Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]3[N:16]=[CH:17][CH:18]=[CH:19][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CS(C)=O>[O:24]1[CH:22]([CH3:20])[CH:23]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]3[N:16]=[CH:17][CH:18]=[CH:19][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: Cn1c(-c2ccc(O)cc2)nc2cccnc2c1=O
Solvent: CS(C)=O
Product: CC1OC1Oc1ccc(-c2nc3cccnc3c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.4 gm (0.037 mol) of 2-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-pyrido[2,3-e]-pyrimidin-4-one were dissolved in 100 ml of dimethylsulfoxide, and the solution was mixed, while stirring with 4.5 gm (0.04 mol) of potassium tert. butylate. After a clear solution was formed, 9.4 ml of epibromohydrin were added, and the reaction mixture was stirred for one hour at room temperature. Thereafter, it was poured into 600 ml of ice water, and the resulting crystalline product was suction-filtered off and dried at 40° C. in a vacuum shelf-drier.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Yield: 57.7 %

Procedure:
N-Phenyl-o-phenylenediamine 13.27 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 14.51 g of product (yield=57.71%).
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[CH2:6]([Br:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]=[O:2])=[CH:10][CH:9]=1
Reactant: BrCCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of dichloromethyl methyl ether (62 ml) in methylene chloride (40 ml) was added titanium tetrachloride (75 ml) over 10 minutes under a nitrogen atmosphere at 4-5° C. Then, a solution of phenethyl bromide (85 ml) in methylene chloride (50 ml) was added thereto over 50 minutes at 5-7° C. and the mixture was stirred for 5 hours while gradually raising the temperature of the mixture to room temperature. Water (200 ml) was added to the reaction mixture over 1 hour and the mixture was extracted with chloroform (200 ml). The chloroform layer was washed with water, a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (167 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=20:1) to give 4-(2-bromoethyl)benzaldehyde (32.3 g) as a yellow solid, melting point 50-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[OH-].[K+].[N+:12]([CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])#[C-:13]>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]1[O:9][CH:13]=[N:12][C@H:14]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: O=Cc1ccncc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccncc1Br)N1CCCC1
Temperature: 0 °C

Procedure:
BAL 01028A was prepared in accordance with method D using 3-bromo-4-pyridinecarboxaldehyde (1.010 g, 5.43 mmol), KOH (0.305 g, 5.43 mmol) in methanol (5 mL) and 2-isocyano-1-pyrrolidin-1-yl-ethanone BLE 04134 (0.75 g, 5.43 mmol). The mixture was stirred at 0° C. until precipitation and concentrated. The mixture was partitioned between EtOAc (50 ml) and H2O (25 ml). The aqueous layer was extracted twice with EtOAc (25 mL). The EtOAc fractions were combined, washed twice with brine (2×25 mL), dried over MgSO4 and filtered. After evaporation and trans-(5-(3-bromopyridin-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone BAL 01028A was obtained (1.20 g, 68% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:44][C:45]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:46]=1[CH2:47]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@H:9]1[CH2:33][N:34]([CH2:47][C:46]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:45]=1[F:44])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CNCc1cc(F)ccc1F
Reactant: Fc1ccc(F)c(CBr)c1
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN(Cc1cc(F)ccc1F)Cc1cc(F)ccc1F

Procedure:
Analogously, (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated with 2,5-difluoro-benzylbromide to give (2S,4R)-2-{[bis-(2,5-difluoro-benzyl)-amino]-methyl}-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester which was treated with TFA according to general method B (variation 0° C. to RT) to give (2S,4R)-bis-(2,5-difluoro-benzyl)-(4-tritylsulfanyl-pyrrolidin-2-ylmethyl)-amine yellow oil, MS: 627 (MH+).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.Cl.[OH-].[Na+:41]>CN(C1C=CN=CC=1)C.C(N(CC)CC)C.ClCCl>[Na+:41].[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:14](=[O:31])[CH:3]([NH:2][C:32](=[O:38])[CH2:33][CH2:34][C:35]([O-:37])=[O:36])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([O-])CCC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a mixture of the compound of part (e) (215 mg) and dichloromethane (3 ml) cooled to -78° C. under argon, was added with stirring dry triethylamine (70 μl). To the resulting solution was added succinic anhydride (50 mg) and 4-dimethylaminepyridine (5 mg), and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for a further 3 hours before pouring into aqueous 2N hydrochloric acid (4 ml). The organic layer was separated, and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was treated with one equivalent of aqueous sodium hydroxide, sufficient acetonitrate added to render the mixture homogeneous, and the resulting solution freeze dried. The resulting solid was dissolved in ethyl acetate (1 ml) and petroleum ether (10 ml) added. The mixture was boiled to half volume, and the solid product collected by filtration, and dried in-vacuo to afford the title compound. 1N NMR (360 MHz; D6 -DMSO) δ2.15 (2H, m), 2.25 (2H, m), 2.72 (1H, m), 2.87 (4H, m), 3.05 (1H, dd, J=5.7, 14.5 Hz), 4.42 (1H, m), 6.97 (1H, t, J=7.8 Hz), 7.05 (1H, t, J=8.0 Hz), 7.18 (1H, d, J=2.2 Hz), 7.32 (1H, d, J=8.3 Hz), 7.48 (1H, d, J=7.7 Hz), 7.79 (2H, s), 7.85 (1H, s), 9.00 (1H, d, J=6.8 Hz), 10.90 (1H, s); m/e (CI+) 528 (MH+). Found: C, 52.12; H, 3.99; N, 4.67. C25H21F6 N2O4Na.1.5(H2O) requires C, 52.00; H, 4.19; N, 4.85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[C:26](Cl)=[CH:25][C:23]([NH2:24])=[C:22]([N+:28]([O-:30])=[O:29])[CH:21]=1>CS(C)=O>[Cl:19][C:20]1[C:26]([O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])=[CH:25][C:23]([NH2:24])=[C:22]([N+:28]([O-:30])=[O:29])[CH:21]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-(trifluoromethyl)phenol (2 g, 10.18 mmol) in DMSO (250 ml) was added potassium carbonate (4.2 g, 30.17 mmol). The resulting solution was stirred overnight at room temperature, then 4,5-dichloro-2-nitroaniline (2.1 g, 10.14 mmol) was added. The resulting solution was stirred for an additional overnight at 90° C. and then quenched with water (1000 ml) and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with saturated aqueous brine (3×1000 ml), dried by anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column, eluting with 1% to 1.5% ethyl acetate in petroleum ether to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroaniline as a yellow solid (450 mg, crude). Next, to a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroaniline (450 mg, crude) in ethanol (10 ml) was added hydrochloric acid (conc) (0.484 ml) and Zn (478 mg, 7.35 mmol) in several batches at room temperature. The resulting solution was stirred for 10 min at room temperature and 2 h at 80° C. The reaction was concentrated under vacuum and dissolved in water (200 ml), pH adjusted to 8 with potassium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-HPLC to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a off-white solid (150 mg, 61%). Finally, a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (50 mg, 0.15 mmol) in trifluoroacetic acid (5 ml) and conc. HCl (1 ml) was refluxed overnight. The reaction was then quenched with water (100 ml), pH value adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-TLC with 12.5% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenoxy]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (36.4 mg, 53%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[N:27]1([CH2:26][CH2:25][NH:24][C:2]([NH:1][CH2:4][CH:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])[O:6]2)=[O:3])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NCCN1CCOCC1
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 60 °C
Yield: 18 %

Procedure:
A solution of 3-(3-isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (70 mg, 0.23 mmol) and 4-(2-aminoethyl)morpholine (90.0 μl, 0.69 mmol) in THF (2.0 ml) was stirred at room temperature for 25 minutes. The reaction was heated for 5 minutes at 60° C. and then partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 aqueous solution, and water, and then extracted with 4% HCl aqueous solution. The combined aqueous layers were basified with saturated NaHCO3 aqueous solution and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow foam. The yellow foam was chromatographed through silica gel column (CHCl3 to 5% MeOH/CHCl3 gradient) to afford 1-(2-morpholin-4-yl-ethyl)-3-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-urea as a yellow foam (18 mg, 18%).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:23]([C:25](=[O:36])[CH2:26][C:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH:28]=2)[CH3:24])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)(C)(C)C.Cl.C(OCC)(=O)C>ClCCl.O>[O:29]1[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:27]([CH2:26][C:25]([N:23]([CH3:24])[CH:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:37])=[O:5])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)=[O:36])=[CH:28]1
Reactant: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O)C1)c1cccc(OCC(=O)O)c1
Reaction time: 24 h

Procedure:
To a solution of Example 27 (0.79 g, 1.55 mmol) in dichloromethane (12 mL) and water (0.5 mL) was added HCl (2.5 mL of 4 M solution in dioxan). After stirring for 24 hours, all volatiles were removed in vacuo to give a pale pink solid. The solid was stirred with ethyl acetate (75 mL) for 2 hours, then the solvent removed by pipette. This was repeated. The resulting solid was dissolved in acetonitrile (50 mL) and all solids removed by filtration. Ethyl acetate was added until the solution became cloudy, and the precipitate was allowed to settle. All supernatant was then removed and the resulting solid dried. Yield 0.25 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1>COCCOCCOC.[Cl-].[Na+].O>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(C)nc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A solution of piperazine (195 g, 2.26 mol) in diglyme (250 mL) was heated to 160° C. and a solution of 2-chloro-4,6-dimethylpyridine (40 g, 0.283 mol) in diglyme (150 mL) was added over a period of 30 min. The mixture was maintained at this temperature for 36 hand then the reaction mixture was allowed to cool to ambient temperature, diluted with brine and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude compound. Vacuum distillation to remove diglyme afforded 1-(4,6-dimethyl-2-pyridyl)piperazine (50 g, 92%) as an oil.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([O:28]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:38]1([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 48 mg (0.47 mmol) of thiomorpholine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 45 mg (60% of theory)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl.CO>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)N1CCc2c(F)cccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.27 g, 0.897 mmol) and diisopropylethylamine (0.2 mL, 0.919 mmol) in anhydrous dichloromethane (6 mL) was treated with 4-fluorophenyl isocyanate (0.105 mL, 0.934 mmol) and stirred at RT for 16 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product which was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give 5-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a colorless oil. MS (ESI pos. ion) m/z: 433 (M+H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.NN>>[NH2:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Product: C=CCCCCCCCCCN
Yield: 66 %

Procedure:
Compound XXXI was prepared as described in Scheme I from 10-undecen-1-ol, 1, by a three step procedure in an overall yield of 31%. Alkylation of phthalimide with alkanol, 1, under Mitsunobu conditions, followed by reaction with hydrazine gave 1-aminoundec-10-ene, 2, in 66% yield. The amine was derivatized with O-acetylsalicyloyl chloride and the resulting alkene, 3, was oxidized to the acid using potassium permanganate. Removal of the acetate, followed by acid precipitation provided compound XXXI in 47% yield based on amine 2.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:25][C:26](C)([O-:28])C.[K+].ClCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][OH:28])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CC(C)(C)[O-]
Agent: OCCCl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccccc1C
Reaction time: 48 h
Yield: 32.4 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) was dissolved in tetrahydrofuran (150 ml), potassium t-butoxide (1.83 g, 15 mmol) added, stirred to dissolve, then 2-chloroethanol (1.3 ml, 20 mmol) added and the mixture heated at reflux overnight. A further portion of potassium t-butoxide (1.83 g) and of 2-chloroethanol (1.3 ml) was added and heating continued for 2 days. The tetrahydrofuran was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Recrystallisation from ethyl acetate/petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (1.18 g, 32%), m.p. 125°-127°.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(#N)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][O:16][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Reactant: O=C1CCC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CCC(=O)O)nc12
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
To a suspension of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.2 g, 0.68 mmol) in acetonitrile (10 ml) was added sodium hydride (50% in oil) (0.036 g, 0.75 mmol) and the mixture was stirred for 5 min. To the mixture was added succinic anhydride (0.1 g, 1.0 mmol) and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure. To the residue was added water and the solid that formed was isolated by filtration and washed with acetonitrile to give 0.24 g (89%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22]([O:24]C)=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O[N:30]1[C:34]2C=CC=CC=2N=N1.CN>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22](=[O:24])[NH:30][CH3:34])[C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A 10 ml portion of tetrahydrofuran solution containing 0.62 g (1.80 mmol) of 2-t-butoxycarbonyl-9-methoxycarbonylmethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was mixed with 2 ml of aqueous solution containing 0.22 g (5.40 mmol) of sodium hydroxide and stirred overnight at room temperature. This was acidified by adding 1 N hydrochloric acid and extracted with chloroform. The extract was washed with water and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was dissolved in 12 ml of acetonitrile, and the solution was mixed with 557 mg (2.70 mmol) of N,N-dicyclohexylcarbodiimide and 365 mg (2.70 mmol) of 1-hydroxybenzotriazole and stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C., mixed with 2 ml of 40% methylamine aqueous solution and again stirred at room temperature for 30 minutes. The insoluble matter was removed by filtration, the solvent was removed by evaporation under a reduced pressure and then the resulting residue was purified by a silica gel column chromatography (130 cc; elution by chloroform-methanol=30:1) to obtain 542 mg of the title compound (88% in yield).