Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:11]O>C(O)CCC>[N+:1]1([O-:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1ccc2ncccc2c1
Solvent: CCCCO
Product: [O-][n+]1cccc2ccccc21

Procedure:
A quantity of 40 ml n-butanol, 25 ml 96% quinoline i.e. 203 mmoles and 250 mg SeO2 is introduced successively into a reactor with a capacity of 125 ml. 6 ml of 85% H2O2 are then added in 10 minutes (i.e. 200 mmoles), and the mixture is allowed to react for 2 hours at 343 K. whilst removing the water formed by azeotropic distillation. 140 mmoles of quinoline oxide are obtained in this way. The results are as follows:
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(Cl)=[O:17]>C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]=[C:16]=[O:17])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(COc2ccccc2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 4-phenoxymethylaniline (10 g) in toluene (100 ml) was added dropwise to a solution of phosgene (20 g) in toluene (100 ml) at 10° to 20° C. The mixture was gradually heated and refluxed for 30 minutes. Thereafter, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give 7 g of 4-phenoxymethylphenyl isocyanate. M.P., 56°-57° C.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH2:14])[C:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(=O)[O-])cc1N
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cyanogen bromide (5M, 1.44 mL, 7.22 mmol) was slowly added to a suspension of 3,4-diaminobenzoate (1.0 g, 6.02 mmol) in water (10 mL). The mixture was stirred at room temperature for 24 hours. An aqueous solution of Na2CO3 (10%) was added slowly until the product had precipitated as a brown solid (890 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.[NH:18](/[C:22](/[CH3:28])=[CH:23]\[C:24](OC)=[O:25])[C:19]([CH3:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:28])[N:18]=[C:19]2[CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(N2CCCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 3-fluoro-4-(pyrrolidin-1-yl)aniline (0.50 g, 2.78 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (14 mL, 14 mmol, 1 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (480 mg, 3.06 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (300 mg, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:34])([F:33])[C@@H:20]([N:22]1[CH:26]=[N:25][N:24]=[C:23]1[C:27]1[S:28][CH:29]=[C:30]([NH2:32])[N:31]=1)[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:32][C:30]4[N:31]=[C:27]([C:23]5[N:22]([C@@H:20]([CH3:21])[C:19]([F:34])([F:33])[F:18])[CH:26]=[N:25][N:24]=5)[S:28][CH:29]=4)=[O:17])[CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](n1cnnc1-c1nc(N)cs1)C(F)(F)F
Reactant: O=C(O)c1cc(-n2cnc(C3CC3)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](n1cnnc1-c1nc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1)C(F)(F)F
Yield: 69.9 %

Procedure:
A solution of 4-(4-cyclopropyl-1H-imidazol-1-yl)picolinic acid (50 mg, 0.218 mmol), (S)-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-amine (53 mg, 0.208 mmol), HATU (99 mg, 0.262 mmol), and N-methylmorpholine (30 μL, 0.262 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile/water and the solids were isolated by filtration, washed with water (2 mL), acetonitrile (2 mL) and diethyl ether (5 mL) and dried under vacuum to afford (S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide as a white powder (69 mg, 71% yield).
Reaction SMILES: [Na].Cl[C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:15][CH3:16])[CH:4]=1.Cl.[CH3:18][OH:19]>>[CH3:16][O:15][C:5]1[CH:4]=[C:3]([O:19][CH3:18])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CO
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Na]
Product: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C

Procedure:
In a stream of argon, 0.30 g of metallic sodium was added to 5 ml of methanol under ice-cooling, the mixture was stirred at room temperature for a while and then 1.00 g of 4-chloro-2-methoxy-5-nitrobenzoic acid was added to the resulting solution in small portions, followed by stirring at 80° C. for 8 hours. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.80 g of 2,4-dimethoxy-5-nitrobenzoic acid.
Reaction SMILES: C[N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:28]([O:27][C:25]([N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1)=[O:26])[CH3:29]
Reactant: CN1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 712 mg of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine in 5 ml toluene is added 1.2 g of ethyl chloroformate and the reaction mixture is heated at reflux temperature with stirring for 8 hours. On cooling to room temperature the reaction mixture is diluted with 50 ml of diethyl ether and the resulting precipitate collected by filtration and washed well with ether. The filtrate is evaporated to dryness under reduced pressure to yield 1,3,4,16b-tetrahydro-2-ethoxycarbonyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine as an oil which is used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:13][CH:12]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.N.[K].[CH2:24](I)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:4]1([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: N
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCCC1(C(=O)OC)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 2-methoxynaphthoate (3.25 g, 15 mmol) and tert-butyl alcohol (1.48 ml, 15 mmol) in tetrahydrofuran (10 mL) at −78° C. was added liquid ammonia (60 mL). Potassium metal (2.9 g, 75 mmol) was added in small pieces until the solution stayed dark blue for 30 min. Butyl iodide (5.47 mL, 48 mmol) was added dropwise (the blue coloration disappeared about half-way through addition) and stirring was continued for 1 hour at −78° C. The solution was allowed to warm to room temperature and purged with nitrogen to remove excess ammonia. To the resulting slurry a solution of saturated sodium bicarbonate (100 mL) was added, and the solution was extracted with ether (3×50 mL). The combined organic phases were washed with 10% Na2S2O3 (aq), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) gave the title compound as a light yellow oil. This oil was triturated with hexane to afford a white solid (3.2 g, 77.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([OH:33])=O)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([NH2:40])=[O:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
To a solution of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoic acid (145 mg, 1.37 mmol) in CH2Cl2 (5 mL) was added HOBt (167 mg, 1.24 mmol), EDCl (243 mg, 1.24 mmol) and DIEA (194 mg, 1.55 mmol) under NH3 at 0° C. The mixture was stirred at rt overnight. 1N HCl was added and the mixture was extracted with CH2Cl2. The organic layer was dried and concentrated to give the residue, which was purified by preparative HPLC to give 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide (21 mg, 15%). LC-MS Method 2 tR=1.16 min, m/z=491, 469, 425. 1H NMR (CDCl3, 400 MHz): 1.43 (d, 3H), 1.88-1.95 (m, 1H), 2.07-2.19 (m, 5H), 2.40 (m, 1H), 2.83 (m, 1H), 4.21 (m, 1H), 5.18 (s, 1H), 5.33 (s, 1H), 5.56 (m, 1H), 6.64 (d, 2H), 6.85 (d, 2H), 6.97 (t, 2H), 7.17 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[O:21]=[C:22]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1)[CH2:23][CH2:24][C:25](O)=[O:26].CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:18][O:17][C:15]([CH2:14][C@@H:10]1[N:11]([C:25](=[O:26])[CH2:24][CH2:23][C:22](=[O:21])[N:28]2[CH2:29][CH2:30][N:31]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:32][CH2:33]2)[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9]1=[O:19])=[O:16]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(O)CCC(=O)N1CCN(c2ncccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CCC(=O)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.1 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.45 g) and 4-oxo-4-(4-pyrimidin-2-ylpiperazin-1-yl)butanoic acid (0.46 g) produced in Reference Example 4 in acetonitrile (20 ml) and dimethylformamide (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g) and the suspension was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the solution was added saturated brine and the solution was extracted with ethyl acetate. The extract was dried over Na2SO4 and was concentrated under reduced pressure. To the produced ester derivative was added trifluoroacetic acid (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.45 g) as a white amorphous powdery product.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+:7]([CH3:9])C.CO[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[N:13]=1.N1C=CC=CC=1.F[B-](F)(F)F>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:12][N:13]1[C:6]([O:7][CH3:9])=[CH:17][CH:16]=[CH:15][CH:14]1[CH:18]=[O:19]
Reactant: COc1cccc(C=O)n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=CC=CC(C=O)N1C

Procedure:
A 3 mL glass vial was equipped with a rubber septum and magnetic stir bar. The vial was brought into a glove box and charged with trimethyloxonium tetrafluoroborate (198 mg, 1.33 mmol). The vial was sealed and removed from the glove box. A separate 3 mL vial was charged with 2-methoxy-6-pyridinecarboxaldehyde (Aldrich #662933, 184 mg, 1.34 mmol) and was dissolved in CH2Cl2 (1.5 mL). The solution of pyridine was added via syringe onto the solid trimethoxonium tetrafluoroborate at room temperature. The vial which contained the pyridine was rinsed with CH2Cl2 (1 mL) and the rinse solution was injected into the reaction vial. The reaction vial was kept at room temperature and stirring was maintained at ca. 400-600 rpm. Over the course of the reaction (17 h), the solid trimethoxonium tetrafluoroborate gradually dissolved, the solution clarified, and an oil gradually formed. At the end of the reaction, hexanes (2 mL) were added after which stirring was stopped. Any solid or oil was allowed to settle and the solvent was removed by glass pipette. The solid or oil was then rinsed with several portions of hexanes followed by diethyl ether. Residual solvent was then removed in vacuo to provide the compound N-methyl-6-methoxy-2-pyridinecarboxaldehyde tetrafluoroborate. This oil was used for oxime formation without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:22][CH2:21][C:18]3([O:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][C:18]([CH2:19][NH:26][CH:23]3[CH2:25][CH2:24]3)([OH:20])[CH2:21][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(N3CCC4(CC3)CO4)cc2)cc1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1(CNC2CC2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Yield: 85.8 %

Procedure:
6-[4-(benzyloxy)phenyl]-1-oxa-6-azaspiro[2,5]octane (500 mg, 1.69 mmol) and cyclopropylamine (195 mg, 3.38 mmol) were mixed in methanol, and heated overnight under reflux. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product. The resulting crude product was purified through silica gel column chromatography (eluate: methanol/chloroform=1/99 to 6/94) to obtain the entitled compound (511 mg, 85%) as a yellow solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][CH:28]([CH2:32][CH3:33])[C:29](O)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[CH:28]([CH3:27])[CH2:32][CH3:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CCC(C)C(=O)O
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (77 mg, 75%), MS (ISP) m/z=411.4 [(M+H)+], mp 172° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>O>[NH2:1][C@H:2]([C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: NCC(=O)O
Reactant: CSCC[C@H](N)C(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)NCC(=O)O

Procedure:
The title compound was prepared according to the procedures of Example 1A and B above by replacing DL-methionine with L-methionine (Aldrich Chemical Co., Beil. 4(2),938). The title compound had a melting point of 188° to 190° C (d). The compound was found to be water soluble. The product thus obtained was subjected to amino acid analysis and found to contain 49.42 mole percent glycine and 50.58 mole percent methionine.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[CH:20]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[CH:20]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(-c2ccccc2)nc(Cl)c1C#N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)nc(N2CCN(c3ccc(O)cc3)CC2)c1C#N
Temperature: 110 °C
Reaction time: 10 h
Yield: 51.1 %

Procedure:
12.26 g (36 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 8.24 g (36.1 mmol) of 2-chloro-3-cyano-4-methyl-6-phenylpyridine and 7.46 g (54 mmol) of powdered K2CO3 in 135 ml of absolute DMF were reacted at 90° C. according to the procedure described in Example 20. The mixture was subsequently stirred for 10 hours at 110° C. After removal of the DMF by distillation, the residue was taken up in CH2Cl2 /water. After thorough mixing, separating the phases and extraction of the aqueous solution, the CH2Cl2 extracts were combined, dried and evaporated. The crystalline residue (14.6 g) was recrystallized three times as follows. The substance was dissolved in a boiling mixture of CH2Cl2 /CH3OH 1:1, and the majority of the CH2Cl2 was then removed by distillation. A product crystallized out of the CH3OH solution obtained, and was filtered off under suction and again recrystallized in this fashion. Further impure substance was isolated from the mother liquors by concentration etc, and this was finally recrystallized again as described above. In this fashion, 6.82 g (=51% yield) of 1-(4-hydroxyphenyl)-4-(3-cyano-4-methyl-6-phenylpyrid-2-yl)piperazine, melting point 207°-08° C., were obtained;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[CH3:21][C:20]1[C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:13][C:12]=2[N:17]=[CH:18][CH:19]=1
Reactant: CC#CCN
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a mixture of 5-(2-methylphenyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.86 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.74 g), and the mixture was stirred at room temperature for 1 hour and then refluxed for 17 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred at 220° C. for 4 hours, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.52 g).
Reaction SMILES: Cl.CO[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1OC)[NH:9][C:8](C)=[C:7]2CCN1CCC(C2C=CC=CC=2)CC1.C([SiH](CC)CC)C.[Sn].Cl>FC(F)(F)C(O)=O.C(O)C>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COc1cc2[nH]c(C)c(CCN3CCC(c4ccccc4)CC3)c2cc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CCN2

Procedure:
The appropriately substituted intermediate indoles (5) are dissolved in trifluoroacetic acid and are treated with triethylsilane at 45°-50° C. for 48-96 hours, or are heated at reflux in ethanol for 48 hours in the presence of tin and hydrochloric acid, and in each case the mixture is then poured onto cracked ice. The resultant mixtures are made basic and are extracted with solvents such as chloroform, methylene chloride, or ethyl acetate. The extracts are evaporated to give the substituted-2-methyl-3-[2-(4-phenylpiperidino), (4-phenyl-1-piperazinyl) and [4-(2pyridyl)-1-piperazinyl]ethyl]-indoline compounds (6). The acid salts are obtained by treating the indoline (6) with hydrogen chloride in a solvent such as ethyl ether, ethyl acetate, or ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14](I)[C:13]([CH3:22])=[N:12]2)=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:14]2[C:13]([CH3:22])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(I)c(C)nn1-c1cnc(OC)nc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-3-methyl-1H-pyrazole-5-carboxylate (Step 52.2) and 4-chlorobenzaldehyde at RT for 30 min. tR: 5.02 min (HPLC 1); tR: 1.11 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.38 (hexane/EtOAc 1:1).