Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:33][CH2:34][CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)(=O)=O)=CC=1.C(Cl)Cl.CCOC(C)=O>CN(C=O)C>[C:43]([C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH2:35][CH2:34][CH2:33][N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:38][CH:39]=1)#[N:44]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 90 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 16.5 mmol; from Preparation B above) in DMF (75 mL) was added K2CO3 and 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate (5.5 g, 16.5 mmol; from Preparation D, step (b) above). The resulting solution was warmed to 90° C., stirred for 5 h, cooled and concentrated in vacuo. The residue was suspended in H2O and extracted with CH2Cl2 (3×). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography on silica gel eluting with CH2Cl2:EtOAc (3:1) gave 4.7 g (77%) of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH2:12](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:13]>CN(C)C=O.O.CCCCCC>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:12][CH3:13]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
1 mol of sodium hydride was added to the solvent dimethylformamide, and 1 mol of hydroxypivalic acid methyl ester was added thereto while the temperature of the solution did not exceed 30° C. The solution was stirred at room temperature for 90 minutes. Then, 1.2 mol of p-toluenesulfonic acid ethyl ester was added to the solution while the temperature of the solution did not exceed 30° C. Then, a water/hexane mixture having the same mass as that of the dimethylformamide was added to and mixed with the solution, after which water was removed therefrom. The resulting organic material was concentrated, and the residue was fractionated at atmospheric pressure and 108-111° C., thereby obtaining the intermediate 3-ethoxy-2,2-dimethylpropionic acid methyl ester at a yield of 34%.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>[OH-].[Na+].O1CCOCC1>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)OC1NC(=O)C1Cc1ccccc1
Reactant: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)SC1NC(=O)C1Cc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 0.76 g (10 mmole) of thioacetic acid in 10 ml of 1N sodium hydroxide solution is added dropwise to a solution of 2.19 g (10 mmole) of 4-acetoxy-3-benzylazetidin-2-one (racemic mixture of cis- and trans-isomer in the ratio of 9:13) in 10 ml of dioxan at room temperature under a nitrogen atmosphere, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated bv evaporation in vacuo. The residue is chromatogra.ohed over silica gel with toluene/ethyl acetate (9:1) and yields a cis-trans mixture of the title compound in the ratio of 2:10. By recrystallisation from methylene chloride/hexane at -10° the pure trans-compound having a melting point of 42°-43° is obtained.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[C:12]1([OH:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:22])=[CH:13][CH:14]=1)=[O:9]
Reactant: COC(=O)C(=O)Cl
Reactant: Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(O)c2ccccc12
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a suspension of AlCl3 (1.11 g, 8.3 mmol) in 50 mL DCM, methylchloroglyoxylate (1.02 g, 8.3 mmol) was added. The resulting solution was stirred for 5 min., after which naphthalen-1-ol (1 g, 6.9 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (10-30% EtOAc/Hex), to afford the target compound in 38% yield. Calculated mass=230. Observed mass=231.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1CO
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 86.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methoxyphenyl)methanol (65 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:2]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1nc(-c2cccnc2)cs1
Product: O=S(=O)(Nc1nc(-c2cccnc2)cs1)c1c(Cl)cc(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(3-pyridyl)-1,3-thiazol-2-amine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (29.3 mg) with purity >90%: MS (pos) m/z 422.1; HRMS m/z 418.9134 (calc. of monoisotopic mass for C14H8Cl3N3O2S2 gives 418.9123).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([NH:32]C(=O)C(F)(F)F)[CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[NH2:32][C:30]1[N:31]=[C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:10])=[CH:12]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Reactant: O=C(Nc1cccc(CBr)n1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(N)n3)c3ccccc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 75 mg (0.27 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 13 mg (0.32 mmol) of 60% sodium hydride, 92 mg (0.32 mmol) of N-(6-bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide and 0.7 mL of N,N-dimethylformamide. Yield: 20 mg of a white solid: LC-MSD, m/z for C23H20N4O2 [M+H]+=385.1; HPLC retention time: 0.3 min.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>CCOC(C)=O>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a vigorously stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (47.0 g, 238 mmol) in EtOAc (450 mL) at room temperature, anhydrous aluminum chloride (38.1 g, 286 mmol) was added in one portion. Then pyridine (77 mL, 954 mmol) was added drop wise at 45-50° C. for 30 min. The reaction mixture was refluxed for 2 h and allowed to cool down to 60° C. The reaction mixture was carefully poured into ice/concentrated HCl mixture (265 mL). After stirring at 50° C. for 1 h, the reaction mixture was cooled to 0° C. The formed precipitate was separated by filtration, washed with water, and vacuum-dried to afford the desired compound (29.4 g, 161 mmol, 67.3% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.O>C1C=CC=CC=1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]1=[O:16]
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCCCC1COCc1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: O=C1C(COCc2ccccc2)CCCC1Cc1ccccc1Br
Reaction time: 3 h

Procedure:
To a solution of the ketone of Example 113 in benzene is added pyrrolidine (4 equivalents). The mixture is heated to reflux for 24 hours removing the water formed by use of a Dean-Stark type apparatus. The reaction mixture is concentrated in vacuo. The organics are dissolved in dioxane followed by addition of 2-bromobenzyl bromide (1.5 equivalents). The mixture is heated to reflux for 6 hours. Water is added and the refluxing continued for 3 hours. The solution is concentrated in vacuo to dryness. The remaining organics are partitioned between ether and water. The ether layer is dried (MgSO4), concentrated in vacuo, then chromatographed to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[N:3]1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1
Reactant: O=[N+]([O-])O
Reactant: Cn1nccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cn1ncc([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C

Procedure:
A quantity comprising 69.0 gm (0.547 mol) of 1-methyl-1H-pyrazole-5-carboxylic acid of m.p.: 227°-228° C. (R. Huttel and M. E. Schon, Liebigs Ann. Chem 625, 55 [1959]) was added in small portions to a mixture of 200 ml of concentrated sulfuric acid and 60 ml of 90% fuming nitric acid under stirring. The temperature of the mixture rose from 75° C. at the beginning to a maximum temperature of 95° C. After the exothermal reaction was finished, heating was continued for 30 minutes up to 95° C. The cold mixture was stirred into 300 gm of cracked ice, and the resulting ice-cold suspension was filtered off by suction filtration. The filtration residue was washed with water, and after recrystallization from ethyl acetate, 44.0 gm (47% of theory) of pale yellow crystals were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH3:12])=[C:4]([OH:13])[CH:3]=1.[CH2:14]=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCOCC1>[CH3:12][O:11][C:5]1[C:6]([O:9][CH3:10])=[C:7]([OH:8])[C:2]([CH3:1])=[C:3]([CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:4]=1[OH:13]
Reactant: C1COCCN1
Reactant: C=O
Reactant: COc1c(O)cc(C)c(O)c1OC
Solvent: C1COCCO1
Product: COc1c(O)c(C)c(CN2CCOCC2)c(O)c1OC

Procedure:
A solution of 2,3-dimethoxy-5-methyl-1,4-benzohydroquinone (2.2 g), 37% formaldehyde (2.4 ml) and morpholine (2.4 ml) in dioxane (11 ml) was refluxed at 100° C. for 2 hours. The reaction mixture was evaporated to dryness and the residue was suspended in water. The suspension was extracted with chloroform and the extract was treated in a conventional manner. The residue was recrystallized from ether-hexane to give 2,3-dimethoxy-5-methyl-6-morpholinomethylhydroquinone (2.23 g), melting at 127°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.C1(C)C=CC=CC=1.[CH2:17](O)[C@@H:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC.N#N>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:17]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC[C@H](O)CO
Reactant: COc1cscc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1COc2cscc2O1
Yield: 68.8 %

Procedure:
A solution of 3,4-dimethoxythiophene (1.90 g), toluene (30 ml), (S)-1,2-dodecanediol (2.50 g) and p-toluenesulfonic acid monohydrate (100 mg) was heated at 95° C., continuously leading a N2-stream over the solution. After 24 h the reaction mixture was poured into ethyl acetate, washed with NaHCO3 and the organic phase was concentrated. Subsequent filtration over SiO2 using n-hexane/CH2Cl2 (98/2) as eluant resulted in pure product (2.40 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:25]=[CH:26][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:24][CH2:23]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.038 g, 0.18 mmol) and isopropanol (3 ml) was added 1-(4-chlorobenzyl)piperazine (0.042 g, 0.20 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.035 ml, 0.20 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (4 ml). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.034 g, 50%); 1H-NMR (500 MHz, DMSO-d6) 2.48 (br s, obscured by DMSO peak, 4H, piperazine N(CH2)2), 3.06 (br s, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 6.95 (s, 2H, NH2), 7.35 (d, J=8.50 Hz, 2H) and 7.38 (d, J=8.55 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.06 (s, 1H, 6-H);
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35]>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:40][CH:39]=1)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)C(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-isobutyryl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H34N4O4
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: NCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: CN(C)C=[O:4].Cl[C:7]([Cl:17])(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:18]([N:25](C=CC)C(=O)C)[C:19]1[CH:24]=C[CH:22]=[CH:21][CH:20]=1>>[Cl:17][C:7]1[C:21]([CH:22]=[O:4])=[CH:20][C:19]([CH3:24])=[CH:18][N:25]=1
Reactant: CC=CN(Cc1ccccc1)C(C)=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: Cc1cnc(Cl)c(C=O)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
Dimethylformamide (2.71 g, 0.037 moles) was added to a well stirred and cooled material of triphosgene (10.99 g, 0.037 moles) at 4° C. in 30 minutes in an ice bath followed by N-benzyl-N-(1-Propenyl)acetamide (1 g, 0.005 moles) at the temperature. The reaction mixture was further continued for 2 hours at 25° C. The ice cold bath was removed and heated to75° C. for 5 hours. Work up procedure was carried out according to the procedure of example 1. The obtained residue was subjected to chromatographic purification on silica gel to give 2-chloro-5-methylpyridine-3-carbaldeyde in 92% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:30][CH:31]=[O:32])#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C=CC=O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
To a solution of 3-cyanobenzaldehyde (4.5 g) in toluene (200 ml) was added (triphenylphosphoranylidene)acetaldehyde (13.6 g), and the resulting mixture was stirred at 70° C. for 4 hours and then evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using dichloromethane as the eluent. The crude product obtained was recrystallized from a mixture of toluene and hexane to afford the title compound (3.09 g, yield: 57%) as pale yellowish needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li]CCCC.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Cl.Cl[P:25]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[P:25]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1cccc(OC)c1
Reactant: Clc1ccccc1Br
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 36 %

Procedure:
To a solution of 1,3-dimethoxybenzene (2 ml, 15.30 mmol) in anhydrous THF (35 ml) at 0° C., nBuLi (6.2 ml, 15.50 mmol) is added to the dropping funnel for 5 min. The reaction medium is stirred at room temperature for 3.5 h, then 2-bromochlorobenzene (1.6 ml, 13.70 mmol) is added by syringe, dropwise, at 0° C., for 30 min. After 15 min of stirring, the reaction medium is cooled to −78° C. and nBuLi (6.20 ml, 15.50 mmol) is added to the dropping funnel dropwise for 5 min. After 30 min, chlorodicyclohexylphosphine (3.03 ml, 13.70 mmol) is added. The reaction medium is maintained at −78° C. for 1 h, under rapid stirring (mechanical stirring). After returning to room temperature, the precipitate obtained is filtered on a fritted disc containing silica topped with a layer of cellulose acetate, with 600 ml ethyl acetate. The solvents are evaporated with a rotary evaporator, and the orange oil obtained is recrystallized in acetone to obtain S-Phos ligand in the form of white crystals with a yield of 36% (1.22 g, 2.97 mmol).
Reaction SMILES: NC[C:3](O)=[O:4].[NH2:6][CH:7]([CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][OH:15])[C:8]([OH:10])=[O:9]>>[NH2:6][CH:7]([CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][O:15][CH:3]=[O:4])[C:8]([OH:10])=[O:9]
Reactant: NCC(=O)O
Reactant: NC(C(=O)O)C(O)CCCO
Product: NC(C(=O)O)C(O)CCCOC=O
Reaction time: 0.5 h

Procedure:
From the first aliquot taken at 0.5 h, two new amino aids were noted upon amino acid analysis. A small peak appeared at 15.6 min, just after the glycine peak. The other was a large, sharp peak at 22.5 minutes. By three hours, the peak at 22.5 minutes, corresponding to the expected amino acid reached a maximum at about 10% of the glycine peak and then slowly decreased while the peak at 15.6 minutes increased slightly in intensity. The amino acid eluting at 15.6 min is the product from slow hydrolysis of the formate ester in the reaction medium. The structure corresponds to α-amino-β-hydroxy-6-hydroxyhexanoic acid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: BrCCCc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.17 g), 1-bromo-3-phenylpropane (0.08 g) and potassium carbonate (0.15 g) in dry dimethylformamide (10 ml) was stirred at room temperature under nitrogen atmosphere. After 2 hours, additional 1-bromo-3-phenylpropane (0.14 ml) and potassium carbonate (0.15 g) were added, and the mixture was stirred overnight. Water (50 ml) and dichloromethane (50 ml) were added to the mixture. The dichloromethane layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (10 g) eluting with a mixture of toluene and ethyl acetate (4:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(3-phenylpropyl)piperazine (0.17 g) as a syrup.