Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@:10]([CH3:27])([C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])(O)=O.[Na+].[CH2:33]([O:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCCl.Cl>[CH3:27][C@@:10]1([C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])[CH2:11][CH2:12][N:8]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:42])[CH2:9]1
Reactant: C[C@]1(C(=O)N2C(=O)OC[C@H]2c2ccccc2)CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@]1(C(=O)N2C(=O)OC[C@H]2c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a suspension of (R)-3-((S)-1-benzyl-3-methylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one (145.50 g, 399.25 mmol) and NaHCO3 (33.54 g, 399.25 mmol) in dry DCE (1000 mL) at ambient temperature was added dropwise a solution of benzylchloroformate (134.87 mL, 958.19 mmol) in DCE (100 mL) and the reaction was stirred at ambient temperature for 24 hours. The reaction was diluted with 1N HCl (500 mL) and the layers were separated. The organic layer was washed with 1M HCl (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a thick yellow residue. The residue was purified by flash chromatography (5% ethyl acetate/DCM) to give (R)-benzyl 3-methyl-3-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)pyrrolidine-1-carboxylate (85.1 g, 208.35 mmol, 52.2% yield).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][NH:21][C:20](=O)[C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B.C1COCC1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C(=O)NCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1CNCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of intermediate 40a (15.6 g) in anhydrous THF (94 ml), at 0° C., under N2, BH3.THF 1M/THF (154 ml) was added. The solution was heated at reflux for 3 hr. HCl 37% (54 ml) was slowly added maintaining the reaction mixture in an ice-bath and the reaction mixture was stirred at rt for 1 hr. Water was then added (125 ml) and solid NaHCO3 (62.4 g) was added portionwise until a pH of 6.5. The aqueous phase was extracted with Et2O (4×160 ml) and the combined organic extracts were dried over Na2SO4, the solids were filtered and evaporated to leave a colourless oil which was purified by flash chromatography (silica gel, EtOAc/Methanol 7/3). The obtained product was suspended in Et2O (220 ml) and washed with NaHCO3 sat. (2×36 ml). The combined organic phases were dried (Na2SO4) and evaporated to give the title compound as white foam (8.7 g,).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[CH:12]=[CH2:11]
Reactant: O=Cc1ccc(O)cc1O
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C=O)c(O)c1

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (15 g), allyl bromide (9.6 ml), potassium carbonate (15.4 g), potassium iodide (18.5 g) and tetra-n-butylammonium bromide (3.59 g) in methyl ethyl ketone (200 ml) was heated at reflux for 1 hour. The reaction mixture was filtered and evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was evaporated and the residual oil (20 g) purified by flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (95:5, v/v). Fractions homogenous in the required product were combined and evaporated to give the title compound (13.8 g) as an oil.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH:17]=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CNN=CC(C)=O
Reactant: Cc1cc(C)cc(C(=O)C=O)c1
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
2-Oxopropanal methylhydrazone (7.29 mmol, 730 mg) and (3,5-dimethylphenyl)(oxo)acetaldehyde (7.29 mmol, 1.18 g) synthesized in Reference Synthetic Example 10 were dissolved in acetic acid (25 mL) and stirred at 100° C. for 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) and then by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as an orange liquid (93 mg, yield 5%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[N:6]=1)(=O)C.IC>CO.C(Cl)Cl>[CH3:1][O:4][C:5]1[N:6]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: CC(=O)Nc1ccc(C)c(OC(C)=O)n1
Solvent: CO
Solvent: CI
Solvent: ClCCl
Product: COc1nc(NC(C)=O)ccc1C
Temperature: 35 °C
Reaction time: 18 h
Yield: 143.6 %

Procedure:
To a stirred solution of 6-acetamido-3-methylpyridin-2-yl acetate (3.44 g, 16.5 mmol) in 2:1 MeOH/DCM (105 mL) at rt was added Ag2CO3 (9.11 g, 33.0 mmol) followed by iodomethane (3.09 mL, 49.6 mmol). The resulting mixture was stirred at 35° C. for 18 h then stood at rt for 2 d. The reaction mixture was combined with 2 previous batches derived from 6-acetamido-3-methylpyridin-2-yl acetate (590 mg, 2.83 mmol and 3.44 g, 16.5 mmol) and the combined batches were filtered through celite, rinsing with DCM. After concentration of the filtrate in vacuo purification by gradient column chromatography eluting with 20-50% EtOAc in heptane yielded the title compound (4.27 g, 23.7 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[CH2:19][CH2:20]1)=[O:25])[CH3:28]
Reactant: O=C(Cl)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Reactant: CCN
Product: CCNC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
In a manner analogous to that of Example 1(e) but using 1-[(6-fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarbonyl chloride and ethylamine as starting materials the named compound was obtained as cream-colored needles, mp 225°-227° dec after recrystallization from methanol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:18]=O.C(O)CCCC>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[CH:18][N:15]=3)[N:14]=2)=[CH:7][CH:8]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Agent: Cl
Solvent: CCCCCO
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)nn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine hydrochloride (50 mg, 0.2 mmol) and 2-chloro-3-(4-methoxyphenyl)propanal (48 mg, 0.24 mmol) in tent-amyl alcohol (1 mL) was heated at 130° C. for 4 h. After cooling, the mixture was purified by preparative HPLC to afford the desired product. (7.1 mg) LCMS: (M+H)=335.1.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C1C=CC=CC=1>[CH2:10]1[C:9]2([CH2:12][CH2:18][C:16](=[O:17])[CH:14]=[CH:15]2)[CH2:8][CH2:7][O:6][CH2:11]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCOCC1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C1C=CC2(CCOCC2)CC1
Reaction time: 3 h

Procedure:
0.5 ml of sulphuric acid is added to 317 mmol of tetrahydro-2H-pyran-4-carboxaldehyde and 317 mmol of methyl vinyl ketone in 500 ml of benzene. The reaction mixture is then refluxed for 3 hours, water being removed using a Dean-Stark apparatus, and then a further 317 mmol of methyl vinyl ketone are added and reflux is continued for 3 hours. The mixture is subsequently washed, dried and then concentrated, and the residue obtained is distilled to yield the expected product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C@H:17]([CH3:18])[CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][C@@H:13]2[CH3:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].ClC(OC(Cl)C)=O>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C@H:17]([CH3:18])[CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:26])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: C[C@@H]1CNC[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1
Temperature: 80 °C

Procedure:
A solution of the product from step (i) (1 g) in 1,2-dichloroethane (10 ml) was treated with 1-chloroethyl chloroformate (0.44 ml). The mixture was heated at 80° C. for 16 h. The solvents were then evaporated under reduced pressure and the residue dissolved in methanol (50 ml). The mixture then heated at 50° C. for 1 h. The solvents were then evaporated under reduced pressure. Purification was by trituration with ethyl acetate and filtration to give the subtitle compound as a white solid. Yield: 0.85 g
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:36][CH:33]4[CH2:35][CH2:34]4)[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(OCCNC3CC3)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.336 g, 0.711 mmol) and cyclopropylamine (1.0 mL, 14 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. Additional cyclopropylamine (1.0 mL, 14 mmol) was added, and the reaction mixture was stirred for 6 hours at 80° C. in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol in chloroform. After drying in vacuo at 55° C. temperature for 25 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-cyclopropyl-amine as a light yellow foam (0.127 g, 50.0%) was obtained. This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a buff solid (0.131 g): MP: 184-5° C. dec.; Mass Spectrum (+EI, [M+H]+) m/z 358.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CCCCCC>[C:1]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCCCO
Solvent: CCCCCC
Product: CCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCC
Yield: 90 %

Procedure:
cis-9-Myristoleate, 3 (4.2 g, 0.0175 mol) was enzymatically transesterified with cetyl alcohol (5.08 g, 0.021 mol) in the presence of Novozyme 435 (0.930 g, 10 wt % of the total substrate) at 68° C. for 8 hr. The reaction was monitored by TLC and after completion of the reaction, hexane (50 ml) was added and the lipase was separated by filtration and the solvent was evaporated to get the crude product and was purified by column chromatography to obtain hexadecyl cis-9-tetradecenoate, 4 (7.48 g, 0.0166 mol) in 90% yield with 90% purity by GC. The structure of hexadecyl cis-9-tetradecenoate, 4 was confirmed by 1H NMR, IR, and GC-MS.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[CH2:18]([NH2:28])[C:19]1[CH:27]=[CH:26][C:25]2[O:24][CH2:23][O:22][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:28][CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[O:24][CH2:23][O:22][C:21]=3[CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1nc(Cl)c2cc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Yield: 92.3 %

Procedure:
2.72 g (0.0100 mol) of 2-ethoxycarbonyl-4,6-dichloroquinazoline, 1.75 g (0.0116 mol) of piperonylamine and 1.60 g (0.0151 mol) of sodium carbonate were mixed with 100 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from chloroform/n-hexane to give 3.56 g of the title compound as a colorless needle.
Reaction SMILES: [C:1]([CH:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11](OC)=[O:12])=[CH:8][CH:7]=1)=[O:5])#[N:2].[OH-].[K+].O.[NH2:20][NH2:21].[Cl-].[Na+]>CO>[C:1]([CH:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11]([NH:20][NH2:21])=[O:12])=[CH:8][CH:7]=1)=[O:5])#[N:2]
Reactant: CCC(C#N)C(=O)c1ccc(C(=O)OC)s1
Reactant: NN
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C#N)C(=O)c1ccc(C(=O)NN)s1

Procedure:
Methyl 5-(2-cyanobutyryl)thiophene-2-carboxylate (213 mg, 0.90 mmol) in methanol was stirred with 0.1 M potassium hydroxide in methanol (9.0 mL, 0.90 mmol) at room temperature for 10 minutes and then with hydrazine monohydrate (225 mg, 4.50 mg) at 80° C. for 6 hours. After addition of saturated aqueous sodium chloride, the reaction solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to give the crude desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.[OH-].[Na+]>[Zn].C(O)C>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 20 °C

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 3 parts of zinc dust, 10 parts of a 20 wt % aqueous sodium hydroxide and 50 parts of ethanol was refluxed for 2 hours with stirring and, after cooled to 20°C, filtered. The residue was washed with water and poured into a dilute hydrochloric acid to dissolve zinc dust. Crystals were recovered by filration, washed with water and dried under reduced pressure to obtain 3.8 parts of 1-aminoanthraquinone.
Reaction SMILES: [N+:1]([C:4]1[C:13](Cl)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>>[N+:1]([C:4]1[C:13]([N:16]([CH3:17])[CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Reactant: CNC
Product: CN(C)c1ccc2ncccc2c1[N+](=O)[O-]

Procedure:
5-Nitro-6-chloroquinoline, prepared as described by Maneke & Kulka, Organic Reactions, Vol. VII, 59 (1953) and Campbell et al., J. Am. Chem, Soc., 68, 1559 (1946), was allowed to react with dimethylamine to yield 5-nitro-6-dimethylaminoquinoline. This material was converted to the title compound by the procedure described in Example 33.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH:24]=[N:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2]>C(O)(=O)C.O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH:24]=[N:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (Intermediate 6, 0.180 g) and palladium hydroxide on carbon (˜0.005 g) in acetic acid (2 mL) and dioxane (20 mL) was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The resultant mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (0.100 g) as a gum which was used without further characterisation.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].C(OC(=O)C)(=O)C.Cl>C(OCC)C.C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
1-[3-(tert-Butyl)-4-hydroxyphenyl]-1-ethanone (739 g) was added to a mixture of 69% nitric acid (354 g), water (1 l) and methylene chloride (2 l) at 10° C. to 15° C. while stirring. After then adding diethyl ether (3 l) and acetic anhydride (28 ml), 5 N hydrochloric acid was further added at 10° C. to 15° C. The temperature of the reaction mixture was raised to room temperature over a period of 1.5 hours, and the mixture was then poured into ice water. The mixture was extracted with diethyl ether, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield the title compound (894 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[CH3:11][O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:11][O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1])\[CH3:16]
Reactant: COc1cccc(O)c1F
Reactant: CC#CC(=O)OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C(\C)Oc1cccc(OC)c1F
Yield: 67.4 %

Procedure:
To a stirred mixture of 2-fluoro-3-methoxy-phenol (3.88 g, 0.027 mol) and methyl-2-butynoate (5.97 g, 0.061 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(2-fluoro-3-methoxy-phenoxy)-but-2-enoic acid methyl ester (4.37 g, 63%) as a colorless oil and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]3[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][C:19](=O)[CH3:20].O.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[CH3:20][C:19]1[N:1]([C:2]2[C:10]3[O:9][C:8]4[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cccc2c3c(oc12)CCCC3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)n1-c1cccc2c3c(oc12)CCCC3
Yield: 72.1 %

Procedure:
A mixture of 6-amino-1,2,3,4-tetrahydrodibenzofuran (230 mg), 2,5-hexanedione (145 mg) and conc. hydrochloric acid (1 drop) in ethanol (3 ml) was refluxed for 1 hour and poured into water. The mixture was neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethanol and water to give 6-(2,5-dimethylpyrol-1-yl)-1,2,3,4-tetrahydrodibenzofuran (235 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[F:10][C:11]([N:14]=[C:15]=[O:16])([F:13])[F:12]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH:14][C:11]([F:13])([F:12])[F:10])=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Cc1cc(N)ccc1Cl
Reactant: O=C=NC(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-methyl-4-chloroaniline (70 grams; 0.5 mol) in toluene (150 ml) is placed into a pressure vessel, and is cooled in an acetone-dry ice bath. Trifluoromethyl isocyanate (56 grams; 0.5 mol) is added and the pressure vessel is sealed. The reaction mixture is warmed to about 25° C. and is allowed to stand for about 24 hours. After this time the reaction vessel is opened and its contents are stripped of toluene by evaporation under reduced pressure. The residue is then recrystallized to yield N-(3-methyl-4-chlorophenyl)-N'-trifluoromethyl urea.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([C@@H:7]1[C:13]2[CH:14]=[CH:15][CH2:16][CH2:17][C:12]=2[CH2:11][CH:10]([NH2:18])[N:9]([CH3:19])[C:8]1=[O:20])=[O:6])[CH3:4].C([NH:28][C@H:29]([C:39](O)=[O:40])[CH:30]([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])(OC(C)(C)C)=O>>[F:32][C:31]([F:33])([F:34])[CH:30]([C:35]([F:36])([F:38])[F:37])[C@@H:29]([C:39]([NH:2][C@H:3]([C:5]([C@@H:7]1[C:13]2[CH:14]=[CH:15][CH2:16][CH2:17][C:12]=2[CH2:11][CH:10]([NH2:18])[N:9]([CH3:19])[C:8]1=[O:20])=[O:6])[CH3:4])=[O:40])[NH2:28]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C(F)(F)F)C(F)(F)F
Reactant: C[C@H](N)C(=O)[C@H]1C(=O)N(C)C(N)CC2=C1C=CCC2
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](N)C(C(F)(F)F)C(F)(F)F)C(=O)[C@H]1C(=O)N(C)C(N)CC2=C1C=CCC2

Procedure:
Following General Procedure D above using 1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride (Example 7-30, below) and N-Boc-hexafluorovaline (Aldrich), the protected intermediate was prepared. The Boc-group was removed using 5.0 M HCl in dioxane and the resulting free-base purified by chromatography CHCl3/MeOH (95:5) yielding the title compound as a mixture of diastereomers.