Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH2:12][CH2:11][NH:10][C:9](=[O:15])[C:8]=2[C:7]=1[C:16]([F:19])([F:18])[F:17])=[O:5])[CH3:2].[H-].[Na+].Br.Br[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:9](=[O:15])[C:8]=2[C:7]=1[C:16]([F:18])([F:19])[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)NCC2
Reactant: CCN(CC)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)N(CCN(CC)CC)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
A stirred mixture of 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.6 g, 9.4 mmol) in 40 ml of N,N-dimethylformamide was cooled down to 0° C. in an ice-water bath, added with sodium hydride slowly. Upon the completion of the addition, the reaction mixture was cooled down to −30˜−40° C. and added with (2-bromo-ethyl)-diethyl-amine hydrobromide (2.95 g, 11.3 mmol) in 15 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature overnight and extracted with saturated sodium chloride (100 ml) and dichloromethane (100 ml). The combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane: methanol:ammonia (16:1:0.1) as eluents to give 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1 g, 28.4) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(C=O)c1
Yield: 88 %

Procedure:
A solution of 3-hydroxybenzaldehyde (1.22 g, 10 mmol) in anhydrous acetone (50 mL) was treated with K2CO3 (2.76 g, 20 mmol) and Mel (0.9 mL, 15 mmol) at room temperature for 12 hours. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by flash column chromatography (0–15% EtOAc in hexanes, 1.2 g, 88% yield). 1H NMR (300 MHz, CDCl3) δ: 3.88 (s, 3 H), 7.17–7.21 (m, 1 H), 7.38–7.42 (m, 1 H), 7.45–7.47 (m, 2 H), 9.99 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH:12]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=2[N:14]2[C:31]([CH3:34])=[N:32][N:33]=[C:13]12)C)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[CH3:1][NH:8][CH2:10][CH2:11][CH:12]1[C:18](=[O:19])[N:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:16]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=2[N:14]2[C:31]([CH3:34])=[N:32][N:33]=[C:13]12
Reactant: [H][H]
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2CCN(C)Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CNCCC1C(=O)N(c2ccccc2)c2cc(Cl)ccc2-n2c(C)nnc21

Procedure:
4 g of 4-[2-(N-benzyl-N-methylamino)ethyl]-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of ethanol containing 0.4 g of Raney nickel is hydrogenated at 50 p.s.i. hydrogen pressure until 0.0085 moles of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.
Reaction SMILES: C([Li])CCC.CCCCCC.[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:21]1([CH2:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][NH:12][C:13]2=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCCN1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NCCCCC1Cc1ccccc1
Temperature: -50 °C
Reaction time: 3 h

Procedure:
A solution of n-butyl lithium in hexane (2.5 M, 178 ml, 0.444 mol) was added dropwise to a mechanically stirred solution of hexahydroazepin-2-one (22.8 g, 0.202 mol) in tetrahydrofuran (400 ml) over a period of 90 minutes at 0° C. The solution was stirred for 3 hours and then cooled to -50° C. Benzyl bromide (24 ml, 0.202 mol) in tetrahydrofuran (100 ml) was then added dropwise over a period of 1 hour and the reaction mixture allowed to warm slowly to room temperature and stirred for 15 hours. Addition of water (100 ml) and saturated aqueous ammonium chloride (100 ml) was followed by extraction of the aqueous phase with ethyl acetate (3×100 ml). The combined organic phases were washed with brine, dried with sodium sulphate and evaporated in vacuo. Flash column chromatography upon silica gel of the resulting oily solid using ethyl acetate: methanol (25:1) as eluant afforded a solid which was recrystallised from benzene/hexanes to give the desired product as an off white solid, 10.3 g, M.pt. 99°-104° C., M+ found: 203.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15]>CO.CCOC(C)=O.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[CH2:5]2
Reactant: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N)c2c1CN(C)C2=O
Reaction time: 8 h

Procedure:
Pd/C (7.67 mg, 0.0720 mmol) was added to a solution of 4-methoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one in MeOH (2 mL) and EtOAc (2 mL) and the mixture was hydrogenated at stp overnight. The solution was filtered and the title compound was not further purified. MS (ES+): m/z 193.14 (100) [MH+]; HPLC: tR=0.65 min (UPLC, analytical).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc2cc(N)ccc2nn1
Product: CCOC(=O)c1cc2cc(NC(C)=O)ccc2nn1
Temperature: 100 °C

Procedure:
Ethyl 6-aminocinnolin-3-yl carboxylate (obtained as described below) was dissolved in acetic anhydride (25 ml.). The solution was heated at 100° C. for 16 hours and then allowed to cool to room temperature, and the resulting mixture was filtered to give, as solid residue, ethyl 6-acetylamino-cinnolin-3-yl carboxylate, m.p. 256°-258° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([O:31]C)=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([OH:31])=[O:30])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of methyl 2-phenyl-3-(4-phenylpiperazin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.24 mmol, 1.00 equiv) and sodium hydroxide (47 mg, 1.18 mmol, 5.00 equiv) in methanol (10 mL) was placed in a 100-mL round bottom flask and stirred for 2 h at 50° C. in an oil bath. The pH value of the solution was adjusted to 4-5 with hydrochloric acid (1 M). The resulting solution was extracted with 3×10 mL of dichloromethane, and the organic layers combined and concentrated under vacuum, yielding 70 mg (72%) of 2-phenyl-3-(4-phenylpiperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (40 mg, 0.11 mmol, 1.00 equiv) in methanol (10 mL). Then a solution of sodium hydroxide (22.67 mg, 0.57 mmol, 5.00 equiv) in water (1 mL) was added. The resulting solution was stirred for 5 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 30 mg (76%) of 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CC)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Temperature: 60 °C
Yield: 98 %

Procedure:
To a solution of ethyl (2E)-3-(4-{[3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoate (59) (0.67 g, 1.49 mmol) in THF (10 mL) and EtOH (10 mL) was added 1 N NaOH (12 mL). The resulting mixture was heated at 60° C. for 2 h. Cooled in an ice bath, the mixture was acidified with 2 N HCl and extracted with EtOAc (3×50 mL). The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was triturated with hot hexanes (containing a small amount of CHCl3 and MeOH) to give 0.62 g (98%) of the title compound (60) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J=7.5 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 6.23 (d, J=15.9 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.10-7.16 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 7.20-7.30 (m, 5H), 7.60 (s, 1H), 7.63 (d, J=15.8 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 423 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[F:31][C:25]1[CH:24]=[C:23]([NH:22][C:10]2[C:9]([OH:8])=[C:14]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[N:13]=[CH:12][N:11]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cc1ccc(-c2ncnc(Nc3ccc(C#N)c(F)c3)c2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ncnc(Nc3ccc(C#N)c(F)c3)c2O)cc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
The compound from step 5 (0.3 g, 0.73 mmol) was dissolved in (3:1) MeOH/THF (7.3 ml), 10% Palladium on carbon (30 mg) was added and the mixture placed under H2 (1 atm). After 1 hour LCMS showed that the reaction was complete, the catalyst was removed by filtration and the mixture concentrated to give 200 mg of the title compound. LCMS=321.2 (MH+)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:20])C(Cl)(Cl)Cl)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@H:29]([NH2:32])[CH2:30][CH3:31].C(N(CC)CC)C.[OH-].[K+]>O1CCCC1.CO.O>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@H:29]([NH:32][C:15]([C:8]1[N:9]2[C:10]([CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=1)=[O:20])[CH2:30][CH3:31]
Reactant: CC[C@@H](N)c1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)O)c2n1CCOC2)c1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 4a) (1 g, 2.94 mmol) in anhydrous tetrahydrofuran (9 ml) was added (R)-1-(2,4-difluoro-phenyl)-propylamine (0.5 g, 2.94 mmol) and triethylamine (1.22 ml, 8.8 mmol). The resulting mixture was stirred for 24 h, then another portion of (R)-1-(2,4-difluoro-phenyl)-propylamine (0.05 g) and triethylamine (0.8 ml) was added. The mixture was stirred for 2 days and then evaporated to dryness. To the residue was added 50 ml water, 50 ml methanol and potassium hydroxide (0.84 g, 15 mmol) and the mixture was heated to 80° C. for 15 h. A further portion of potassium hydroxide (0.84 g) was added and the mixture was heated to 80° C. for 17 h. After evaporation of methanol, dilution with 70 ml water and acidification with excess aqueous 2 N hydrochloric acid, the precipitate was filtrated and washed with 50 ml water to give 0.65 g (60% over 2 steps) of 6-[(R)-1-(2,4-difluoro-phenyl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as yellowish powder. LC/MS (method 4): Rt=1.19 min; m/z=365.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:36][NH:37][CH3:38]>O>[CH3:36][N:37]([CH3:38])[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Reactant: CNC
Solvent: O
Product: CN(C)c1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 0.69 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 7 ml of 50% aqueous dimethylamine solution was stirred in a sealed tube at 80° C. of outer temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and the solvent was evaporated. The residue was washed successively with isopropanol and diisopropyl ether to give 0.52 g of colorless crystals. Recrystallization from isopropanol gave colorless crystals having the melting point of from 170.5 to 171.5° C.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3cccc4cccc2c34)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
(RS)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (1.5 g, 4 mmol) was dissolved in dimethylformamide (DMF, 15 ml). Sodium hydride (200 mg, 60%) was added and the suspension was stirred at 50° C. for 30 min. The mixture was cooled to room temperature, ethyl bromoacetate (0.75 g, 4.5 mmol) was added and the mixture was stirred for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.6 g) as pale-yellow crystals.
Reaction SMILES: C/C=C(\C([O:7][C@@H:8]1[C@:16]2([CH3:38])[C@@H:17]([CH2:33][C:34]([O:36]C)=[O:35])[C@:18]3([CH3:32])[C:22]4=[C:23]([CH3:31])[C@H:24]([C:26]5[CH:27]=[CH:28][O:29][CH:30]=5)[CH2:25][C@H:21]4[O:20][C@@H:19]3[C@H:14]3[C@H:15]2[C@:11]([CH3:39])([CH2:12][O:13]3)[C@H:10]([O:40]C(C)=O)[CH2:9]1)=O)/C>[OH-].[Na+].CO>[CH3:31][C:23]1[C@H:24]([C:26]2[CH:27]=[CH:28][O:29][CH:30]=2)[CH2:25][C@H:21]2[O:20][C@@H:19]3[C@@H:14]4[O:13][CH2:12][C@@:11]5([CH3:39])[C@H:15]4[C@:16]([CH3:38])([C@@H:8]([OH:7])[CH2:9][C@H:10]5[OH:40])[C@@H:17]([CH2:33][C:34]([OH:36])=[O:35])[C@:18]3([CH3:32])[C:22]=12
Reactant: C/C=C(/C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C)CO[C@H]3[C@H]4O[C@@H]5C[C@@H](c6ccoc6)C(C)=C5[C@@]4(C)[C@H](CC(=O)OC)[C@]1(C)[C@@H]32
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C2[C@@H](C[C@H]1c1ccoc1)O[C@@H]1[C@@H]3OC[C@]4(C)[C@H](O)C[C@H](O)[C@@](C)([C@@H]34)[C@@H](CC(=O)O)[C@]21C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
Salannic acid (1c) was prepared by a modification of the method of de Silva et al. (1969), supra. Salannin (30 mg, 0.050 mmol) was dissolved in 2.0 mL of 0.5 N NaOH in 50% aqueous methanol and incubated at 60° C. for 6 h. The reaction mixture was poured onto 10 mL of 0.5 N HC1 and extracted three times with 10-mL portions of diethyl ether. The organic layers were combined, washed once with 10 mL of saturated aqueous sodium chloride, and rotary evaporated in vacuo. Purification of the crude product by silica gel preparative HPLC (solvent = isopropanol-n-hexane acetic acid, 10:90:1) yielded salannic acid (16 mg). The IR spectrum of salannic acid showed the loss of the absorptions at 1710, 1655, and 735 cm-1, assigned to the tigloyl group (Henderson et al., 1968; Butterworth, J. H., et al. J. Chem. Soc.. Perkin Trans. I. 1972, 1445-2450; Yamasaki and Klocke, unpublished data), and the appearance of a very broad, intense absorption at 3400 cm-1 characteristic of a carboxylic acid (Silverstein et al., Spectrometric Identification of Organic Compounds, 4th ed. Wiley, New York, 1981, pp. 204-208). All of the 1H-NMR absorptions of the tigloyl (δ1.81, 1.94, and 6.96), acetyl (δ1.94, and carbomethoxyl (δ3.24) groups had vanished.
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](Cl)=[O:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C=C(C)C)CC3)nc(N)c2cc1OC
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.7 g of 3,3-dimethylacryloyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from dimethylformamide to give 1.24 g of the desired product in the form of colourless powdery crystals melting at 278°-280° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:32][S:33]([O:22][CH2:21][C@H:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 87.5 %

Procedure:
A mixture of (R)-(1,4-dibenzylpiperazin-2-yl)methanol (4.00 g, 13.49 mmol, US2007/0088039) and Hünig's base (2.35 mL, 13.49 mmol) in CH2Cl2 (27 mL) was stirred at 0° C. and methanesulfonyl chloride (1.04 mL, 13.49 mmol) was added drop-wise. The reaction mixture was filtered through a short pad of silica gel, using 19:1 CH2Cl2/Et2O (1000 mL) to rinse. The filtrate was concentrated in vacuo while maintaining the temperature below 25° C. Diethyl ether was added to the residue, the resulting slurry was placed in a sonicator for 1 min, filtered through a fitted funnel and the filtrate was concentrated to give a white solid ((2R)-1,4-dibenzyl-2-piperazinyl)methyl methanesulfonate (4.42 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15][O:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1c(O)cccc1C=O
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1OCc1c(C)cccc1C

Procedure:
The solution of 3-hydroxy-2-methoxybenzaldehyde (5.06 g, 32.7 mmol), 2,6-Dimethylbenzyl chloride (5.04 g, 33.1 mmol) and K2CO3 (4.78 g, 34.6 mmol) in dry DMF (15 ml) was stirred at room temperature under argon for 16 hours, then diluted with EtOAc (40 ml), and washed with water (20 ml). The organic layer was concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound as an off white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH:16][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=4)=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C2CCCCC2)c2sc(N)nc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Temperature: 70 °C
Yield: 13.7 %

Procedure:
To a solution of 0.05 g (0.19 mMol) 7-cyclohexyl-4-methoxy-benzothiazol-2-ylamine in 2 ml THF were added 0.1 ml ethyl diisopropyl amine and 0.027 ml (0.23 mMol) 4-fluoro-benzoyl chloride. The reaction mixture was heated to 70° C. for 2 h. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:9, 1:4) to yield 0.01 g (14%) of N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide as a light yellow solid; F.p.: 192-195° C.