Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]1[O:28][C:19]([CH3:27])([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:18][CH2:17]1.[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O1CCCC1.CS(C)=O>[CH3:27][C:19]1([CH2:20][CH:21]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:18][CH2:17][CH2:16][O:28]1
Reactant: CCOC(=O)CCC1(C)OCCO1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCC(CC1(C)OCCO1)C(=O)OCC
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a solution of about 34.35 g of isopropylcyclohexylamine in about 150 ml of tetrahydrofuran at about -20° C. was added about 156.89 ml of an about 1.55M n-butyllithium, at a rate so that the final temperature reached about 10° C. The solution was then cooled to about -70° C. and about 25 g of ethyl levulinate ethylene ketal was added dropwise. After about 15 minutes, the solution was warmed to about -30° C. and maintained at that temperature while it was added rapidly, dropwise to a stirred solution of about 80.44 g of octadecyl iodide in about 150 ml of dimethyl sulfoxide and about 50 ml of tetrahydrofuran at room temperature. This mixture was stirred overnight, the volatile solvents were removed and water was added. The resulting solid was collected by filtration and extracted with ether giving a solution and a solid. This solution and original filtrate were combined and extracted with ether. This ether extract was dried and the solvent removed giving an oil. This oil was subjected to HPLC, eluting with hexane:ether (about 9:1). The product band was collected and the solvent removed, giving about 30.76 g of the desired title compound as a solid, mp 33°-34° C.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g (0.0168 mole) of 1-nitro-2-carboxyanthraquinone, 100 g of a 4% aqueous solution of sodium hydroxide and 0.25 g of 5% palladium-carbon. The inside of the reactor was purged with hydrogen, and the 1-nitro-2-carboxyanthraquinone was hydrogenated at 50° C. with stirring. In 5 hours, 0.0504 mole of hydrogen was absorbed, whereupon the reaction was stopped. The reaction mixture was filtered to separate the catalyst. The filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours, and then neutralized with 20% sulfuric acid to a pH of 2 to 3. The crystals precipitated were filtered, washed with water, and dried to afford 4.1 g of 1-amino-2-carboxyanthraquinone in a yield of 91.3%.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:18]1([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:7]2[CH:8]=[C:4]([CH2:3][OH:2])[N:5]=[CH:6]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 20 h

Procedure:
To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [H-].[Na+].CS(O[CH:8]([CH:20]1[CH2:22][CH2:21]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])(=O)=O>CS(C)=O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]1[CH2:9][CH:8]1[CH:20]1[CH2:22][CH2:21]1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
0.48 g of sodium hydride (12 mmol) is introduced into 10 ml of dimethyl sulfoxide and a solution consisting of the 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate and 15 ml of DMSO is added. Stirring is then carried out for 5 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:15). After removal of the eluant, 0.28 g of 2-(2-nitrophenyl)-bicyclopropane (64% of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.1:1).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=[C:3]1[C:13]([O:15]CC)=O.O.[NH2:19][NH2:20]>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=[C:3]1[C:13]([NH:19][NH2:20])=[O:15]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCCCC2
Reactant: NN
Solvent: O
Product: NNC(=O)c1cnc2n(c1=O)CCCCC2
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 2.36 g. of ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate in 10 ml. of 98% by W/V hydrazine hydrate is allowed to stand at room temperature for 2 hours. The precipitated crystals are filtered and washed with water and ethanol. 1.8 g. of (81%) 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carbohydrazide are obtained melting at 184°-186° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:22]2[CH2:21][S:20][CH2:19][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[NH:17][C:16](=[O:27])[C@@H:15]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:14][O:13][C:12](=[O:36])[C:11]=2[CH:10]=[C:9]([N:37]2[C:45](=O)C3C(=CC=CC=3)[C:38]2=O)[CH:8]=1)(C)(C)C.[BH4-].[Na+].S(=O)(=O)(O)O.C=O>O1CCCC1.C(OCC)(=O)C>[OH:6][C:7]1[C:22]2[CH2:21][S:20][CH2:19][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[NH:17][C:16](=[O:27])[C@@H:15]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:14][O:13][C:12](=[O:36])[C:11]=2[CH:10]=[C:9]([N:37]([CH3:45])[CH3:38])[CH:8]=1
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(N3C(=O)c4ccccc4C3=O)cc2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CSCc2c(O)cc(N(C)C)cc2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
A solution of 47 mg of the product of Example 159 and 27 mg of sodium borohydride in 5 ml of tetrahydrofuran was added within 10 minutes to a mixture of 0.08 ml of 6N sulfuric acid and 0.05 ml of 40% aqueous formaldehyde in 2 ml of tetrahydrofuran at 0° C. Stirring was continued for 4 hours at 0° C. The mixture was diluted with ethyl acetate, and then washed with 10% sodium carbonate solution and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate/diethylether to give 25 mg of tert-butyl (4R, 7S)-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-4-methoxycarbonyl-12-dimethylamino-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([N+:20]([O-:22])=[O:21])[C:13]=1[F:23])[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:27].S(Cl)(Cl)=O.[CH2:34](O)[CH3:35]>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([N+:20]([O-:22])=[O:21])[C:13]=1[F:23])[CH:9]=[C:8]([C:24]([O:26][CH2:34][CH3:35])=[O:25])[C:7]2=[O:27]
Reactant: O=C(O)c1cn(-c2c(F)cc(F)c([N+](=O)[O-])c2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(-c2c(F)cc(F)c([N+](=O)[O-])c2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 830 mg of 8-chloro-6,7-difluoro-1-(2,4,6-trifluoro-3-nitrophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added 2 ml of thionyl chloride. The solution was stirred at 80° C. overnight. With ice cooling, 4 ml of ethanol was slowly added dropwise to the reaction solution. The reaction solution was distilled of the solvent whereupon the precipitated solid was collected by filtration to give 310 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([CH:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36][N:35]1[C:49]([OH:51])=[O:50])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:38]3[CH2:37][CH2:36][N:35]([C:49]([O:51][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:50])[CH2:34][CH:39]=3)[CH:3]=2)[CH2:9][C:10]([C:20]([C:22]([F:23])([F:24])[F:25])([C:26]([F:29])([F:27])[F:28])[OH:21])=[N:11]1
Reactant: CC(C)(C)C1C=C(B2OC(C)(C)C(C)(C)O2)CCN1C(=O)O
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 123.4 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (1.1 g, 2.2 mmol) prepared in Step 4 of Preparation 16, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1 (2H)-carboxylic acid (805.5 mg, 2.6 mmol), potassium carbonate (900.0 mg, 6.5 mmol), and Pd(dppf)Cl2 (159.0 mg, 0.20 mmol) were added to a mixed solvent of 1,4-dioxane (35.0 mL) and distilled water (9.0 mL). The reaction mixture was stirred for 15 minutes, additionally at 90° C. for 16 hours, and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 820.0 mg of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[C:5]([NH2:25])=[C:4]([NH2:26])[N:3]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:25]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=3)[NH:26]2)=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1nc(N)c(N)c(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(Br)cc3)[nH]c2n1
Yield: 74 %

Procedure:
This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]pyrimidine and 4-bromobenzaldehyde in 74% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[NH:10][C@H:11]([C:16](=[O:43])[NH:17][C@@:18]1([C:33](=[O:42])[NH:34][C@H:35]([C:40]#[N:41])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][C:29]2[C:28]3[C:23](=[C:24]([Cl:32])[CH:25]=[C:26]([Cl:31])[CH:27]=3)[NH:22][C:21]=2[CH2:20][CH2:19]1)[CH:12]([CH3:15])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:45]=[N+:46]=[N-:47].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:44])[NH:10][C@H:11]([C:16](=[O:43])[NH:17][C@@:18]1([C:33](=[O:42])[NH:34][C@H:35]([C:40]2[NH:47][N:46]=[N:45][N:41]=2)[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:30][C:29]2[C:28]3[C:23](=[C:24]([Cl:32])[CH:25]=[C:26]([Cl:31])[CH:27]=3)[NH:22][C:21]=2[CH2:20][CH2:19]1)[CH:12]([CH3:15])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@]1(C(=O)N[C@H](C#N)CC(C)C)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@]1(C(=O)N[C@@H](CC(C)C)c2nnn[nH]2)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Reaction time: 6 h

Procedure:
0.122 g (0.19 mmol) of {(S)-1-[(R)-6,8-Dichloro-3-((S)-1-cyano-3-methyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl-butyl}-carbamic acid benzyl ester synthesized according to 84 (see below), 0.028 g (0.44 mmol) of sodium azide and 0.026 (0.48 mmol) of ammonium chloride were heated in 2 mL of DMF in a microwave at 110° C. and 100 watt for 6 h. The reaction solution was separated on a preparative HPLC column.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Br.Br.[C:27]12[CH2:34][NH:33][CH2:32][C:31]=1[CH2:30][NH:29][CH2:28]2.N12CCCN=C1CCCCC2>C(#N)C>[C:27]12[CH2:34][NH:33][CH2:32][C:31]=1[CH2:30][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:28]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 67 %

Procedure:
1-(4-Fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.33 g), 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (0.27 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 1 ml) were dissolved in acetonitrile (10 ml) and refluxed for 4 hours. The reaction mixture was kept overnight at room temperature and the produced precipitate was filtered, washed with acetonitrile, methanol to give the title compound (0.28 g, yield 66%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[CH3:23]N(C=O)C>>[F:22][C:2]([F:1])([F:21])[C:3]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH3:23]
Reactant: FC(F)(F)c1nc(NCCc2ccccc2)nc2nc[nH]c12
Reactant: CN(C)C=O
Product: Cn1cnc2c(C(F)(F)F)nc(NCCc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of 6-Trifluoromethyl-2-phenethylaminopurine (compound 9, 0.600 g, 1.95 mmol) in DMF (14 ml) K2CO3 (0.351 g, 2.54 mmol) and Mel (0.158 ml, 2.54 mmol) were added. The mixture was stirred at room temperature and after 0.5 h the reaction was complete (HPLC: Rt,product=4.1). Crystallization occurred after the slow addition of water (17 ml). After stirring for 0.5 h the mixture was filtrated and the residue was washed with four 10-ml portions of water. The filtrate was again filtrated after 1 h and the residue was washed with three 5-ml portions of water. The residue was dried in vacuo at 60° C. obtaining the product as a white solid (503 mg, 80%).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]([OH:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH2:16][C:15]1=[O:35])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].CC(O)C.C([O-])(=O)C>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][C:19](=[O:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:22])[CH2:16][C:15]1=[O:35])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cr+6]
Agent: CC(=O)[O-]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Anyhdrous chromium trioxide (16.88 g 169 mmol) is added to a solution of anhydrous pyridine (27.3 ml, 338 mmol) in anhydrous methylene chloride (470 ml). The resulting mixture is stirred at room temperature for 30 minutes and then treated with a solution of N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one (8.92 g, 21.1 mmol) in methylene chloride (80 ml). The reaction mixture is stirred an additional 15 minutes at room temperature and then treated with 2-propanol (6.75 ml). The methylene chloride phase is decanted from the dark, tary residue and evaporated under vacuum. The residue from this operation is triturated with diethyl ether (350 ml) and filtered through a pad of magnesium sulfate which is washed with additional ether (150 ml). The ethereal filtrate is washed with water (200 ml), 5% aqueous sodium bicarbonate (200 ml) and brine, dried with magnesium sulfate, filtered, evaporated under vacuum, and stripped with toluene to afford the crude product (5.99 g) as an amber oil. Chromatigraphy on a silica gel column using 3:2 petroleum etherethyl acetate as eluting solvent yields N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (5.17 g, 58%) as a pale yellow, viscous oil which solidifies. Trituration with diethyl ether gives the product as small, white crystals: mp 65°-66.5°, IR (CH2CL2) 1732, 1522, and 1350 cm) NMR (CDCl3) 8 0.20 (s,3,CH3), 0.23 (s,3,CH3), 0.93 (s,9,C(CH3)3), 2.58 (dd,1,J=2.7 and 15.7, H3β), 2.72 (dd,1,J=9.4 and 18.2, CH2COCH2CO2), 3.19 (dd,1,J=4.0 and 18.2, CH2COCH2CO2), 3.35 (dd,1,J=5.3 and 15.7,H3α), 3.55 (s,2,COCH2CO2), 3.90 (m,1,H4), 5.30 (s,2,CH2Ar), 7.55 and 8.25 (two d15,4,J-8.5, ArH); MS m/e 405 (M+ -15), 363 (M+ -57), 321 (363-42) and 136.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=O)[CH3:10])=[N:6][CH:7]=1.[ClH:12].[NH2:13][OH:14]>C(O)C>[ClH:12].[N:13](=[C:9]([CH3:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)[OH:14]
Reactant: NO
Reactant: CC(=O)Cc1ccc(O)cn1
Agent: Cl
Solvent: CCO
Product: CC(Cc1ccc(O)cn1)=NO

Procedure:
The starting material is prepared as follows: The mixture of 8.64 g of 5-hydroxy-2-pyridylacetone, 4.08 g of hydroxylamine hydrochloride and 170 ml of anhydrous ethanol is refluxed for 64 hours and evaporated. The residue is taken up in the minimum amount of ethanol, the solution filtered and the filtrate evaporated, to yield the 2-(2-oximinopropyl)-5-pyridinol hydrochloride melting at 141°-145°.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[CH2:24])=[CH:20][CH:21]=1
Reactant: CC(O)c1ccc(CCCBr)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CCCBr)cc1

Procedure:
Also disclosed herein is a method of making 4-vinylbenzenepropanethiol. The method includes providing 1-bromo-3-phenylpropane, adding acetic anhydride and aluminum chloride, incubating the mixture at from about −20 to about 20 degrees Celsius for from about 1 hour to about 12 hours, isolating the resulting p-(3-bromopropyl)acetophenone, adding sodium borohydride to the p-(3-bromopropyl)acetophenone solution in methanol, incubating the mixture at about 0 degrees Celsius for about 2 hours, isolating the resulting p-(3-bromopropyl)-α-methylbenzenemethanol, adding toluensulfonic acid to the solution of p-(3-bromopropyl)-α-methylbenzenemethanol in toluene, refluxing the mixture under inert atmosphere for about 4 hours, isolating the resulting p-(3-Bromopropyl)styrene, adding thiourea to the p-(3-Bromopropyl)styrene, gently refluxing the mixture for about 16 hours, adding sodium hydroxide, and gently refluxing the mixture for about 4 hours.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:19][CH:18]([OH:20])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(O)(C)C.[N+:25]([O-])([OH:27])=[O:26]>C(OCC)(=O)C>[N+:25]([O:20][CH:18]1[CH2:19][N:16]([CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[S:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:17]1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])OC1CN(CCCOCCc2ccc3sccc3c2)C1
Reaction time: 1 h

Procedure:
In 20 mL of ethyl acetate was dissolved 10.0 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol, and 20 mL of isopropanol was added thereto, after which 2.60 mL of concentrated nitric acid (61%) was added dropwise thereto at room temperature. To the reaction mixture was added dropwise 60 mL of ethyl acetate, and the resulting mixture was stirred at the same temperature for 1 hour and then at 5° C. for 1 hour. The crystals precipitated were collected by filtration to obtain 11.3 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol nitrate as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([OH:21])=O)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23)#[N:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23)#[N:2]
Reactant: N#Cc1cc2c3c(c1)[nH]c(=O)c(=O)n3C(CC(=O)O)CC2
Reactant: Nc1ccccc1
Product: N#Cc1cc2c3c(c1)[nH]c(=O)c(=O)n3C(CC(=O)Nc1ccccc1)CC2
Yield: 68 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-cyano-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (70 mg, 0.245 mmol) and aniline (70 mg, 0.75 mmol) to give 60 mg of the title compound (68%): mp 171°~176° C. (dec); 1H NMR (270 MHz, DMSO-d6)δ12.22 (bs, 1H), 10.02 (s, 1H), 7.56 (d, 2H, J=7.8 Hz), 7.52 (s, 1H), 7.33 (s, 1H), 7.30 (t, 2H, J=7.8 Hz), 7.05 (t, 1H, J=7.8 Hz), 5.18~5.29 (m, 1H), 3.08 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.87 (dm, 1H, J=17.1 Hz), 2.54~2.70 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.CO[CH:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:13][CH:12](OC)O1.C(#[N:31])C>>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][NH:31][CH:10]=2)=[CH:16][CH:17]=1
Reactant: COC1CC(c2ccc(-c3ncccn3)cc2)C(OC)O1
Reactant: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(-c2ccc(-c3cc[nH]c3)cc2)nc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Trifluoroacetic acid (61 μL, 0.80 mmol) was added to a solution of Compound 5 (39 mg, 0.06 mmol) and 2-[4-(tetrahydro-2,5-dimethoxy-3-furanyl)phenyl]pyrimidine (24 mg, 0.08 mmol, prepared as described in Reference Example 441) in acetonitrile (1 mL) at room temperature. The reaction mixture was stirred at 55° C. for 3 h, cooled to room temperature, quenched with sat. aq. NaHCO3, extracted with dichloromethane, dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 95:5:0.2 dichloromethane/methanol/conc. NH4OH) gave 22 mg (70%) of the title compound. MS 861 (M+H)+.