Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][N:9]1[C:13](=[CH2:14])[C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:11][C:10]1=[O:20]>C(#N)C>[CH2:1]([NH:5][C:6]([N:17]1[CH2:18][CH2:19][C:12]2([O:11][C:10](=[O:20])[N:9]([CH3:8])[C:13]2=[CH2:14])[CH2:15][CH2:16]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Reactant: CCCCN=C=O
Solvent: CC#N
Product: C=C1N(C)C(=O)OC12CCN(C(=O)NCCCC)CC2
Yield: 91.3 %

Procedure:
2.25 ml of n-butyl isocyanate are dropped to a suspension of 3.64 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 18 ml of acetonitrile while stirring under argon. Since the reaction is exothermic, the temperature is maintained at 25° to 30° C. by cooling. After 15 minutes the reaction mixture is evaporated under reduced pressure. The white solid evaporation residue is recrystallized from ethyl acetate to obtain the title compound in 91.3% yield, m.p.: 129°-130° C.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(C(=O)O)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: COc1ccc(C(=O)NC2C3CC4CC2CN(C4)C3)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-methoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.92-1.99 (m, 4H), 2.12 (s, 1H), 2.31 (d, J=14 Hz, 2H), 2.39 (s, 1H), 3.50 (s, 2H), 3.60 (s, 3H), 3.84-3.87 (m, 3H), 4.37 (s, 1H), 6.97-7.03 (m, 2H), 7.75-7.88 (m, 2H); MS (APCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:10]([O:16][Si](CC)(CC)CC)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: Cl
Solvent: CO
Product: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A mixture of (1R,2R,5R)-8-benzyl-1-phenyl-2-triethylsilyloxy-8-azabicyclo[3.2.1]octane (Description 52; 107 mg, 0.26 mmol), 2M hydrochloric acid (3 ml) and methanol (6 ml) was stirred at +55° C. for 15 minutes, then concentrated in vacuo and quenched with saturated aqueous NaHCO3. The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (79 mg, 96%).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:20])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: CC(C)(C)N1CC(O)C1
Product: CC(C)(C)NCC(O)COc1cccc2c1CCCC2

Procedure:
1-(tert.-butyl)-3-azetidinol and 5,6,7,8-tetrahydro-α-naphthol were reacted in the same manner as in Example 1 to form 1-(5,6,7,8-tetrahydro-α-naphthoxy)-3-(tert.-butylamino)-2-propanol. A hydrochloric acid gas was blown into the obtained propanol. As a result 1-(5,6,7,8-tetrahydro-1-naphthoxy)-3-(tert.-butylamino)-2-propanol hydrochloride having a melting point of 148°-150° C was obtained. The yield was 70%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17](F)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)ncnc3cn2)cc1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of 4-[(3-bromophenyl)amino]-6-fluoro-pyrido[3,4-d]pyrimidine (0.48 g) and 4-methoxybenzyl-amine (10.3 g) in ethanol (50 mL) was heated to 100° C. for 5 days. The resulting product was chromatographed on silica gel, eluting with CH2Cl2:EtOAc (3:1), to give 4-[(3-bromophenyl)amino]-6-[(4-methoxyphenyl)methyl-amino]pyrido[3,4-d]pyrimidine (0.18 g,) mp (aqueous methanol), 178-179.5° C. A 0.10 g portion of this was dissolved in 5 mL trifluoroacetic acid and heated under reflux for 1 hour, and the mixture was evaporated to dryness. The residue was partitioned between EtOAc and aqueous ammonia, and the crude product was chromatographed on alumina, eluting with CH2Cl2:MeOH (97:3) to give 6-amino-4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidine (0.040 g,), mp (CH2Cl2) 241.5-242° C.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[O:6][P:7](Cl)[O:8][C:9]3[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH3:20])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.C(N(CC)CC)C.[NH2:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([CH3:44])[C:38]([CH3:46])([CH3:45])[CH2:37]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[O:6][P:7]([NH:35][CH:36]3[CH2:37][C:38]([CH3:45])([CH3:46])[N:39]([CH3:44])[C:40]([CH3:43])([CH3:42])[CH2:41]3)[O:8][C:9]3[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH3:20])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C)cc1C(C)(C)C)C2
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(C(C)(C)C)c1)OP(NC1CC(C)(C)N(C)C(C)(C)C1)Oc1c(cc(C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
10.12 g (25.0 mmol) of 2,10-dimethyl-4,8-di-tert-butyl-6-chloro-12H-dibenzo[d,g][1,3,2]-dioxaphosphocine [GB-A-2 250 990, Example 1a, page 17], 10.5 ml (75.0 mmol) of triethylamine and 100 ml of toluene are charged at room temperature and under nitrogen to a 350 ml sulfonation flask. With stirring, a solution of 4.26 g (25.0 mmol) of 4-amino-1,2,2,6,6-pentamethylpiperidine [Beilstein EII, Vol. 22, page 321 (1953)] in 30 ml of toluene is added dropwise to this suspension. The reaction mixture is refiuxed for 2 hours, then cooled to room temperature and filtered. The filtrate is concentrated on a vacuum rotary evaporator. Crystallisation of the residue from hexane yields 7.7 g (57%) of 2,10-dimethyl-6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)-4,8-di-tert-butyl-12H-dibenzo-[d,g][1,3,2]dioxaphosphocine (57%) (compound (101)) as a white powder, m.p. 207°-216° C. Analysis: calcd: C 73.57%; H 9.54%; N 5.19%; found: C 74.38%; H 10.03%; N 4.68%.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[C:10]([CH:11]=O)=[CH:9][N:8]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:7]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.Cl.[NH2:27]O.C([O-])=O.[Na+].O>C(O)=O>[S:1]1[CH:5]=[C:4]([C:6]2[C:10]([C:11]#[N:27])=[CH:9][N:8]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:7]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: O=Cc1cn(-c2ccc(C(=O)O)cc2)nc1-c1csc2ccccc12
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1cn(-c2ccc(C(=O)O)cc2)nc1-c1csc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.4 %

Procedure:
A solution of 4-(3-benzo[b]thiophene-3-yl-4-formylpyrazole-1-yl)benzoic acid (0.26 g), hydroxylamine hydrochloride (0.058 g) and sodium formate (0.10 g) in formic acid (5 mL) was heated under reflux for 24 hours. To this reaction mixture was added water at room temperature, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. This obtained residue was dissolved with pyridine (5 mL), to this mixture was added trifluoroacetic anhydride (0.48 g) in a dropwise manner under ice cooling, and this mixture was stirred at room temperature for 5 hours. To this reaction mixture was added 2 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was washed with n-hexane/diethyl ether=1/1 to give the title compound (0.13 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17]Cl)[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:20][C@H:21]([C:23]([NH:25][CH3:26])=[O:24])[CH3:22].Cl.C(N(C(C)C)CC)(C)C>CC#N>[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17][NH:20][C@@H:21]([CH3:22])[C:23]([NH:25][CH3:26])=[O:24])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC(=O)[C@H](C)N
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1CCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](C)NCc1cc(=O)c(OCc2ccccc2)cn1C
Temperature: 85 °C
Yield: 87.1 %

Procedure:
A mixture of 5-(benzyloxy)-2-(chloromethyl)-1-methylpyridin-4(1H)-one hydrochloride (7.55 g, 25.0 mmol), H-Ala-NHMe.HCl (5.14 g, 37.0 mmol) and diisopropylethylamine (12.5 mL, 72.0 mmol) in CH3CN (50 mL) was heated at 85° C. under a nitrogen atmosphere for overnight. Volatiles were removed in vacuo, and the residue was pre-purified by column chromatography on silica gel using a mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate). The fractions rich in product were combined and evaporated to dryness. Further purification by column chromatography on silica gel using a mixture of H2O and CH3CN (1-5% H2O content) and then a 10% MeOH in dichloromethane solution afforded (S)-2-((5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (7.17 g) in 87% yield. MS m/z 352 [M+Na]+, 330 (100%) [M+1]+, 228, 138, 91.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC>C1COCC1.O=[Mn]=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: O=[Mn]=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 100 h

Procedure:
36 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-hydroxymethylindole are dissolved in 1.6 liters of THF, and 300 ml of ether are added. 55 g of MnO2 are added with stirring. The mixture is stirred for 16 hours at 20°, a further 100 g of MnO2 are added in portions, and stirring is continued for a further 100 hours at 20°. Filtration and working up in the customary manner gives 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-formylindole, m.p. 131°.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:6]2[C:10]=1[S:9][CH:8]=[N:7]2
Reactant: Fc1cccc2ncsc12
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(F)c2scnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
7-fluorobenzo[d]thiazole 25D (500 mg, 3.26 mmol) was added dropwise to chlorosulfonic acid (2.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.44 (s, 1H), 8.32 (dd, J=8.6, 4.6 Hz, 1H), 7.38 (t, J=8.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 91.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and p-methoxyaniline (70 mg, 0.57 mmol) to give 179 mg of the title compound (91%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.86 (s, 1H), 7.46 (d, 2H, J=9 Hz), 7.24 (d, 1H, J=2 Hz), 7.16 (d, 1H, J=2 Hz), 6.88 (d, 2H, J=9 Hz), 5.15~5.25 (m, 1H), 3.72 (s, 3H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.50~2.64 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.78~1.94 (m, 1H).
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:5](/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:4]1.C(N(CC)CC)C.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:23][O:22][C:20]([CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[C@@H:5]1[CH2:4][C@@H:3]([NH:2][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:7][N:6]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:21]
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](N)CN1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(C)cc2)CN1Cc1ccccc1
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
To a solution of (2S,4R)-4-amino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidine hydrobromide (371 mg) in dichloromethane (4 ml) were added triethylamine (0.67 ml) and p-toluenesulfonyl chloride (200 mg) at 0° C. and the mixture was stirred at the same temperature for 1.5 hours. The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of ethyl acetate and n-hexane (1:2) as an eluent to give (2S,4R)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-4-(4-methylphenylsulfonylamino)-1-(phenylmethyl)pyrrolidine (249 mg) as an oil.
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[OH:13].Br>O>[OH:13][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccccc1
Reactant: CO
Agent: Br
Agent: BrBr
Solvent: O
Product: O=C(CO)c1ccccc1
Temperature: 60 °C

Procedure:
About 13 parts of bromine was added with stirring to a mixture of 474.6 parts of acetophenone in about 640 parts of methanol, while the mixture was stirred and maintained at a temperature between 5°-10° C. Hydrogen bromide gas was then introduced into the mixture until bromine coloration disappeared, at which point an additional amount of bromine was added over a 2 hour period to make a total of 631.3 parts. There was then added 71 parts of water while the mixture was stirred and externally cooled for a period of about 30 minutes. An excess of about 2700 parts of water was then slowly added to effect the precipitation in the form of crystals of α-bromo acetophenone from the mixture. The crystals were decanted by means of a vacuum siphon, washed, then neutralized with a 20% sodium hydroxide solution and decanted to dryness. There was then added about 940 parts water, 1600 parts of methanol, 333 parts of sodium bicarbonate and a sodium formate solution prepared from 161 parts of a 90% formic acid and sufficient sodium hydroxide to neutralize the acid. The mixture was heated at 60° C. with vigorous stirring for 7 hours after which time it was cooled to ambient temperature and filtered. Based on method of preparation and gas chromatographic analysis of the mixture there was produced α-hydroxy acetophenone in quantitative yields.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][C:12]([CH:24]=[O:25])=[CH:13][CH:14]=1)([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyldimethyl(3-(thiophen-2-yl)propoxy)silane (787 mg, 3.07 mmol) in 15 mL 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (1.35 mL, 2.5 M in hexanes) dropwise over 5 minutes. The resulting solution was stirred at −78° C. for 1 h. Dimethylformamide (1.18 mL, 15.35 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature before being poured into 100 mL of 1 N hydrochloric acid. Organics were extracted with ether (2×75 m), dried over magnesium sulfate, filtered and concentrated to give crude 5-(3-((t-butyldimethylsilyl)oxy)propyl)thiophene-2-carbaldehyde. Used without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:32]>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[C:11]([F:32])[CH:12]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 14.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (119 mg) described in Preparation Example 4 and (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (230 mg) described in Preparation Example 125 and by the reaction and treatment in the same manner as in Example 4, the title compound (38 mg) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.S(Cl)([Cl:14])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11])[N:3]=[N:2]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution/suspension of 4-(1H-1,2,3-triazol-4-yl)butanoic acid (150 mg, 0.967 mmol) in dry DCM (10 mL) was added thionyl chloride (0.847 mL, 11.60 mmol) at RT. After 30 mins some solid still remained so a further 0.4 ml thionyl chloride was added and the reaction mixture allowed to stir at RT for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford the title product which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[OH:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:17][C:5]2[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[C:6]=2[N+:14]([O-:16])=[O:15])=[O:32])=[CH:29][CH:28]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(C)=O)c(OC(=O)c2ccc(N(C)C)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The imidazole flavonoid was prepared according to scheme 5. To a mixture of N-(4-acetyl-3-hydroxy-2-nitrophenyl)acetamide (1, 1 g, 4.1 mmol, 1.0 eq) and triethylamine (1.5 mL) was added 4-(dimethylamino)benzoyl chloride (2 hydrochloride, 6.3 mmol, 1.5 eq.) in 3 portions at 0° C. Then the mixture was stirred at rt for 3 h. Diluted with DCM (100 mL), washed with 1N HCl (100 mL) and water (50 mL). The organic phase was separated, dried with sodium sulfate, filtered and concentrated to afford gray solid, which was purified by SGC (PE/EA=1/1) to afford (3-acetamido-6-acetyl-2-nitrophenyl 4-(dimethylamino)benzoate (3), 1.2 g, 75%).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[OH:1][CH2:2][C:3]1[N:22]([OH:23])[C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: NO
Reactant: COc1ccc(COc2c(CO)oc(C)cc2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2c(CO)n(O)c(C)cc2=O)cc1
Reaction time: 7 h
Yield: 8.3 %

Procedure:
To a solution of 4 g of 6-hydroxymethyl-5-p-methoxybenzyloxy-2-methyl-4-pyrone in 50 ml of pyridine was added 5 g of hydroxylamine hydrochloride at room temperature. The mixture was stirred at 70° to 75° C. for 7 hours. After the reaction liquid was concentrated under reduced pressure, the residue was dissolved in 200 ml of chloroform and washed in succession with water, 5% cold hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the chloroform layer was dried and concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (100 g) to give 350 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 65813.4 %

Procedure:
Nitrogen was bubbled through dioxane (800 mL) for 1 h followed by the addition of 4-chloro-2-(methyloxy)-1-nitrobenzene (61 g, 0.33 mol), 3-pyridinylboronic acid (Boron Molecular, 40 g, 0.33 mmol), dichloro(triphenylphosphine)palladium (10 g, 14 mmol), and degassed aqueous 3 N Na2CO3 (325 mL, 975 mmol). The reaction mixture was stirred with a mechanical stirrer and heated at 90° C. for 3 h. The reaction was cooled and most of the dioxane was removed in vacuo. It was diluted with water and then extracted with Ethyl acetate. Combined organic phases were dried (Mg2SO4), filtered and concentrated. The resultant solid was washed with diethyl ether to afford 4-(3-methoxy-4-nitrophenyl)pyridine (50 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.05 (s, 3 H), 7.53 (dd, J=8.4, 1.8 Hz, 1 H), 7.69 (d, J=1.8 Hz, 1 H), 7.84 (d, J=6.2 Hz, 2 H), 8.02 (d, J=8.4 Hz, 1 H), 8.72 (d, J=6.2 Hz, 2 H). ESIMS (M+H)+=231.