Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20](Cl)=[CH:19][C:18]=2[N+:24]([O-])=O)[CH:13]([C:27](O)=[O:28])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[ClH:30]>C(O)(=O)C.[Fe]>[Cl:30][C:21]1[CH:22]=[C:17]2[C:18]([NH:24][C:27](=[O:28])[CH:13]3[CH2:12][N:11]([C:1]([O:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:2])[CH2:16][CH2:15][N:14]32)=[CH:19][CH:20]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Cl)cc2N2CCN(C(=O)OCc3ccccc3)CC12
Temperature: 60 °C
Yield: 37 %

Procedure:
To a solution of the above residue 4-carbobenzyloxy-l-(4-chloro-2-nitrophenyl)piperazine-2-carboxylic acid in 200 ml glacial acetic acid warmed to 60° C. was added iron powder (14 g) in portions. The reaction was heated at 60° C. for 3 h. The reaction was cooled to rt and 1N HCl was added. The resulting precipitate was filtered and dried. The crude material was dissolved in methylene chloride and passed through a plug of celite. The filtrate was concentrated to a dark red residue. This was purified by the Biotage 40i (4.0×15.0 cm column, load methylene chloride, elute 30-50% ethyl acetate/hexanes) to give 9-chloro-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one as an off-white solid (4.8 g, 37% yield over 3 steps). 1H NMR (CDCl3, 300 MHz) δ7.32-7.37 (m, 5H), 6.82-6.85 (m, 1H), 6.68-6.75 (m, 2H), 5.18 (m, 2H), 4.73 (m, 1H), 4.31 (m, 1H), 3.49-3.54 (m, 2H), 3.07 (m, 2H), 2.74-2.81 (m, 1H) ppm. MS (ESI) m/z=372 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][NH:31][CH3:32])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C=O.[C:38]([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][N:31]([CH3:38])[CH3:32])=[O:22])=[CH:34][CH:35]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-methylaminomethylphenyl)benzamide (154 mg) in a mixture of methanol (10 ml) and acetic acid (0.5 ml) were added aqueous formaldehyde (0.2 ml) and sodium cyanoborohydride (20.9 mg) and the solution was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-dimethylaminomethylphenyl)benzamide (65 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[O-]CC.[Na+].O[NH:18][C:19](=[NH:22])[CH2:20][CH3:21]>C(O)C>[CH2:20]([C:19]1[N:22]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=2)[O:8][N:18]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCC(=N)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1noc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a mixture of 29.9 parts of ethyl 4-hydroxybenzoate and 316 parts of ethanol there were added portionwise 35.6 parts of sodiumethoxide. After stirring for 1/2 hour at room temperature, there was added dropwise a solution of 31.7 parts of N-hydroxypropanimidamide in 79 parts of ethanol. Stirring was continued for 1/2 hour at room temperature and overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. After neutralizing with acetic acid, the precipitate was filtered off and dried. It was purified by column chromatography (HPLC; silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was stirred in petroleumether. The precipitate was filtered off and dried, yielding 7.56 parts (22.1%) of 4-(3-ethyl-1,2,4-oxadiazol-5-yl)phenol; mp. 137.7° C. (interm. 6).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:39]([NH:38][CH2:36][CH3:37])=[O:40])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(NC)nc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 g (0.5 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was dissolved in dry dichloromethane (10 ml). Triethylamine (0.28 ml, 2 mmol) was added followed by the addition of ethylisocyanate (0.06 ml, 0.753 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.17 g, 72%) MS (EI): 459.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, (ppm)): 0.96 t (3H); 0.88-1.13 m (4H); 1.13-1.31 m (1H); 1.54-1.85 m (6H); 2.74 s (3H); 2.98 q (2H); 2.89-3.16 m (4H); 3.19-3.33 m (1H); 3.34-3.58 m (4H); 4.12-4.30 m (2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:32]2[C:23](=[N:24][C:25]3[C:30]([N:31]=2)=[CH:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH:26]=3)[CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:4][CH2:5][O:6][C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[I:46]I.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:32]2[C:23](=[N:24][C:25]3[C:30]([N:31]=2)=[CH:29][CH:28]=[C:27]([I:46])[CH:26]=3)[CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:4][CH2:5][O:6][C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2nc3c(C(=O)NCCN(CC)CCOc4cccnc4F)cccc3nc2c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(CCNC(=O)c1cccc2nc3cc(I)ccc3nc12)CCOc1cccnc1F
Yield: 54.1 %

Procedure:
To a stirred solution of compound 83 (270 mg, 0.37 mmol) in chloroform (7 mL), was added during 4 h, a solution of diiodine (192 mg, 0.76 mmol) in chloroform (14 mL), dropwise. The mixture was then stirred 14 h at room temperature before addition of an aqueous saturated sodium carbonate solution (40 mL). The solution was decanted and the organic layer was washed with a 5% aqueous sodium hydrogenosulfite solution (2×15 mL), dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, AcOEt/cyclohexane, 7/3, v/v) to give compound 84 (112 mg, 0.20 mmol) as a yellow oil. Yield 54%; Rf (Al2O3, AcOEt/cyclohexane, 7/3, v/v) 0.68; IR (CCl4) ν 1119, 1189, 1246, 1286, 1458, 1509, 1649, 2800-3000, 3246 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.14 (t, 3H, J=7.1 Hz), 2.86 (m, 4H), 3.05 (t, 2H, J=5.5 Hz), 3.76 (q, 2H, J=5.5 Hz), 4.10 (t, 2H, J=5.5 Hz), 6.80 (dd, 1H, J=4.9, 7.9 Hz), 6.97 (m, 1H), 7.53 (m, 1H), 7.83 (dd, 1H, J=1.4, 9.2 Hz), 7.93 (m, 2H), 8.25 (dd, 1H, J=1.5, 8.7 Hz), 8.60 (se, 1H), 8.92 (dd, 1H, J=1.5, 7.2 Hz), 10.92 (m, 1H); ESI-MS m/z 560.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][OH:25])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][O:25][S:41]([CH3:40])(=[O:43])=[O:42])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)NC1CCCc2nc(CCO)ncc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ncc2c(n1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(4-fluorophenyl)-N-[2-(2-hydroxy-ethyl)-5,6,7,8-tetrahydro-quinazolin-5-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (56.6 mg, 0.1 mmol) in dry CH2Cl2 at 0 C was added MsCl (34 mg, 0.3 mmol), followed by Et3N (50 mg, 0.5 mmol). After stirring at 0° C. for 20 min, the reaction was quenched with Sat. NaHCO3 solution, extracted with EtOAc, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, EtOAc/MeOH=100:3 to 100:5 to 100:7) gave the title compound as a white solid. MS: 645.0 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][N:10]=1)=[O:4].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH:20]1[C:32]2[NH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[C:23]([O:33][CH2:34][CH:35]([OH:43])[CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:22][CH:21]=1>C1COCC1>[CH:20]1[C:32]2[NH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[C:23]([O:33][CH2:34][CH:35]([OH:43])[CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]([NH:5][C:6]3[S:7][C:8]([CH3:11])=[CH:9][N:10]=3)=[O:4])[CH2:39][CH2:38]2)=[CH:22][CH:21]=1
Reactant: Cc1cnc(NC(=O)CBr)s1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)CN2CCN(CC(O)COc3cccc4[nH]c5ccccc5c34)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-Bromo-N-(5-methyl-1,3-thiazol-2-yl)acetamide (prepared following the procedure described in step I, example 58, 0.2 g, 0.92 mmol) in THF (10 mL) was added NaI (0.06 g, 0.38 mmol), and the reaction mixture was stirred at room temperature for 1 hour, subsequently K2CO3 (0.05 g, 0.38 mmol) was added and stirring was continued further for 10-15 minutes. To the above solution, 1-(9H-carbazol-4-yloxy)-3-piperazin-1-ylpropan-2-ol (prepared following the procedure described in step 11, example 26, 0.25 g, 0.76 mmol) in THF (10 mL) was added dropwise, followed by TEA (0.32 mL, 2.3 mmol) and the above was stirred at room temperature for 3 hours. The reaction mixture was then concentrated and diluted with EtOAc (50 mL), washed with water and brine. The organic layer was dried over anhydrous Na2SO4, concentrated and purified by silica gel column chromatography, using dichloromethane/MeOH (9.2:0.8) to afford of the title compound as yellow colored hygroscopic solid (0.152 g, 42% yield). 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 2.51-3.00 (m, 10H), 3.26 (s, 2H), 4.23-4.36 (m, 3H), 6.68 (d, 1H, J=8.0 Hz), 7.06-7.10 (m, 2H), 7.27-7.42 (m, 3H), 8.20 (s, 1H), 8.26 (d, 1H, J=8.0 Hz), and 10.16 (s, 1H). MS m/z: 480.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[Cl:8][C:7]1[C:2]([N:17]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:12])[CH2:18]2)=[N:3][CH:4]=[C:5]([CH2:9][O:10][CH3:11])[CH:6]=1
Reactant: C[C@@H]1CNCCN1
Reactant: COCc1cnc(Cl)c(Cl)c1
Product: COCc1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of 2,3-dichloro-5-methoxymethyl-pyridine from step (a) above (370 mg, 1.93 mmol) and (R)-(−)-2-methyl-piperazine (231 mg, 2.3 mmol, Aldrich) reacted under the condition of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 256 (M+1).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:10][C:11](=[O:14])[CH2:12][NH2:13]>>[CH:1]1([NH:13][CH2:12][C:11]([OH:14])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN
Reactant: O=C1CCCCCC1
Product: O=C(O)CNC1CCCCCC1

Procedure:
N-Cycloheptylglycine was synthesized by reductive amination of cycloheptanone with glycine methyl ester following the procedure described in Gera et al., Immunopharmacology. 33:174–177 (1996). The crude product was converted to the N-Boc derivative (mp, 89–90° C.).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: OCc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3-Amino-5-(trifluoromethyl)phenyl)methanol (1.0 g, 5.23 mmol) in dry acetonitrile (6 mL) was added dropwise to a solution of copper (II) chloride (0.83 g, 6.2 mmol) and tert-butyl nitrite (0.9 mL, 7.5 mmol) in acetonitrile (6 mL) at 65° C. After 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) afforded 0.8 g (73%). 1H-NMR (CDCl3, 500 MHz) δ 7.54 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 4.74 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH2:10][CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 39.8 g (185 mmol) 4-bromo-2-ethyl-6-methyl-phenol, 63.9 g (0.46 mmol) K2CO3 and 22.0 mL (185 mmol) benzyl bromide in 450 mL acetonitrile was refluxed for 3 h, cooled to RT and concentrated by evaporation i. vac. The residue was combined with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i. vac.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:18]=[CH:17][C:9]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1.C(OC(N1CCC(CC2C=CC(C3OCCN=3)=CC=2)CC1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:17][CH:18]=1
Reactant: c1cc(C2=NCCO2)ccc1CC1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C3=NCCO3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1

Procedure:
4-[4-(2-oxazolin-2-yl)benzyl]piperidine from 1-tert.butoxycarbonyl-4-[4-(2-oxazolin-2-yl)benzyl]piperidine and trifluoroacetic acid. Melting point: 110° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:21])[C:15]1[O:16][CH2:17][C:18](=[O:20])[N:19]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][C:37]([Cl:41])=[CH:38][CH:39]=2)[C:34]([CH2:42]Cl)=[CH:33]1)=O)C1C=CC=CC=1>O1CCCC1.CCCCCC.O>[Cl:41][C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[C:34]2[CH2:42][CH:17]1[O:16][C:15]([N:14]([CH3:21])[CH3:13])=[N:19][C:18]1=[O:20]
Reactant: CN(C)C1=NC(=O)CO1
Reactant: O=C(OCc1ccccc1)n1cc(CCl)c2cc(Cl)ccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C1=NC(=O)C(Cc2c[nH]c3ccc(Cl)cc23)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a solution of diisopropylamine (1.18 ml) in tetrahydrofuran (24 ml) was added a 1.6 M solution (5.24 ml) of n-butyllithium in hexane under ice cooling. The mixture was cooled to −78° C., to which was added 2-dimethylamino-2-oxazolin-4-one (1.07 g). The mixture was stirred for 30 minutes at room temperature and cooled again to −78° C. 1-benzyloxycarbonyl-5-chloro-3-chloromethylindol (1.40 g) was added. The whole was stirred at −78° C. to −40° C. for 30 minutes, at 0° C. for 2 hours and at room temperature for 40 minutes respectively. To the reaction mixture was added water and the whole was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give a residue, which was subjected to silica gel chromatography. Elution with hexane-ethyl acetate (1:1) gave 5-[(5-chloroindol-3-yl)methyl-2-dimethylamino-2-oxazolin-4-one (232 mg) as a crystal.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[C:16]1([C:22]2([CH2:28][C:29]#[N:30])[CH:27]=[CH:26][CH2:25][CH:24]=[CH:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([C:22]2([CH2:28][CH2:29][NH2:30])[CH:27]=[CH:26][CH2:25][CH:24]=[CH:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCC1(c2ccccc2)C=CCC=C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: NCCC1(c2ccccc2)C=CCC=C1

Procedure:
0.68 g. of aluminum trichloride and 0.24 g. of lithium aluminum hydride are placed in 8 ml. of absolute ether. 1 g. of 1-phenyl-2,5-cyclohexadien-1-acetonitrile in 5 ml. of absolute ether is added dropwise while stirring. After stirring at room temperature for 2 hours, the mixture is worked-up as follows: The mixture is treated with 1 ml. of water and 25 ml. of 3 N aqueous sodium hyroxide, filtered under suction and the filter rinsed with ether. After separating the phases, the organic phase is dried over sodium sulfate, filtered and concentrated to dryness. The crude product obtained is chromatographed on 50 g. of Alox (neutral), educt being first of all eluted with ether and then end product being eluted with methylene chloride/methanol (10:1). There is obtained 1-phenyl-2,5-cyclohexadien-1-ethylamine as an oily product. 3 g. of this product are converted in the usual manner into the hydrochloride which, after recrystallization from methylene chloride/ether, has a melting point of 170°-172° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Li]CCCC.[C:17](=[O:19])=[O:18].O>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=[O:18]
Reactant: Cc1cccc2c1ccn2C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2c1cc(C(=O)O)n2C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
A solution of 1,4-dimethyl-1H-indole (0.9 g, 6.2 mmole) in anhydrous Et2O (20 mL) was treated with 2.5 M n-BuLi in hexanes (5.0 mL, 12 mmole) and the reaction was heated at reflux for 15 hr. The dark reaction mixture was poured into a slurry of excess crushed dry ice in Et2O, and the mixture was allowed to stand for 1 hr. Water (10 mL) was added, the layers separated, and the aqueous layer was filtered through Celite®. The clear filtrate was acidified with 2.0 N HCl to pH 2, and the precipitate was collected and dried to afford the title compound (0.29 g, 26.4%) as an off-white solid: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5].[C:19](=O)=O.C[Mg]Cl.[Cl-].[NH4+]>C1COCC1.C(OCC)C.C(O)C>[C:12]1([C:9]2[N:10]=[CH:11][C:6]([C:4](=[O:5])[CH3:19])=[CH:7][N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1cnc(-c2ccccc2)nc1
Reactant: O=C=O
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)c1cnc(-c2ccccc2)nc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution consisting of N-methoxy-N-methyl-2-phenylpyrimidine-5-carboxamide (Step I, 1.80 g, 7.39 mmol) in anhydrous THF (20 mL) was cooled in a −60° C. bath (ethanol, CO2(s)). Methylmagnesium chloride (Aldrich, 3.0 M in THF, 2.75 mL, 8.14 mmol) was subsequently added dropwise to the reaction mixture. The reaction mixture was stirred for 30 minutes in the −60° C. bath and was subsequently allowed to warm to room temperature over one hour. The crude reaction mixture was then poured into a separatory funnel that contained diethyl ether (200 mL) and saturated ammonium chloride (150 mL). The organic layer was separated and the aqueous layer was washed again with diethyl ether (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a white solid as the crude product. The crude solid was triturated with a hexane-ethyl acetate (9:1 v/v) mixture (20 mL). The precipitate in solution was filtered to afford the title compound as a white solid (1.15 g, 78% yield); Rf 0.72 with 1:1 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 9.25 (s, 2H), 8.53 (dd, 2H), 7.58 (m, 3H), 2.63 (s, 3H); MS (APCI+) m/z 199.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:37][CH2:38][CH2:39][F:40])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: FCCCBr
Product: COc1ccc(CC2c3c(OC)ccc(OCCCF)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [CH:1](N(CCOC1C(C)=CC(C(C)(C2C=CC=CC=2)CC(C2C=CC=CC=2)=O)=CC=1)C(C)C)(C)C.O1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][O:43][C:44]2[C:49]([CH3:50])=[CH:48][C:47]([C:51]([CH3:67])([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH2:52][C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:54])=[CH:46][CH:45]=2)[CH2:37][CH2:36]1>>[N:38]1([CH2:41][CH2:42][O:43][C:44]2[C:49]([CH3:50])=[CH:48][C:47]([C:51]([CH3:67])([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH2:52][C:53]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:46][CH:45]=2)[CH2:37][CH2:36][CH2:1][CH2:40][CH2:39]1
Reactant: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1OCCN(C(C)C)C(C)C
Reactant: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1OCCN1CCOCC1
Product: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1OCCN1CCCCC1

Procedure:
4-[2-(N,N-diisopropylamino)-ethoxy]-3,5-dimethyl-β,β-diphenylpropiophenone (hydrochloride: hereinafter "BC 79") 4-[2-morpholino-ethoxy]-3,5-dimethyl-β,β-diphenylpropiophenone
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:21])[CH:18]=[N+]=[N-])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:22].CC(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:21])[CH2:18][Br:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
4-(2-Diazo-acetyl)-piperidine-1-carboxylic acid benzyl ester (44 g, 0.15 mol) in EtOAc (300 mL) was cooled to 0° C. The solution was treated with 33% HBr/HOAc (75 mL, 0.42 mol) over 15 min and stirred at ambient temperature for 2 hours. The mixture was slowly treated with saturated NaHCO3 solution (300 mL) until pH was neutral or slightly basic and filtered. The solution was dried over MgSO4 and subjected to a 330 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford 4-(2-bromo-acetyl)-piperidine-1-carboxylic acid benzyl ester (38.1 g, 81%): MS (ESI) m/z 341 [M+H]+.