Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[O:17][C:16]2=O)[CH2:13][O:12]1.[C:27]([O-])(=O)C.[Na+].[H-].[Na+]>C(O)C>[CH2:16]([O:17][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:15][CH2:14][C:11]1([CH3:13])[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1)=[O:25])[CH3:27]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(Cn2c(=O)oc(=O)c3ccccc32)CO1
Reactant: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccccc1NCC1(C)Cn2cc([N+](=O)[O-])nc2O1
Yield: 55 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (891 mg, 6.04 mmol), 1-(2-methyloxiran-2-ylmethyl)-1H-benzo[d][1,3]oxazin-2,4-dione (1.41 g, 6.04 mmol), sodium acetate (545 mg, 6.64 mmol) and ethanol (10 ml) was stirred under reflux for 10 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (20 ml). To the solution, sodium hydride (219 mg, 5.48 mmol) was added followed by stirring under reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, ice-water was added, and the precipitates were filtered off, which were purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford N-(2-ethoxycarbonylphenyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamine (1.15 g, yield 55%) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:10][CH2:11][CH3:12])([C:6](Br)([F:8])[F:7])=[O:5].I[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CCOCC>CN(C=O)C.Cl[Cu]>[CH2:2]([O:3][P:4]([C:6]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([F:8])[F:7])(=[O:5])[O:10][CH2:11][CH3:12])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: Cl[Cu]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(F)(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Under N2, a mixture of bromodifluoromethyl diethylphosphonate (0.427 g, 1.6 mmol) and Cd powder (180 mg, 1.6 mmol) in DMF (0.5 mL) was stirred at room temperature for 2 h. Most of Cd disappeared. 4-Iodo-1-nitrobenzene (249 mg, 1.00 mmol) and CuCl (115 mg, 1.16 mmol) were then added. The mixture was again stirred at room temperature for 3 h. Ether (20 mL) was added to the reaction mixture and the precipitated solids were filtered off and washed with 10 mL of ether. The combined ether layers were washed with NH4Cl (aq), dried over MgSO4, and evaporated to give the title product (267 mg, yield: 86%). 1H NMR (CD3OD, 400 MHz): δ=1.33 (t, J=7.2 Hz, 6H), 4.20-4.28 (m, 4H), 7.86 (d, J=8.4 Hz, 2H), 8.39 (d, J=8.4 Hz, 2H). MS (ES+): m/z 310.06 [MH+]. HPLC: tR=3.92 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(=O)C)[CH:6]=1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C(#N)C>[CH3:1][C:2]1[N:3]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:4]=[N:5][CH:6]=1
Reactant: CC(=O)n1cnc(C)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CC#N
Product: Cc1cncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.4 %

Procedure:
To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL of acetonitrile at 0° C. was added NEt3 (4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to attain RT then filtered to remove the ppt and the filtrate was concentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was used without further purification in the next step. To a solution of 1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mL acetonitrile was added SEM-Cl (5.80 g, 35.0 mmol) and the solution was stirred at 25° C. for 10 h. The solvents were removed by evaporation and to the residue was added 100 mL of 2.5 M NaOH and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then extracted with ether (3×100 mL), dried over Na2SO4 and concentrated. The title compound was purified by chromatography on Silica gel eluting with 75% EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C10H20N2O4Si, 213.1 (M+H). found 213.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])=[O:28]
Reactant: C=C(F)C(=O)Cl
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 71 %

Procedure:
A solution of 21.5 g (0.067 mol) of 2-(4-bromophenyl)-hexafluoro-2-propanol and 6.8 g (0.067 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 8.7 g (0.08 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 30 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.005 g of hydroquinone monomethyl ether. 18.8 g (71 percent of theory) of 2-(4-bromophenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 66° to 69° C. (under 0.13 mbar) were obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH3:32])[CH:17]=[CH:16][C:15]([S:18]([O:21]CC[C@@H](C)COC(C)(C)C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:1]([O:5][CH2:6][C@H:7]([CH3:11])[CH2:8][CH2:9][OH:10])([CH3:3])([CH3:4])[CH3:2].[CH3:32][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(CCO)COC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)COC(C)(C)C)cc1
Product: C[C@H](CCO)COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 90 %

Procedure:
Using the procedure of Example 8, (R)-(+)-(4-tert. butoxy-3-methyl-1-butanol was converted into (R)-(+)-4-tert. butoxy-3-methyl-1-butanol p-toluenesulfonate which was isolated in 90% yield as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10]O)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][Cl:14])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CO)on1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.12 g of (3-t-butyl-isoxazol-5-yl)methanol was dissolved in 35 ml of dichloromethane, and 2.4 ml of thionyl chloride was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was washed with hexane to obtain 1.12 g of 3-t-butyl-5-(chloromethyl)-isoxazole.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[SH:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1.C(N(CC)CC)C>CN(C)C=O>[NH:11]1[C:10]([S:9][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:14][N:13]=[N:12]1
Reactant: Clc1ccncc1
Reactant: Sc1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc(Sc2nnn[nH]2)ccn1
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (7.25 g), 5-mercapto-1H-tetrazole (4.93 g) and triethylamine (14.64 g) in dimethylformamide (120 ml) was stirred for one hour at 82° to 85° C. and then cooled in an ice bath. The resulting precipitates were removed by filtration and the filtrate was mixed with water (60 ml). The aqueous solution was adjusted to pH 2 with 2N hydrochloric acid and evaporated to dryness under reduced pressure. The residue was triturated in chloroform (300 ml) and the resulting precipitates were collected by filtration and washed with the same solvent. To the precipitates was added ethanol (650 ml) and an insoluble material was removed by filtration. The filtrate was evaporated to dryness to give 4-(1H-tetrazol-5-ylthio)pyridine (4.03 g), mp. 159° to 161° C. (dec.).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:33])[C:23]=2[N:22]=[C:21]1[CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH3:12][S:13]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:33])[C:23]=2[N:22]=[C:21]1[CH2:34][CH2:35][CH3:36])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCSC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCS(C)=O
Reaction time: 0.33 h
Yield: 42 %

Procedure:
3-Chloroperoxybenzoic acid (0.62 g of ˜77%, 2.8 mmol) was added in portions over a period of 5 minutes to a solution of 1-{2-[3-(methylthio)propoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.8 mmol) in chloroform (14 mL). After 20 minutes analysis by TLC showed that all of the starting material had been consumed. The reaction mixture was partitioned between dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL). The organic layer was washed sequentially with saturated aqueous sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a white foam. This material was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) followed by recrystallization from ethyl acetate (60 mL) to provide 0.44 g of 1-{2-[3-(methylsulfinyl)propoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as crystalline plates, mp 148-151° C. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.43 (bs, 2H), 4.72 (t, J=5.0 Hz, 2H), 3.84 (t, J=5.0 Hz, 2H), 3.40 (t, J=6.2 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.46 (m, 2H), 2.39 (s, 3H) 1.86 (sextet, J=7.6 Hz, 2H) 1.71 pentet, J=7.6 Hz, 2H) 1.04 (t, J=7.6 Hz, 3H); MS (APCI) m/z 375 (M+H)+; Anal. Cacld for C19H26N4O2S: C, 60.94; H, 7.00: N, 14.96. Found: C, 60.73; H, 6.82; N, 14.85.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[OH:21][CH:19]([CH2:20][N:38]1[CH2:39][CH2:40][N:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36][CH2:37]1)[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: COc1cc(-c2cc(=O)c3ccc(OCC(O)CN4CCN(c5ccccc5)CC4)cc3o2)cc(OC)c1OC

Procedure:
3′,4′,5′-Trimethoxy-7-(2,3-epoxy-propoxy)-flavone, 31 (1.1 g, 3 mmol) and 1-phenyl piperazine (0.5 mL, 3.27 mmol) in dry methanol (130 mL) were reacted in a similar manner to that described under 34 to afford 42. Yield 1.4 g (85%); mp 170-171° C.; MS (FAB) 547 (M++1); IR (KBr) 3406, 1635; 1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=9.5 Hz, 1H), 7.27 (t, J=7.9 Hz, 2H), 7.10 (s, 2H), 7.04-7.01 (m, 2H), 6.95-6.87 (m, 3H), 6.70 (s, 1H), 4.21-4.12 (m, 3H), 3.95 (s, 6H), 3.93 (s, 3H), 3.23 (t, J=4.6 Hz, 4H), 2.87-2.83 (m, 2H), 2.68-2.65 (m, 4H). Analysis Calcd for C31H34N2O7: C, 68.12; H, 6.27; N, 5.12. Found: C, 68.26; H, 6.37; N, 5.41.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
4-Amino-benzoic acid (100 mmol) was dissolved in DMF (50 mL) and N-bromosuccinimide (100 mmol) was added. Stirred at ambient temperature for 18 h, the reaction mixture was then poured into water (100 mL). The product was removed by filtration, washed with water and dried in vacuo to give 4-amino-3-bromo-benzoic acid.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.C([OH:28])CCC.[C:29]1(C)C=C[CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[Cl:11][C:9]([Cl:10])([Cl:12])[C:7]1[N:8]=[C:3]([C:2]([Cl:23])([Cl:22])[Cl:1])[N:4]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([O:18][CH2:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:15][CH:14]=2)[N:6]=1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reactant: Cc1ccccc1
Reactant: CCCCO
Solvent: c1ccncc1
Product: CCCCOC(=O)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
4-(4,6-Bis(trichloromethyl)-s-triazin-2-yl)-benzoyl chloride (9 pw) and n-butanol (1 pw) are added to dry toluene (100 pw). The mixture is stirred at 15° C., and 1.9 pw of pyridine is added dropwise. Stirring is continued for 3 hours. The resulting mixture is washed with 2% strength hydrochloric acid, 2% strength sodium hydroxide solution and then with water. After drying of the organic phase over magnesium sulfate, the solvent is removed by distillation, and the residue is recrystallized from ethanol. M.p. 109 to 110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=NO)[C:6](=[O:13])[NH:7]2.[OH:17]C1C(O)=C(O)C2C(=CC=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[C:5]([OH:17])[C:6]([OH:13])=[N:7]2
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=NO
Reactant: Oc1nc2ccccc2c(O)c1O
Product: Oc1nc2cc(Cl)cc(Cl)c2c(O)c1O

Procedure:
Compound 11b was prepared from 10b similar to 11a. mp 270°-273° C. 1H NMR (DMSO-d6), 7.257 (s, 2) 9.306 (mb, 1), 9.998 (s, 1), 11.919 (s, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1.Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:23]([Cl:28])[CH:22]=1
Reactant: O=C(N1CCc2ccc(Cl)c(NCc3ccc(O)c(Cl)c3)c2CC1)C(F)(F)F
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(C)C(=O)COc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1Cl
Yield: 82.2 %

Procedure:
Use a method similar to the General Procedure 4-1 to react 7-chloro-6-(3-chloro-4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (438 mg, 1.01 mmol) and 1-bromopinacolone (217 mg, 1.21 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:4) to give 7-chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (441 mg, 82%). MS (ES+) m/z: 531 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7].[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:10]([N+:18]([O-:20])=[O:19])=[C:5]([CH:4]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCOc1ccc(C(=O)OC)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COCCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Yield: 79.9 %

Procedure:
Using the procedure described in Example 6A Step 2, methyl 3-methoxy-4-(2-methoxyethoxyl)benzoate (8.39 g, 34.9 mmol) was reacted with fuming nitric acid (90%, 3.15 g) in AcOH (60 mL) at 50° C. for 8 hours, to afford methyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate as a yellow solid (7.956 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.07 (s, 1H), 4.25 (t, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.82 (t, 2H), 3.46 (s, 3H); LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1N=CN[CH:5]=1.[N:12]1C(N)=C2C(N=CN2)=N[CH:13]=1>>[NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:13][NH2:12]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: Nc1ncnc2nc[nH]c12
Product: NCCCC[C@H](N)C(=O)O

Procedure:
An ADE2 fragment and a LYS2 fragment were also prepared under similar reaction conditions using A451 genomic DNA as a template and ADE-1 (5′ ATG GAT TCT AGA ACA GTT GGT 3′ (SEQ ID NO: 127)) and ADE-2 (5′ TTA CTT GTT TTC TAG ATA AGC 3′ (SEQ ID NO: 128)) or LYS-1 (5′ ATG ACT AAC GAA AAG GTC TGG 3′ (SEQ ID NO: 129)) and LYS-2 (5′ TTA AGC TGC TGC GGA GCT TCC 3′ (SEQ ID NO: 130)) as primer DNAs. The resultant HIS3 fragment and ADE2 fragment were introduced into pRS435GGF/YH1 successively to thereby obtain pRS435GGF/YH1-AH that exhibited non-histidine requirement and non-adenine requirement as phenotypes. On the other hand, the LYS2 fragment and URA3 fragment were introduced into YPH500 successively to thereby obtain YPH500-KU that exhibited non-lysine requirement and non-uracil requirement as phenotypes.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.ICC[CH:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[OH:24].O>C1COCC1.C(OCC)(=O)C>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[CH:23]([OH:24])[CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:9]=[CH:8][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:17][CH:16]=1
Reactant: OC(CCI)C1CCCCO1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC(CCC#Cc1ccc(-c2ccccc2)cc1)C1CCCCO1
Reaction time: 1 h

Procedure:
Biphenyl acetylene 5.6 g was dissolved in THF (150 mL) at -78° C. One equivalent n-BuLi was added over one hour. The reaction was allowed to reach room temperature for one hour. 1-Iodo-3-0-tetrahydropyranylpropan-3-ol was added, (one equivalent). The reaction was refluxed for 24 hours. The product 1-0-tetrahydropyranyl-5-(4'-biphenylyl)-pent-4-yn-1-ol, (oil C: 82.47, H: 7.55) was isolated by addition of water and extraction with ethyl acetate. The product (1 g) was dried (60° 10-3 mmHg), dissolved in CH2Cl2 (50 mL) and Ph3P.Br2 (1.95 g) was added, after stirring for 15 minutes at room temperature NaCN (0.54 g) in 20 mL DMSO was added. The mixture was heated at 45° for 16 hours. The intermediate 1-cyano-6-(4'-biphenylyl)pent-5-yne m.p. 60°-61° C.: 88.13, H: 6.16, N: 5.71 was isolated by addition of water and extraction with EtOAc-hydrolysis to the title acid 10 was achieved by refluxing the nitrile in 10 mL (2N NaOH in 50 mL ethanol) followed by acidification with 6N HCl. The product 10 was filtered off and dried, 70% yield. m.p. 95°-96°.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].C([Li])CCC.CCCCCC.[I:33]I>C1COCC1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([I:33])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCn1ccnc1-c1sc(I)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-2-thienyl]-1H-imidazole (2.50 g, 7.46 mmol) in THF (80.0 mL) cooled to −78° C. was added dropwise 2.50 M of n-butyllithium in hexane (3.28 mL, 8.20 mmol) and the mixture was stirred for 30 min. To the solution was added dropwise a solution of iodine (2.84 g, 11.2 mmol) in THF (10.0 mL) and the resulting solution was stirred for 15 min at −78° C. The reaction mixture was quenched by addition of saturated sodium bisulfite solution (200 mL) and the resulting mixture was warmed to room temperature while stirring for 30 min. The mixture was extracted with EtOAc (3×250 mL) and the combined organic layers were washed with brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 1-6% EtOAc in hexane) to give crude product which was further purified by column chromatography (SiO2, elution with 2% MeOH in DCM) to provide 2.57 g of product (71%). LC/MS (FA), ES+ 462. 1H NMR (400 MHz, d6-DMSO) δ: 7.30 (d, J=2.2 Hz, 1H), 7.09 (s, 1H), 6.97 (dd, J=2.2, 8.2 Hz, 1H), 6.75 (d, J=1.3 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.60 (d, J=1.3 Hz, 1H), 5.10-5.21 (m, 1H), 4.60-4.65 (m, 1H), 4.35-4.41 (m, 1H), 3.80-3.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:26]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH3:46])[CH:41]=[C:40]([O:47][CH:48]([CH3:50])[CH3:49])[C:39]=2[F:51])[C:27]2[CH:36]=[CH:35][C:30]([C:31]([NH2:34])=[N:32][OH:33])=[CH:29][CH:28]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:52][C:53](OC(C)=O)=[O:54].CO>CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:26]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH3:46])[CH:41]=[C:40]([O:47][CH:48]([CH3:50])[CH3:49])[C:39]=2[F:51])[C:27]2[CH:36]=[CH:35][C:30]([C:31]([NH2:34])=[N:32][O:33][C:53](=[O:54])[CH3:52])=[CH:29][CH:28]=2)[N:5]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: CCOc1cc(CN(c2ccc(C(N)=NO)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(CN(c2ccc(C(N)=NOC(C)=O)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Intermediate 66.1 in 20 mL EtOAc, was added 0.5 mL Ac2O. The reaction mixture was stirred at rt for 1 h, then was treated with 1 mL MeOH and evaporated to afford Intermediate 66.2, which was used in the following step without further purification.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O>[CH3:3][C:2]([CH3:4])=[CH:1][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: CC(C)C=O
Solvent: O
Product: CC(C)=CN1CCOCC1

Procedure:
Isobutyraldehyde (19.4 g; 0.27 mol) is added slowly with stirring to morpholine (21.75 g; 0.25 mol). The ensuing reaction is exothermic. On completion of the addition the reaction mixture is stirred and heated at reflux for 5 hours while water (4.1 ml) is being azeotroped out of it. The reaction mixture is then vacuum distilled. A fraction collected at 64°-67° C. and 13 mm Hg weighs 15.6 g and consists of 90% by weight of title product and 10% by weight of morpholine. A second fraction collected at 67°-67.5° C. and 13 mm Hg (lit. 56°-57° C.; 11 mm Hg) weighs 16.2 g (46%) and is shown to be pure title product by nuclear magnetic resonance (nmr) and infrared (ir).