defined above were also prepared from intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33). Intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was reacted with tert-butyl-1-piperazine carboxylate to yield 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (36). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield intermediate of structure (37), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (II) with R2 as carbonitrile, and R1 and R3 as defined above, as shown in Scheme 18.
Reaction SMILES: OCC[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.N[C:51]1C=CC(C2C=NN(CCCCO)C=2)=C2[C:59]=1[C:58](=[O:60])N(C)C2>>[OH:60][CH2:58][CH2:59][CH2:51][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1
Reactant: CN1Cc2c(-c3cnn(CCCCO)c3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Yield: 38 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 7-amino-4-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 17C, 80 mg, 265 μmol) and to afford 73 mg of the title compound (38%). 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=8.3 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.83 (d, J=4.8 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 4.54 (s, 2H), 4.24 (t, J=7.1 Hz, 2H), 4.02-4.12 (m, 4H), 3.90 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 3.34 (d, J=3.5 Hz, 1H), 3.28 (s, 1H), 3.16 (s, 3H), 1.93-2.03 (m, 2H), 1.49-1.60 (m, 2H), 1.26 (t, J=7.1 Hz, 6H). MS (ESI): m/z 718.78 [M+H]+. UPLC: tR=1.20 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:26][S:27]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=[N+]([O-])O
Product: CS(=O)(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitrate salt (515 mg/2 mmol) was suspended in methylene chloride (5 mL) and cooled to 0° C. Triethylamine (620 μL/4.4 mmol) was added followed by methanesulfonyl chloride (dropwise, 160 μL/2.1 mmol). After fifteen minutes the reaction was poured into 25 mL of 1 N hydrochloric acid and extracted with methylene chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to give 3-Methanesulfonyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a light brown solid (520 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 8.05 (m, 2H), 7.3 (d, J=9.1 Hz, 1H), 3.45 (m, 4H), 3.15 (m, 4H), 2.8 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].Cl.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][F:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH:17][C@H:14]([CH2:15][F:16])[CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:18])=[O:4]
Reactant: COC(=O)CC[C@H](N)CF
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](CF)NC(=O)C(F)(F)F
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
0.28 g of triethylamine and 0.96 ml of trifluoroacetic acid were added to 0.28 g of 4, and the mixture was cooled to -10° C. 0.25 ml of trifluoroacetic anhydride was added drop-by-drop. The resulting mixture was allowed to warm to room temperature and stirred for 90 minutes. Volatile materials were evaporated under reduced pressure, and the residue, an oil, was eluted through a column of florisil, using ethyl acetate as eluent. After evaporation of the solvent, the resulting oil was stripped under reduced pressure to give 8, as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 50 °C
Yield: 38.8 %

Procedure:
A mixture of 6,7-dimethoxyquinolin-4-ol (1.4 g, 6.8 mmol, 1.0 eq.), 3,4-difluoro-nitrobenzene (1.44 g, 8.84 mmol, 1.3 eq.) and cesium carbonate (3.6 g, 10.9 mmol, 1.6 eq.) in dry DMF (10 mL) was heated for 1 h at 50° C. in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 5:1) to yield the desired product A1 (909 mg, 2.64 mmol, 38.8%) as a yellow solid. 1H NMR (400 MHz, CDCl3, 300K) δ 4.04 (s, 3H), 4.06 (s, 3H), 6.55 (d, J=5.2 Hz, 1H), 7.34 (dd, J=7.8 Hz, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.46 (s, 1H), 8.13 (m, 1H), 8.19 (dd, J=9.8 Hz, J=2.5 Hz, 1H), 8.58 (d, J=5.2 Hz, 1H). MS (ES) C17H13FN2O5 requires: 344, found: 345 (M+H)+. Furthermore an isomer (941 mg, 2.74 mmol, 40.2%) was isolated as a yellow solid. MS (ES) C17H13FN2O6 requires: 344. Found: 345 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>ClCCl>[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 96.1 %

Procedure:
Triethylamine (7.64 g) was added to a suspension of L-proline methyl ester hydrochloride (5 g) and 2-nitrobenzenesulfonyl chloride (7.4 g) in dichloromethane (150 ml), under ice cooling with stirring and the resulting mixture was stirred at room temperature for 17 hours. After water-washing the reaction liquid, it was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with ethyl acetate/hexane (1/3) to give 9.12 g (yield 96.1%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](Br)[CH2:7][CH2:8][CH:9](Br)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[CH3:1][CH2:2][O:3][C:4]([CH:6]1[N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C(Br)CCC(Br)C(=O)OCC
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C1CCC(C(=O)OCC)N1Cc1ccccc1
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of Diethyl meso-2,5-dibromoadipate (50 g, 139 mmol) in benzene (150 mL) was heated to reflux. Then heating was discontinued and benzylamine (50 mL) was added under stirring in 1 h. At the end of the addition, the mixture was refluxed for 20 h. After cooling down, the hydrobromide salt was filtered off and washed with benzene, and the benzene solution was evaporated. The residue was distilled under reduced pressure (180-190° C./0.3 mmHg) to give a product (39.9 g, 94%) as a yellow oil.
Reaction SMILES: C=CCCCCCCCCCCCCCCCC.C1([O:25]C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CCCCCCC/C=C\CCCCCCCC.C(N)CCCCCCC/C=C\CCCCCCCC.[Se].C([P:80](=[O:97])([CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH3:96])[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])CCCCCCC>C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.CN1C(=O)CCC1.C1(C)C=CC=CC=1.CO.C(#N)C>[CH2:89]([P:80]([CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])(=[O:97])[OH:25])[CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH3:96]
Reactant: CCCCCCCCP(=O)(CCCCCCCC)CCCCCCCC
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: C=CCCCCCCCCCCCCCCCC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCCN
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCP(=O)(O)CCCCCCCC

Procedure:
Materials. 1-methyl-2-pyrrolidinone (99.5%, Aldrich), 1-octadecene (90%, Aldrich), acetonitrile (99.9%, Fisher Chemical), BiCl3 (99.999%, Strem), CdO (99.5%, Aldrich), diphenyl ether (99%, Aldrich), methanol (ACS grade, VWR), oleic acid (90%, Aldrich), oleylamine (70% Aldrich), selenium (99.99%, Strem) trioctylphosphine (90%, Aldrich), trioctylphosphine oxide (99%, Strem), toluene (ACS grade, VWR). 1M TOP-Se was prepared by dissolving selenium powder in trioctylphosphine under inert atmosphere; trioctylphosphine oxide (TOPO) was recrystallized from acetonitrile prior to use; di-n-octylphosphinic acid (DOPA) was synthesized according to the procedure reported by Wang et. al.[1], a stock suspension of 2 mM BiCl3 in NMP was prepared in advance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].C([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](=[NH:41])[NH2:40])[CH:34]=1)[C:27]([C:42]([NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N+:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=1)=[O:43])=[CH:26]2)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(O)C.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[C:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([OH:22])=[CH:31][CH:30]=2)[CH:26]=[C:27]1[C:42]([NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N+:52]([CH3:53])([CH3:54])[CH3:55])=[CH:48][CH:47]=1)=[O:43])(=[NH:40])[NH2:41]
Reactant: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc(OCc4ccccc4)ccc3n2Cc2cccc(C(=N)N)c2)cc1
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc(O)ccc3n2Cc2cccc(C(=N)N)c2)cc1
Yield: 53 %

Procedure:
The starting material, [4-({[5-benzyloxy-1-(3-amidino-benzyl)-1H-indole-2-carbonyl]-amino}-methyl)-phenyl]-trimethyl-ammonium trifluoroacetate trifluoroacetic acid salt (example 56), was dissolved in ethanol, 2 equivalents of trifluoroacetic acid and Pd/C (10%) were added and the mixture was hydrogenated. The reaction mixture was concentrated and purified by flash-chromatography on silica gel with dichloromethane/methanol/trifluoroacetic acid 9:1:0.1. The product was concentrated and lyophilized to give 53% of the desired product. M.p. 78° C. (dec.). MS: 456.4 (M+).
Reaction SMILES: C(O[C:4](=[O:25])[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)C>O>[Br:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4](=[O:25])[C:13]3[C:8](=[CH:9][C:10]([C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=CNc1cccc(C(C)(C)C)c1)c1cccc(Br)c1
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)c(-c3cccc(Br)c3)c[nH]c2c1
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
To 2-(3-Bromo-phenyl)-3-(3-tert-butyl-phenylamino)-acrylic acid ethyl ester (151 mg, 0.388 mmol) was added 10 g of polyphosphoric acid. The resulting mixture was heated at 140° C. for 90 minutes. 80 mL of water was added. The mixture was stirred for 40 minutes. The resulting precipitate was filtered, washed with water, and air dried for 3 days to yield 3-(3-Bromo-phenyl)-7-tert-butyl-1H-quinolin-4-one (123 mg. 0.345 mmol). MS (ESI) 356 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=2)[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (42 mg, 0.156 mmole) and p-trifluoromethylbenzoyl chloride (32.5 mg, 0.156 mmole) were combined in 3 ml of methylene chloride (CH2Cl2), treated with triethylamine (0.0157 g, 0.156 mmole) and stirred at room temperature 15 minutes. The mixture was diluted with CH2Cl2 (20 ml), washed with 10% citric acid (2×5 ml), dilute sodium bicarbonate (2×5 ml), and water (2×5 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate (0.4 ml)/ether (1 ml) to give the title compound which was dried in vacuo at 90°: (m.p. 209°-211°).
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]2)=[CH:8][CH:7]=1)([O:3][CH3:4])=[O:2].C(CCC(C1C=CC(SC2CCCC(=O)C2)=CC=1)=O)(OC)=O>>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]2)=[CH:8][CH:7]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)Cc1ccc(SC2CCCC(=O)C2)cc1
Agent: COC(=O)CCC(=O)c1ccc(SC2CCCC(=O)C2)cc1
Product: COC(=O)Cc1ccc(S[C@@H]2CCC[C@H](O)C2)cc1

Procedure:
Following Step B of Example 6 but substituting the title compound of Step A of this Example for 3-(4-(3-carbomethoxy-1-oxopropyl)phenylthio)cyclohexanone, the title compound was obtained as an oil. NMR (ppm) (CDCl3): 7.33 (2H, d, J=9 Hz, H meta to S), 7.17 (2H, d, J=9 Hz, H ortho to S), 4.00 (1H, m, carbinolic proton). 3.60 (3H, s, CH3O), 3.50 (2H, s, CH2), 1.90-1.30 (8H, m, cyclohexane protons).