Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].ON1C2C=CC=CC=2N=N1.O.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[Br:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:28](=[O:29])[C@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH2:15][CH2:14]2)=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: Brc1cnc2[nH]ccc2c1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
5-Bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.20 g, 0.56 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.677 g, 2.25 mmol) were placed in DCM (5 mL) at room temperature. 1-Hydroxybenzotriazole (“HOBT”)—H2O (0.121 g, 0.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (“EDCI”; 0.14 g, 0.73 mmol), and triethylamine (0.39 mL, 2.82 mmol) were then added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude residue. The crude residue was purified by column chromatography (500:7 DCM:MeOH) to give (R)-tert-butyl 1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.20 g, 62.9% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A 100 mL round-bottom flask was charged with 4-fluoro-2-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol, 1.00 equiv), morpholine (0.500 g, 5.74 mmol, 1.10 equiv), potassium carbonate (1.40 g, 10.1 mmol, 2.00 equiv), DMSO (15 mL). The resulting solution was stirred overnight at 100° C., diluted with H2O (10 mL), extracted with ethyl acetate (3×10 mL). The organic layers were combined and washed with brine (1×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.00 g (74% yield) of 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 260 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>CN(C=O)C.C(Cl)Cl>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH:35][C:8](=[O:10])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=4)[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C=CC(=O)Nc2ccc3nc(N4CCC(N(C)C)C4)sc3c2)cc1
Yield: 62 %

Procedure:
Combine 4-methylcinnamic acid (0.093 g, 0.572 mmol), CH2Cl2 (5.0 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.17 mL, 1.91 mmol) and stir the mixture for 2.5 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a solution of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial for 1 h at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with aqueous 1.0 M NaOH (50 mL), concentrate in vacuo, and purify using silica gel chromatography (12 g column, 10-20% MeOH/CH2Cl2 for 16 min.) to afford the title compound as a yellow solid (96 mg, 62%). mass spectrum (m/e): 407.3 [M+1], 405.2 [M−1]. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.71 (d, 1H, J=15.6 Hz), 7.67 (s, 1H), 7.50 (d, 1H, J=9.2 Hz), 7.39 (d, 2H, J=7.2 Hz), 7.13-7.19 (m, 3H), 6.51 (d, 1H, J=15.6 Hz), 3.82 (t, 1H, J=8.0 Hz), 3.71 (t, 1H, J=9.2 Hz), 3.53 (m, 1H), 3.39 (t, 1H, J=8.0 Hz), 2.89 (m, 1H), 2.36 (s, 3H), 2.30 (s, 6H), 2.25 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1

Procedure:
Starting materials: (2-{(E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A8) (0.141 g), CH2Cl2 (10 ml), TFA (1 ml). Reaction conditions: room temperature, 20 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH2:64])[CH2:40][C@H:41]([OH:63])[C@@H:42]([NH:50][C:51](=[O:62])[C@H:52]([C@H:58]([CH2:60][CH3:61])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1>CN(C=O)C>[S:27]1[C:31]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][N:39]([NH:64][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:40][C@H:41]([OH:63])[C@@H:42]([NH:50][C:51](=[O:62])[C@H:52]([C@H:58]([CH2:60][CH3:61])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:36][CH:37]=2)=[CH:30][N:29]=[CH:28]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl-(L)-valine, 288 mg (1.5 mmol) of EDC and 135 mg (1.0 mmol) of HOBT in 2 ml of DMF and 418 μL of TEA are reacted with 0.5 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane in 5 ml of DMF to form the title compound: m.p: 202-204° C.; HPLC20-100: tRet=14.0; FAB MS (M+H)+=697.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
A solution of isobutylamine (6.64 mL, 66.8 mmol) and pyridine (6.24 mL, 77.1 mmol) in DCM (100 mL) was treated with 4-fluorobenzene sulfonyl chloride (10.0 g, 51.4 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Trituration with pentane gave 4-fluoro-N-isobutyl-benzenesulfonamide (10.48 g, 88%) as a pale yellow solid. 1H NMR (400 MHz, DMSO) δ 7.88-7.81 (m, 2H), 7.63 (t, J=6.1 Hz, 1H), 7.47-7.39 (m, 2H), 2.54 (t, J=6.5 Hz, 2H), 1.67-1.55 (m, 1H), 0.80 (d, J=6.7 Hz, 6H). LCMS (m/z, Method B) ES+ 232.0 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:25])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17](=[O:23])[C:16]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:40][CH:27]1[CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>C(O)(C)C>[CH3:21][C:19]1([CH3:22])[NH:18][C:17](=[O:23])[C:16]2[CH:24]=[C:12]([O:11][CH2:10][CH:9]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:40][CH:27]([OH:26])[CH2:28][O:29][C:30]3[CH:39]=[CH:38][C:33]([C:34](=[O:35])[NH:36][CH3:37])=[CH:32][CH:31]=3)[CH3:25])[CH:13]=[CH:14][C:15]=2[O:20]1
Reactant: CNC(=O)c1ccc(OCC2CO2)cc1
Reactant: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)NCc1ccccc1
Solvent: CC(C)O
Product: CNC(=O)c1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc3c(c2)C(=O)NC(C)(C)O3)cc1

Procedure:
A solution of 13.6 g of 6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one and 10.4 g of 4-(2,3-epoxypropoxy)-N-methylbenzamide in 80 ml of isopropanol is refluxed for 30 hours. The residue remaining after the solvent has been evaporated off is divided between ether and 2N hydrochloric acid. The acidic, aqueous phase is separated off, and, whilst cooling with ice, rendered alkaline with approximately 10% aqueous ammonia solution and extracted with ethyl acetate. By separating off, drying (MgSO4) and concentrating the ethyl acetate extract by evaporation, the crude 1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethyl]benzylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol is obtained as an oil which may be used without further purification for catalytic debenzylation.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22]Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:38]=[N+:39]=[N-:40].[Na+].[I-].[Na+]>CN(C=O)C>[C:32]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][N:38]=[N+:39]=[N-:40])=[O:12])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC(COCCCl)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
195 mg (0.362 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide was dissolved in 10 ml of DMF. 35.3 mg (0.543 mmol) of sodium azide and 54.3 mg (0.362 mmol) of sodium iodide were added to the obtained solution, and they were stirred at 60° C. for 2 days. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: [ClH:1].N[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:11]=[N:10]1.N([O-])=O.[Na+].[S:27](=[O:29])=[O:28]>O.[Cu]Cl.C(O)(=O)C>[CH:18]1([CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[N:9]([C:4]3[CH:5]=[CH:6][C:7]([S:27]([Cl:1])(=[O:29])=[O:28])=[CH:8][CH:3]=3)[N:10]=[N:11]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccccc1-n1nnn(CCCC2CCCC2)c1=O
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1n(CCCC2CCCC2)nnn1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
To a solution of 32 mL of concentrated hydrochloric acid and 8 mL of glacial acetic acid at -20° C. was added 5.42 g of powdered 1-(4-aminophenyl)-4-(3-cyclopentylpropyl)-5-tetrazolone from Step D. The mixture was stirred for 5 min before a solution of 1.6 g of sodium nitrite in 10 mL of water was added at a rate which kept the temperature from rising above -10° C. The diazonium salt mixture was stirred an additional 40 min at -20° C. and then added in one portion to a solution of 32 mL of glacial acetic acid containing 690 mg of copper (I) chloride saturated with sulfur dioxide at 0° C. The resultant reaction mixture instantly changed in color from a dark green with nitrogen evolution to a lime green slurry as time progressed. The reaction mixture was allowed to warm from 0° C. to room temperature over 50 min. The mixture was then poured into ice-water and extracted with ethyl acetate. The combined organic extracts were washed once with cold water, dried over magnesium sulfate, filtered, and concentrated in vacuo to remove acetic acid. The crude sulfonyl chloride was purified by flash chromatography (silica gel, dichloromethane) to yield 3.4 g of the title compound as a white solid: 1H NMR (CDCl3) δ8.37 (d, 2H, J=9.1 Hz), 8.20 (d, 2H, J=8.6 Hz), 4.06 (t, 2H, J=7.1 Hz), 1.93 (m, 3H), 1.81 (m, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.41 (m, 2H), 1.11 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C(=O)([O-])O.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[OH:19][NH:18][C:1]([C:3]1[C:4]2[CH:5]=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1cccc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2[nH]ccc12
Temperature: 55 °C
Yield: 94.1 %

Procedure:
A mixture of 4-cyanoindole (5.0 g, 35.2 mmol), sodium hydrogen carbonate (8.9 g, 105.6 mmol) and hydroxylamine hydrochloride (4.9 g, 70.4 mmol) in ethanol (200 ml) was heated at 55° C. overnight. Sodium hydrogen carbonate (5.9 g, 70 mmol) and hydroxylamine hydrochloride (4.9 g, 70.4 mmol) was added. The mixture was heated for 4 days until only a small amount of starting material was present. The inorganics were filtered off, washing the solid well with ethanol and evaporated off the solvent. The residue was triturated with diethyl ether to give 5.8 g of off-white solid. δH (400 MHz, methanol-d4) 6.76-6.78 (1H, m), 7.12 (1H, t), 7.24 (1H, dd), 7.29-7.33 (1H, m) 7.46 (1H, dd).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F-].[K+].C1OCCOCCOCCOCCOCCOC1.[F:40][C:41]([F:46])([F:45])[C:42]([O-:44])=[O:43].[F:47]C(F)(F)C(O)=O>C1C=CC=CC=1.ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:10]12[CH2:11][CH:12]([C:16](=[O:19])[CH2:17][F:47])[CH2:13][CH:14]1[CH2:15][NH:8][CH2:9]2
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)CBr)CC2C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CF)C1CC2CNCC2C1

Procedure:
A mixture of 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.126 g, 0.380 mmol), potassium fluoride (0.067 g, 1.15 mmol) and 18-crown-6 (0.050 g, 0.19 mmol) in benzene (10 mL) was heated at reflux overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography, eluting with 20-30% ethyl acetate in hexanes, to obtain the cis isomer (0.022 g), trans isomer (0.030 g), and a mixture of cis/trans 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone (0.040 g), as oils. The separated isomers were de-protected and converted into their trifluoroacetate salts by reaction with trifluoroacetic acid in dichloromethane (5 mL) (ambient temperature, 1 h). The solvent was evaporated, and the products were dried by vacuum to obtain 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone trifluoroacetate as cis and trans isomers (0.025 g and 0.032 g, respectively) (1H NMR of trans isomer (CD3OD, 300 MHz): δ 5.08 (s, 1H), 4.93 (s, 1H), 3.37-3.29 (m, 2H), 3.24-3.16 (m, 3H), 3.00-2.95 9m, 2H), 2.34-2.22 (m, 2H), 1.69-1.58 (m, 2H); MS (m/z): 172 (M+1); 1H-NMR of cis isomer (CD3OD, 300 MHz): δ 5.13 (s, 1H), 4.98 (s, 1H), 3.60-3.52 (m, 2H), 3.78-3.67 (m, 2H), 3.12-2.96 (m, 3H), 2.38-2.15 (m, 2H), 1.91-1.64 (m, 2H); MS (m/z): 172 (M+1)). The cis isomer exhibited Ki values at rat and human α4β2 of 6.8 nM and 6.3 nM respectively and did not pass HTS for α7. The trans isomer exhibited a Ki value at rat and human α4β2 of 154 nM and 176 nM respectively and exhibited a Ki value at α7 of >10.000 nM.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[ClH:26].[CH3:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:30][CH2:29]1
Reactant: ClCCCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: CC1CCNCC1
Product: CC1CCN(CCCCCCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)CC1
Product: Cl

Procedure:
The compound was prepared by a method similar to Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-methylpiperidine mp 209°-214° C.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH:21]([CH3:23])[N:11]2[C:12]3[C:13]([C:19]#[N:20])=[CH:14][CH:15]=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:31]CCl>>[ClH:31].[CH3:23][C@H:21]1[N:11]2[C:12]3[C:17]([CH:18]=[C:10]2[CH2:9][NH:8][CH2:22]1)=[CH:16][CH:15]=[CH:14][C:13]=3[C:19]#[N:20]
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2cc3cccc(C#N)c3n21
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCc2cc3cccc(C#N)c3n21
Product: Cl

Procedure:
A solution of 80.0 mg (0.26 mmol) 6-cyano-4-methyl-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 3 ml dichloromethane was cooled to 0° C. and treated dropwise with 1 ml trifluoroacetic acid. After 30 min. the solution was concentrated at a rotary evaporator and the residue was chromatographed on silica gel (0.032-0.063 mm) with ethyl acetate: methanol: ammonia (9:1:0.1) as eluant. The product was dissolved in 3 ml diethyl ether and treated dropwise with 43 μl of a 6M hydrochloric acid solution in ethyl acetate. The suspension was filtered and the solid was dried under high vacuum to give the desired compound as light yellow crystals. EI-MS:: m/e=211.2 ([M]).
Reaction SMILES: [C:1]([O:9][CH:10]([C:18](=[O:20])[CH3:19])[C:11](=[O:17])[CH:12]=[CH:13]N(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:11](=[O:17])[CH:12]=[CH:13][O:20][C:18]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: CC(=O)O
Solvent: CCC(=O)O
Product: Cc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-dimethylamino-1-hexene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-methyl-4-pyrone, and,
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31](=[O:42])[N:32]2[CH2:39][CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:1]([O:5][C:6](=[O:25])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:40][CH2:39][N:32]2[C:33]3[C:28](=[C:27]([Br:26])[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=3)[CH:29]=[CH:30][C:31]2=[O:42])[CH2:10][CH2:9]1)[CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(Br)c2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(Br)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To 5 mL of dichloromethane solution containing 0.18 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.15 g of (5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and 29 μl of acetic acid were added and stirred at room temperature for 1 hour. To the reaction mixture, 0.16 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate] to give 0.17 g of tert-butyl(1-(2-(5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a light brown foam.