Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[CH2:30][N:17]2[CH2:18][CH2:19][C:20]3[C:25]([CH:16]2[CH2:15][C:14]=1[NH2:31])=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:12])[CH3:9].[BH4-].[Na+].[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:8]([O:10][C:11]([CH:13]1[CH2:30][N:17]2[CH2:18][CH2:19][C:20]3[C:25]([CH:16]2[CH2:15][CH:14]1[NH:31][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:12])[CH3:9]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CN2CCc3cc(OC)c(OC)cc3C2CC1NCc1ccccc1
Reaction time: 0.67 h
Yield: 51.3 %

Procedure:
Trifluoroacetic acid (20 mL) was added at 0° C. to a solution of 2-amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (Example 1a; 2.00 g, 6.02 mmol) in tetrahydrofuran (20 mL), then after 30 min the homogeneous solution was treated with sodium borohydride (474 mg, 12.0 mmol) and stirred for another 40 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 2 M aq. sodium hydroxide solution and dichloromethane. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was dissolved in methanol (37 mL) and acetic acid (9 mL) and treated with benzaldehyde (723 mg, 6.81 mmol), then sodium cyanoborohydride (526 mg, 7.95 mmol) was added portionwise at r.t. over 1 h. The reaction mixture was stirred another 15 min, then partitioned between sat. aq. sodium hydrogencarbonate solution and dichoromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatrography of the residue (SiO2, CH2Cl2/EtOAc 4:1, after elution of dibenzylated side-product, CH2Cl2/MeOH/NH4OH 95:5:0.25) afforded the title compound (1.31 g, 51%). Red oil, MS (ISP) 425.2 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1>C1COCC1.[Pd]>[C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)NC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(C=Cc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 15.5 h
Yield: 49.6 %

Procedure:
To a solution of the product from Example 134 (0.178 g, 0.32 mmol) in 15 mL of THF was added 5% Pd/C (0.02 g) and 1 mL of pyridine. The mixture was subjected to hydrogenation for 15.5 hours at 20 psi. The crude reaction mixture was evaporated to dryness and purified by chromatography (silica gel, 50% ethyl acetate/hexane). The product was further purified by crystallizing from petroleum ether and toluene to give the title compound (0.089 g, 50%) as a white solid, mp 95-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[CH:4][C:3]=1C(O)=O.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(Cl)Cl.CS(C)=O.[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1>ClCCCl>[Cl:1][C:2]1([C:9](=[O:11])[NH:8][C:5]2[CH:6]=[CH:41][CH:40]=[C:39]([C:43](=[O:42])[NH:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:4]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:21])[F:19])[C:9](=[O:11])[NH2:10])=[CH:4][CH2:3]1
Reactant: Nc1cccnc1
Reactant: C1CCOC1
Reactant: NC(=O)N(c1ccc(Cl)c(C(=O)O)c1)c1ccccc1C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)N(C1=CCC(Cl)(C(=O)Nc2cccc(C(=O)Nc3cccnc3)c2)C=C1)c1ccccc1C(F)(F)F
Temperature: 36 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N′-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH2Cl2 (1M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36° C. overnight. Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was stirred at 36° C. for 72 h, then cooled to room temp. and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(N-(3-(N-(3-pyridyl) carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) Rf 0.12.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:20][CH:19]=1
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2,2-dimethoxyethylamine (526 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (861 mg) in methanol (25 ml) was added acetic acid (600 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (1.59 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and to the residue was added 1 N sodium hydroxide solution. The mixture was extracted with dichloromethane, dried and concentrated to give colorless oil of the title compound (1.21 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1cc(C2OCCO2)cs1
Yield: 96 %

Procedure:
To a mixture of thiophene-3-carbaldehyde (25.0 g), ethylene glycol (18.7 mL) and toluene (250 mL) was added p-toluenesulfonic acid monohydrate (2.13 g), and the mixture was stirred with heated under reflux for 7 hr while dehydrating using Dean-Stark (Dean-Stark) apparatus. Triethylamine (3.11 mL) was added to quench the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (33.6 g, 96%) as a dark brown oil.
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])C)(C)C.[N:16]1[C:21](C)=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23].[CH3:24][CH2:25][CH2:26]C[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1>[CH3:24][CH2:25][CH2:26][CH2:6][CH2:4][CH2:7][CH2:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:16]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cccc(C)n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCN

Procedure:
Lactol 8 [for the synthesis of 8, see Prostaglandins 1983, 25(3), 311] is condensed with Ph3P+CH2OCH3 Cl− in THF in the presence of potassium t-butoxide to afford enol ether 9. Conversion of 9 to lactol 10 is effected using HCl in aqueous isopropanol. Reaction of 10 with Ph3P+(CH2)3CO2H Br− in THF in the presence of potassium t-butoxide, followed by isolation of the product olefin acid and esterification with isopropyl iodide in the acetone in presence of DBU, provides ester 11. Treatment of 11 with TBSOTf and 2,6-lutidine in CH2Cl2, followed by addition of TBAF in THF, yields amine 12. DPA-mediated coupling of 12 with acid 6 gives amide 13, which is deprotected with TBAF in THF to afford III after chromatographic separation of the carbon 15 diastereomers.
Reaction SMILES: [CH:1]12[NH:16][CH:5]([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1)[CH2:4][O:3][CH2:2]2.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH:5]12[N:16]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:1]([CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.500 g, 2.2 mmol) in dichloromethane (5 ml) was added triethylamine (0.443 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for a few mins, and then benzyl chloroformate (0.751 g, 4.4 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and water. The organic phase was dried, and concentrated. The residue was purified by silica gel chromatography to give 9-benzyl 7-tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate 133b (0.637 g, 80.0%). MS: calc'd (MH+) 363, measured (MH+) 363.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[N:31][CH:32]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: NCc1ccc(F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add to a stirring mixture of 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (5.0 g, 13.25 mmol) and 2-aminomethyl-5-fluoropyridine (dihydrochloride) (2.9 g, 14.57 mmol) in anhydrous methylene chloride (60 mL), EDCI (3.8 g, 19.82 mmol) and 4-DMAP (6.0 g, 49.10 mmol). Stir the resulting solution overnight at room temperature, concentrate to a paste, and partition between ethyl acetate (100 mL), water (100 mL), and brine (100 mL). Dry the organic layer over sodium sulfate and concentrate to an oil. Dissolve the oil in methylene chloride and add to a biotage 65 cartridge. Elute with 1:1 ethyl acetate/hexanes to provide isolation of the pure 3 (N-(5-Fluoro-pyridin-2-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide as a solid, 5.7 g (89%): 1H NMR (DMSO-d6) δ 9.32 (t, J=5.9 Hz, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 2H), 8.12 (s, 1H), 8.03 (m, 3H), 7.82 (d, J=7.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 2H), 7.62 (dt, J=2.9, 8.8 Hz, 1H), 7.50 (t, J=7.3 Hz, 2H), 7.39 (m, 4H), 4.50 (d, J=5.9 Hz, 2H); MS (ESI) m/z 486 (m+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Yield: 89 %

Procedure:
4 g (20 mmol) 5-bromo-indoline in 50 ml CH2Cl2 were treated with 4.4 g (20 mmol) di.-tert.-butyldicarbonate at RT over night. The reaction mixture was concentrated in vacuo and triturated with hexane to yield 5.3 g (89%) 5-Bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless solid, MS: 297 (M, 1Br).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Mg].II.[C:17](O)(=[O:19])C>O1CCCC1.CN(C=O)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:17]=[O:19])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(=O)O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
To a reactor equipped with a stirrer are charged 10 grams of 2-bromo-6-methoxynaphthalene prepared as in Example 7 hereof, 1.05 grams of magnesium and 35 mL of tetrahydrofuran (THF). The reaction is initiated by addition of a crystal of iodine. After one hour of heating at reflux with stirring, 10 mL of DMF mixed with 10 mL of THF is added and the mixture is again refluxed with stirring for 1.5 hours. The reaction mixture is hydrolyzed by addition of dilute acetic acid and a precipitate of crude 6-methoxy-2-naphthaldehyde is formed. The precipitate is recovered by filtration, washed with water, and purified by crystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=O)[CH:6]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1>C(O)(=O)CC>[CH3:1][O:2][C:3]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:18]3[NH:14][C:15]([C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])[CH:6]=4)=[C:15]4[N:14]=[C:18]([C:11]([C:7]5[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])[CH:6]=5)=[C:15]5[NH:14][C:18](=[C:11]([C:7]6[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])[CH:6]=6)[C:15]6[CH:16]=[CH:17][C:18]=2[N:14]=6)[CH:17]=[CH:16]5)[CH:17]=[CH:16]4)=[CH:16][CH:17]=3)[CH:8]=[CH:9][CH:10]=1)=[O:13]
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: COC(=O)Cc1cccc(-c2c3nc(c(-c4cccc(CC(=O)OC)c4)c4ccc([nH]4)c(-c4cccc(CC(=O)OC)c4)c4nc(c(-c5cccc(CC(=O)OC)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
17.82 g (0.10 mol) of (3-formylphenyl)-acetic acid methyl ester (B RN 3231441) is dissolved in 300 ml of propionic acid and the solution is heated to 60° C. 6.71 g (0.10 mol) of pyrrole is instilled slowly and the dark solution is stirred for 1 hour at 110° C. After cooling, it is completely concentrated by evaporation in a vacuum, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After the drying of the organic phase on sodium sulfate, it is filtered and concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. The residue of the product fractions that are concentrated by evaporation is recrystallized from isopropanol.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O.[Pd]>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)C=CCC1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1-c1ccccc1
Yield: 79.4 %

Procedure:
A mixture of ethyl 2-phenylcyclohexa-1,3-dienecarboxylate(90 mg, 0.395 mmol) and 5% Pd/C(50 mg) in acetic acid(1.5 ml) and water(1.5 ml) was refluxed for 2hr. The reaction mixture was filtrated and the solvent was evaporated under reduced pressure. Toluene was added to the residue and it was dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 71 mg of ethyl 2-phenylbenzoate(y=80.0%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.82(1H, dd, J=1.4 and 7.7 Hz), 7.10-7.60(8H), 4.08(2H, d, J=7.0 Hz), 0.98(3H, t, J=7.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[O:8].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:5]1[N:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1
Reactant: Cn1ccnc1C=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)nc1C=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 43.1 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (10 g, 90 mmol) in deoxygenated DMF (300 mL) was treated with N-bromosuccinimide (17.8 g, 100 mmol) and the resulting solution stirred at RT for 6 days. Water (750 mL) was added and the resulting mixture was extracted with EtOAc (4×200 mL) the combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (n-heptane/EtOAc=4/1) to yield the title compound (7.33 g, 40%) as a white solid. LC-MS: m/z=191.2 (MH+), tR=0.48 minutes, method A. 1H NMR (600 MHz, DMSO-d6): δ 9.62 (s, 1H), 7.80 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[S+:11]=1)([CH3:9])([CH3:8])[CH3:7].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(OCC)C>C(OC(=O)C)(=O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([C:10]1[CH:15]=[C:14]([CH:16]=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=2)[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[S+:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc(C(C)(C)C)[s+]c(C(C)(C)C)c1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CN(C)c1ccc(C=Cc2cc(C(C)(C)C)[s+]c(C(C)(C)C)c2)cc1
Temperature: 100 °C

Procedure:
319 mg of 2,6-di-tert-butyl-4-methylthiopyrylium perchlorate and 150 mg of 4-dimethylaminobenzaldehyde were heated in 5 ml of acetic anhydride for 40 minutes on an oil bath maintained at 100° C. After allowing to cool, diethyl ether was added to precipitate crystals and then the crystals were recrystallized from ethanol. Yield: 210 mg; m.p.: 240° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:3].[CH:23]([Br:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Br-:26].[CH:23]([N+:2]([CH2:4][C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])([CH3:1])[CH3:3])([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: COc1ccccc1C=C(CN(C)C)c1ccccc1OC
Solvent: CCOC(C)=O
Product: COc1ccccc1C=C(C[N+](C)(C)C(C)C)c1ccccc1OC
Product: [Br-]
Reaction time: 504 h

Procedure:
2.2 Parts of N,N-dimethyl-2,3-di(2-methoxyphenyl)allylamine is combined with 5 parts by volume of isopropyl bromide. That mixture is allowed to stand at 65° for 21 days. Ethyl acetate is added to the solid which forms and the solid is broken and triturated. That mixture then is filtered, and the solid collected is washed with ethyl acetate and dried to afford N-isopropyl-N,N-dimethyl-2,3-di(2-methoxyphenyl)allylammonium bromide. That compound is structurally represented by the following formula ##STR10##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:21]([OH:24])[CH2:22][OH:23])[C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>ClCCl.CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:21]([OH:24])[CH2:22][O:23][Si:30]([CH3:32])([CH3:31])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C(O)CO[Si](C)(C)C(C)(C)C
Yield: 44.6 %

Procedure:
[(Tert-butoxy)carbonylamino]-3,4-dihydroxy-N-(phenylmethoxy)butanamide (47 g, 138 mmol), imidazole (37.5 g, 552 mmol) and tert-butyldimethylsilyl chloride (57.7 g, 386.4 mmol) were stirred at 0° C. for 1 h and the room temperature for an additional 1 h in a mixture of dichloromethane (1.7 L) and dimethylformamide (17 mL). Water (250 mL) was added and after decantation, water (2×250 mL) and brine (250 mL) was used for washing the organic phases, which was dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography using a mixture of ethyl acetate/hexane (1/4) as eluent to get 28 g of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[C:28]([F:31])([F:30])[F:29])[C:4]=1[C:32]([O:34]CC)=O.[CH3:37][NH:38][NH2:39]>O1CCOCC1>[CH3:37][N:38]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:7](=[O:19])[NH:6][CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[C:28]([F:29])([F:31])[F:30])[C:4]=2[C:32](=[O:34])[NH:39]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1C(F)(F)F
Reactant: CNN
Solvent: C1COCCO1
Product: CN1CC2=C(C(=O)N1)C(c1ccc(C#N)cc1C(F)(F)F)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, ethyl 6-(bromomethyl)-4-[4-cyano-2-(trifluoro-methyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (576 mg, 1 mmol; Example 21A) was initially charged in dioxane (20 ml). Methylhydrazine (128 mg, 3 mmol) was added dropwise to the reaction mixture, and the mixture was then stirred at boiling point for 8 h (bath temperature 120° C.). The reaction mixture was then concentrated, and the residue was purified by preparative HPLC (column: Gromsil C18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the target compound as a solid which was reprecipitated from acetonitrile/water (Yield: 205 mg, 41% of theory).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:22]([O-])(=O)C.[Na+].C=O>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[CH2:20][CH2:21]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)[O-]
Reactant: c1cnc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Product: c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 1-(2-pyridinyl)piperazine (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.49 (m, 4H) 3.45 (m, 4H) 3.67 (s, 2H) 5.59 (s, 1H) 6.60 (dd, J=6.78, 5.09 Hz, 1H) 6.77 (d, J=8.82 Hz, 1H) 7.04 (dd, J=7.97, 4.58 Hz, 1H) 7.49 (m, 2H) 8.06 (m, 1H) 8.19 (dd, J=4.75, 1.70 Hz, 1H) (ESI) 294 m/z (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][SH:26])[CH:22]=[CH:23][CH:24]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][S:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 58, Step 1, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and (3-trifluoromethyl-phenyl)-methanethiol.