Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:49]2[N:50]=[C:51]([NH2:53])[S:52][C:48]=2[C:47]([N:54]([CH3:61])[CH:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[CH:46][CH:45]=1>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:53][C:51]1[S:52][C:48]2[C:47]([N:54]([CH3:61])[CH:55]3[CH2:56][CH2:57][O:58][CH2:59][CH2:60]3)=[CH:46][CH:45]=[C:44]([O:43][CH3:42])[C:49]=2[N:50]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(N(C)C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 7 h
Yield: 62 %

Procedure:
To a stirred solution of 103 mg (0.51 mmol) 2-bromo-isonicotinic acid in 3 ml THF were added 204 mg (0.53 mmol) HATU and 0.11 ml (1.02 mmol) N-methylmorpholine and stirring continued at 30° C. for 7 h. 75 mg (0.26 mmol) 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-yl)-benzothiazole-2,7-diamine was then added and stirring continued at 40° C. for 16 h. The reaction mixture was then diluted with ethyl acetate and washed sequentially with saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane) followed by trituration in ether/pentane afforded 77 mg (63%) 2-bromo-N-{4-methoxy-7-[methyl-(tetrahydro-pyran-4-yl)-amino]-benzothiazol-2-yl}-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 479 (M{81Br}+H+, 100), 477 (M{79Br}+H+, 95).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Br[C:35]1[N:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:41][C:38]1[CH:37]=[N:36][C:35]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:4][CH2:3][C:2]([F:1])([F:32])[F:33])=[C:7]([CH3:21])[CH:8]=2)=[N:40][CH:39]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: Clc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A reaction mixture of 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoic acid (0.500 g), 2-bromo-5-chloropyrimidine (0.251 g), tetrakistriphenylphosphinepalladium (0.125 g), sodium carbonate (0.343 g), DME (3 mL) and water (1 mL) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.407 g).
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:46]([C:48]1[CH:63]=[C:62]([C:64](=[NH:67])[NH:65]O)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]>>[CH2:46]([C:48]1[CH:63]=[C:62]([C:64]2[N:67]=[C:37]([C:36]3[CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:65]=2)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]
Reactant: CC(C)c1cc(C=O)cc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3cc(C=O)cc(C(C)C)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 7.8 %

Procedure:
The title compound (49 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-5-isopropyl-benzoic acid (250 mg, 1.30 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (423 mg, 1.30 mmol); LC-MS**: tR=0.90 min; [M+1]+=481.85.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([OH:16])[CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1.O>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([O:16][CH:7]([CH2:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:21]
Reactant: OC(CSc1ccccc1)Cn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC(CSc1ccccc1)Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(1-imidazolyl)-3-phenylthiopropan-2-ol and 5 g (0.213 mole), in pyridine (15 ml) was cooled in an ice and water bath; then 4.9 g [3.3 ml (0.0235 mole)] 2,4-dichlorobenzoyl chloride was added dropwise. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with a sodium bicarbonate solution, then several times with water and once with brine, dried, treated with activated charcoal, filtered and concentrated to give a brown gum (8.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27]N)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][N:6]2[C:5](=[O:15])[C:4]3[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=3)[C:7]2=[O:14])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CN2C(=O)c3cc(N)c([N+](=O)[O-])cc3C2=O)C1
Temperature: 140 °C
Yield: 45.9 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (994 mg, 4.8 mmol), 3-Aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) and imidazole (493 mg, 7.25 mmol) in dioxane (140 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 61 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (400:10:1) afforded the title compound (830 mg, 46%). 1H NMR (MeOH-d4) δ 1.44 (s, 9H), 2.94 (m, 1H), 3.78 (m, 2H), 3.88 (d, J=6 Hz, 2H), 4.00 (m, 2H), 7.44 (s, 1H), 8.52 (s, 1H); ESI-MS m/z 377.3 (MH+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)=O>CO>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)C
Agent: O=C=O
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@@H](N)CC(C)C)C(C)C

Procedure:
850 mg of Z-Sta-Val-Tyr-Lys(Boc)-OMe are dissolved in 17 ml of 95% strength MeOH and hydrogenated with 85 mg of Pd-on-carbon with CO2 -absorption until saturation (approximately 1 hour). The catalyst is filtered off, the filtrate is concentrated to dryness and dried in a high vacuum at 40° yielding H-Sta-Val-Tyr-Lys(Boc)-OMe in the form of an amorphous powder; Rf (E)=0.58; Rf (H)=0.50. The resulting product is further reacted in stage 1.10.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:37])=[C:34](Br)[CH:35]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:37])=[C:34]([C:9]5[CH:10]=[CH:11][C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:7][CH:8]=5)[CH:35]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: CNS(=O)(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cnc2C)cc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-(4-(N-methylsulfamoyl)phenyl)pyridin-3-yl)cyclopropanecarboxamide was prepared from 4-(N-methylsulfamoyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH:14]([CH3:17])[CH2:15][OH:16].O.ClCCl>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH:14]([CH3:17])[CH2:15][OH:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(N)CO
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: CC(CO)Nc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
A mixture of 20 g of 4,7-dichloroquinoline and 16 g of 2-amino-1-propanol in 60 ml of butanol was stirred at reflux. The reaction was complete after three days of stirring and the vessel was allowed to cool to room temperature. Water was added to the mixture and extraction was conducted with dichloromethane. Drying over anhydrous magnesium sulfate and evaportion of solvents resulted in 17 g of solid which was triturated with ether. Recrystallization from ethanol/acetone gave 16 g of crystalline solid with a melting point of 210°-212° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>[OH-].[Na+]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:39]3[CH2:40][CH2:41][S:37][CH2:38]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CSCN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(F)ccc1-c1cc(N2CCSC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 12 %

Procedure:
A mixture of 0.25 g (0.47 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.59 g (6.6 mmol) thiazolidine was heated three times at 180° C. for 30 minutes and once at 250° C. for 15 minutes under microwave irradiation in a sealed tube. The reaction mixture was diluted with a 0.2 M aqueous solution of sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography and drying in high vacuo (70-90° C./1-2 mbar) for three hours gave 33 mg (12%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[C:6]([N:14]=[C:15]=[S:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:1]([NH:5][C:15]([NH:14][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[S:16])[CH2:2][CH2:3][NH:4][C:15]([NH:14][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:16]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCCN
Solvent: ClCCl
Product: O=C(NC(=S)NCCCNC(=S)NC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To an ice cold solution of propane-1,3-diamine (2.77 g, 37.4 mmol) in CH2Cl2 (60 mL) is added dropwise benzoyl isothiocyanate (12.50 g, 77 mmol). The reaction mixture is stirred at room temp for 3 h and the solvent is removed in vacuo. The residue is suspended in MeOH (80 ml) and filtered to give 13.2 g (88%) of the title compound as a white solid. LC/MS (Condition A): ret. T=3.81 min, (M+H)+ 401.14.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:30][CH3:31])=O)C1C=CC=CC=1.CO>[C].[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:30][CH3:31]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1OC

Procedure:
The same operation as in Example (40e) was performed using methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methoxybenzoate obtained in Example (258a) (35 mg, 0.08 mmol), a 10% palladium-carbon catalyst (9 mg), methanol (1.5 mL) and ethyl acetate (1.5 mL), to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1/[CH:10]=[CH:11]/[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]2OCC[O:20]2)[C:14](=[O:24])[CH2:13]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1/[CH:10]=[CH:11]/[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]=[O:20])[C:14](=[O:24])[CH2:13]1
Reactant: Cc1cccc(C)c1/C=C/C1CCN(CC2OCCO2)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1/C=C/C1CCN(CC=O)C(=O)C1
Yield: 97.3 %

Procedure:
After 3 ml of 10% hydrochloric acid was added to a solution of 818 mg of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]-1-(1,3-dioxolane-2-ylmethyl)piperidin-2-one in 10 ml of tetrahydrofuran, the mixture was heated under reflux for 4.5 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 685 mg of {4-[(E)-2-(2,6-dimethylphenyl)vinyl]-2-oxopiperidin-1-yl}acetaldehyde.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)(=[O:20])[CH3:19]>N1CCCCC1.C(Cl)(Cl)Cl>[C:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[C:3]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:1][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(C=O)c1
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C=C2C(=O)c3ccccc3OC2c2ccccc2)c1

Procedure:
A solid mixture of 9 g flavanone, 7.2 g 3-acetylaminobenzaldehyde and 5 drops piperidine is heated at 150°-160° C. for 3 hours. After allowing to cool, the crude brown glass is dissolved in chloroform and eluted from silicagel with chloroform. The pale yellow oil, obtained on evaporation of the solvent is crystallized from hexane and ethyl acetate to give 3(3-acetylaminobenzylidene)-flavanone as a cream coloured solid; m.p. 172°-173° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:3]1=[O:21].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:3]1=[O:21]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2)c1=O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In a flask were placed 25.88 g (0.086 mole) of 1-methyl-3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 200 mL of methylene chloride. To this flask was added dropwise 258 mL (0.258 mole) of a 1 molar solution of boron tribromide in methylene chloride. Upon completion of addition, this reaction mixture was allowed to stir at ambient temperature for approximately 64 hours after which it was poured over ice. This mixture was filtered to remove insoluble material, and the aqueous and organic layers of the filtrate were separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving 1-methyl-3-(4-hydroxyphenyl)-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione as a residue. The NMR spectrum was consistent with proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35]>CN(C=O)C.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
80 g (250 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) was added in portions over 20 minutes to a mixture of NaH (19.98 g, 500 mmol) in anhydrous DMF (400 mL) at 0° C. under nitrogen. After the addition was complete the ice bath was removed and the mixture was stirred at rt for 1 hour before cooling the solution to 0° C. To the cooled solution was added a solution of 1-(chloromethyl)-2,4-dimethoxybenzene (107 g, 575 mmol) in benzene and the reaction mixture was allowed to warm to rt. After 16 hours the reaction mixture was poured into ice water (2 L) and extracted with EtOAc (3×1 L). The organics were pooled, washed with water (3×1 L), sat. aq. NaCl solution (1 L), dried (MgSO4), filtered and concentrated in vacuo to provide a thick yellow oil. Purification on the Combiflash XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) using four stacked 330 g columns and one 1.5 kg column and eluting with 35-40-45-50-55% EtOAc/hexanes provided a very pale yellow oil. This was dissolved in benzene and the solvent removed in vacuo and dried under vacuum for 2 days to provide the title compound as a white foam (105.8 g, 90%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])([C:22]([OH:24])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]2[CH2:17][CH2:18][C:19]([C:22]([OH:24])=[O:23])([C:25]([OH:27])=[O:26])[CH2:20][CH2:21]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(C(=O)O)CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCC(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
A solution of 5.3 g (0.015 mol) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1,1-dicarboxylic acid (Example 2) in 100 mL of ethanol was combined with 1.2 g of 10% palladium-on-carbon catalyst and hydrogenated on a Parr apparatus at room temperature for 3 h. After the catalyst was removed, the solution was concentrated in vacuo to a gum. This gum was crystallized from ether:hexane and then recrystallized three times from ether:hexane to give 4.0 g (74%) of 4-(2-phenyl-1H-indol-3-yl)cyclohexane-1,1-dicarboxylic acid, m.p. 196°-197° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH:8]=1)(=O)=O.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].[F-].[Cs+]>O1CCOCC1>[C:13]([CH:10]1[CH2:11][CH2:12][C:7]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=2)=[CH:8][CH2:9]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=CCC(C(C)(C)C)CC2)cc1
Reaction time: 16 h

Procedure:
A mixture of Example 5A (286 mg, 1.0 mmol), (4-methoxycarbonylphenyl)-boronic acid (216 mg, 1.2 mmol), Pd(dppf)Cl2CH2Cl2 (37 mg, 0.05 mmol), and cesium fluoride (454 mg, 3.0 mmol) in dioxane (5 mL) was heated to 90° C., stirred for 16 hours, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][O:28][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>CN(C=O)C>[CH3:27][O:28][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:26]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.2 g of NaH (80% suspension in mineral oil), 12 g of 1.4.5-triphenyl-4-imidazolin-2-one, 80 cc. of DMF, 9.5 g of 8-bromocaprylic acid methyl ester and 1.2 g of NaJ.