Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[F:21][C:22]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[F:21][C:22]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]2[O:18][N:17]=[C:15]([C:13]3[S:14][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH2:19][CH3:20])[N:16]=2)=[CH:32][CH:33]=1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), 4-(2,3-difluorophenoxy)benzoic acid (0.14 g, 0.55 mmol) that was obtained in Example 18 (18a), N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 3:7) as the eluent to afford the title compound (0.18 g) in a yield of 88% as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16].[OH2:19]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH3:1][O:2][C:3]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:6]([CH:7]=[O:19])=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16]
Reactant: COc1c(C(F)(F)F)cc(C#N)cc1C(F)(F)F
Reactant: O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COc1c(C(F)(F)F)cc(C=O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-methoxy-3,5-bis(trifluoromethyl)benzonitrile (868 mg, 3.23 mmol, 1.00 equiv), a solution of NaH2PO2.H2O in water (10.0 mL), acetic acid (10.0 mL), pyridine (20.0 mL), Raney-Ni (0.9 g). The resulting solution was stirred for 3 h at 45° C. in an oil bath. The reaction progress was monitored by GCMS. The solids were filtered out. 20.0 mL EtOAc and 20.0 mL H2O were added into the mixture. The organic phase was washed by H2O with 2*20 mL and dried over Na2SO4. The solvent was removed and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 0.43 g (49%) of 4-methoxy-3,5-bis(trifluoromethyl)benzaldehyde as yellow oil. Mass spectrum (GC, m/z): Calcd. for C10H6F6O2, 272.0 (M). found 272.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncnn2cc(C(=O)O)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 80 °C

Procedure:
A suspension of ethyl 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.04 g, 3.18 mmol) in ethanol (10 mL), THF (5 mL) and 1N aqueous sodium hydroxide solution (5.56 mL, 5.56 mmol) was heated (80° C.) for 6 h. The homogeneous solution was cooled to rt and treated dropwise with 1N hydrochoric acid (5.56 mL). The reaction was concentrated in vacuo and the resulting solid triturated with water to give the desired product in quantitative yield. This material could be used without further purification. ES-MS 300.2 (MH)+; HPLC RT (Method A) 1.37 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[CH2:13]([OH:16])[CH2:14][CH3:15]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:16][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: CCCO
Product: CCCOc1cc[n+]([O-])c(C)c1C
Reaction time: 384 h

Procedure:
25 g of 2,3-dimethyl-4-nitropyridine 1-oxide are dissolved in 1250 ml of n-propanol and the solution is stirred at 120° under argon for 16 days. The reaction mixture is concentrated, whereupon the residue is treated with methylene chloride-water and extracted. The organic phases are dried and concentrated. The residue is chromatographed on silica gel and purified with methylene chloride-methanol (20:1, 10:1), the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2,3-dimethyl-4-propoxypyridine 1-oxide obtained is processed directly.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23])[CH3:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:12][CH3:13])=[O:23]
Reactant: CCOc1ccccc1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: CCOc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 81.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.84 g, 81%). EI-MS m/z 318(M+H)+
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2 (1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H) -pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([Br:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Yield: 37.1 %

Procedure:
[4-(Tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (1.60 gm, 5.36 mmol), NBS (1.04 g, 5.90 mmol) and benzoyl peroxide (0.130 g, 0.53 mmol) in carbon tetrachloride (50 ml) was refluxed for 7 hrs. Reaction mixture was diluted with DCM (50 ml), washed with water and brine (100 ml each), dried over anhydrous sodium sulfate, fliltered and concentrated. Crude compound was purified by column chromatography over silica gel using 30% ethyl acetate hexane as eluent to give the pure bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 gm).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:4].[CH3:19]I.Cl>C1COCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:7]([CH3:19])[C:6]([O:5][CH2:3][CH3:4])=[O:18])=[CH:9][C:10]=1[O:16][CH3:17])#[N:15]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension solution of NaH (0.18 g, 4.6 mmol, 60% dispersion in mineral oil) in THF (50 mL) at ° C. under N2 atm was added a solution of ethyl(4-cyano-3-methoxyphenyl)acetate (1.0 g, 4.6 mmol) in THF (10 mL) drop-wise and the mixture was stirred for 30 min at the same temperature. The mixture was then allowed to warm to ambient temperature. The mixture was then allowed to cool back to 0° C. Methyl iodide (0.28 mL, 4.6 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was acidified with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc 15/1) to give ethyl 2-(4-cyano-3-methoxyphenyl)propanoate. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, 1H, J=8 Hz), 6.98 (d, 1H, J=8 Hz), 6.95 (s, 1H), 4.17 (q, 2H, J=3.4 Hz), 3.97 (s, 3H), 3.76 (q, 1H, J=9.1 Hz), 1.53 (d, 3H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz); LCMS: [(M+1)]+=234.28; tR=3.12 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:15]>C1COCC1.CCOC(C)=O>[CH3:15][N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:10]=[CH:9]1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cncc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
To a solution of 4-phenylimidazole (500 mg, 3.47 mmol) in 10 mL THF at rt, was added 60% NaH (146 mg, 3.64 mmol). The mixture was stirred at rt for 5 min, then iodomethane (238 μL, 3.82 mmol) was added. The mixture was stirred at rt for 30 min, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (column #1: 0 to 10% MeOH/CH2Cl2 gradient, column #2: 1 to 2 to 5% MeOH/EtOAc, stepwise gradient) to afford 352 mg of Intermediate 13.1 and 166 mg of Intermediate 13.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[S:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+].Cl>O.CCO>[NH2:17][C:13]1[N:12]=[C:11]([C:9]2[S:8][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)sc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nccc(-c2cc(C(=O)O)c(-c3ccccc3)s2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ester 58 (220 mg, 0.68 mmol) in 1:1 H2O/EtOH (9 mL), 4M aq NaOH (10 eq) was added and the mixture stirred at 100° C. for 1 h. After cooling to rt, the solution was acidified with 2M HCl yielding 5-(2-amino-pyrimidin-4-yl)-2-phenyl-thiophene-3-carboxylic acid as a solid which was filtered, washed with water and dried under reduced pressure (185 mg, 90%).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:56][O:57][CH3:58])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-:55])=[O:54])[CH:48]=2)=[C:35]3[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:56][O:57][CH3:58])[C:27]([NH:29][C@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34]([S:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-:55])=[O:54])[CH:48]=2)=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3cccc([N+](=O)[O-])c3)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)N[C@H]1C(=O)N2C(C(=O)O)=C(Sc3cccc([N+](=O)[O-])c3)SC[C@H]12)c1csc(N)n1
Reaction time: 4 h
Yield: 44.6 %

Procedure:
286 mg of the product of Step B dissolved in 3 ml of 66% formic acid were stirred for 4 hours and then filtered. The filtrate was concentrated to dryness and the residue was dissolve in an acetonitrile-ethanol mixture. The solvents were evaporated and the residue was crystallized from isopropanol to obtain 82 mg of racemic cis 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(3-nitrophenylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid. 65 mg of the same product were recovered from the mother liquors and melted at 180°-200° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(cc(Cl)cc2[N+](=O)[O-])C1=O
Reaction time: 1 h
Yield: 94.11 %

Procedure:
To a solution of 5-chloro-1H-indole-2,3-dione (2.8 g, 15.46 mmol) in conc. H2SO4 (9 mL) was added fuming nitric acid (1.5 mL) very slowly at −5 to 0° C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice, and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (3.2 g, 94.11%) which was used for the next step directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O.Cl.O([NH2:20])C>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH2:20])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1F)c1ccncc1
Reactant: CON
Agent: [Pd]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccccc1F)c1ccncc1
Reaction time: 14 h

Procedure:
The intermediate oxime was prepared from 2-(2-fluoro-phenyl)-1-pyridin-4-yl-ethanone (crude) and methoxylamine hydrochloride (6.50 g, 77.83 mmol) according to the protocol described in general procedure B. The oxime was then dissolved in trifluoroacetic acid (30.00 mL) and Pd/C (0.80 g) was added. The reaction mixture was hydrogenated under 50 psi for 14 hours, then filtered and concentrated. The residue was basified with 5M sodium hydroxide and extracted with methylene chloride. The combined organic phases were dried over potassium carbonate and concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.83-3.00 (m, 2 H) 4.11 (t, J=7.33 Hz, 1 H) 7.34-7.48 (m, 2 H) 7.75 (dd, J=20.96, 11.58 Hz, 2 H) 8.45-8.52 (m, 1 H) 8.53-8.58 (m, J=6.45 Hz, 2 H) 8.79-8.80 (m, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH2:26]([O:28][C:29]([CH2:31][C:32](Cl)=[O:33])=[O:30])[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][C:32](=[O:33])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:18])[CH3:27]
Reactant: COC(=O)CCNCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
N-(p-Nitrobenzyl)-β-alanine methyl ester hydrochloride (32.66 g) and triethylamine (38 ml) are dissolved in methylene chloride (200 ml), and a solution of ethoxycarbonylacetyl chloride (20.0 g) in methylene chloride (100 ml) is added dropwise to the mixture under ice-cooling. The mixture is stirred at the same temperature for one hour, and the mixture is filtered to remove precipitates (triethylamine hydrochloride). The filtrate is washed with 2% HCl, water, 2% NaOH and water, dried and then distilled to remove the solvent to give ethyl[N-(p-nitrobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (40.4 g, 96.4%) as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.C([Li])CCC.[CH:19](N1CCOCC1)=[O:20].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:13][O:12][C:4]1[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=[C:2]([CH:19]=[O:20])[CH:3]=1
Reactant: COc1cc(Br)cc2c1OCOC2
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OCOC2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 31.2 g of 6-bromo-8-methoxy-4H-benzo[1,3]dioxine in 500 ml of THF there was added dropwise 55 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 20 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (21.28 g) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]#[N:12])[S:8][C:7]=2[CH:13]=1.[Cl-].[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]#[N:12])[S:8][C:7]=2[CH:13]=1
Reactant: COc1ccc2cc(C#N)sc2c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: N#Cc1cc2ccc(O)cc2s1
Temperature: 195 °C
Yield: 70.6 %

Procedure:
A mixture of 6-methoxybenzo[b]thiophene-2-carbonitrile (2.6 g, 13.74 mmol) and pyridinium chloride (12.5 g, 108.17 mmol) was heated at 190-200° C. for 1.5 h. The mixture was allowed to cool to room temperature and then triturated with cold water (30 mL). The precipitated solid was collected by filtration, washed with water (10 mL), and recrystallized from toluene to give 1.7 g (71%) of 6-hydroxybenzo[b]thiophene-2-carbonitrile as a brown solid, mp 195-198° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl[C:18]1[C:19]([N+:45]([O-:47])=[O:46])=[C:20]([C:30]2[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][C:33]([N+:39]([O-:41])=[O:40])=[CH:32][C:31]=2[N+:42]([O-:44])=[O:43])[C:21]([N+:27]([O-:29])=[O:28])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].CO>CC(C)=O>[N+:8]([C:7]1[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[CH2:1][C:22]1[C:21]([N+:27]([O-:29])=[O:28])=[C:20]([C:30]2[C:31]([N+:42]([O-:44])=[O:43])=[CH:32][C:33]([N+:39]([O-:41])=[O:40])=[CH:34][C:35]=2[N+:36]([O-:38])=[O:37])[C:19]([N+:45]([O-:47])=[O:46])=[CH:18][C:23]=1[N+:24]([O-:26])=[O:25])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2[N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])c2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
The reaction of 4.5 g (0.02 mole) of TNT with 4.6 g, (0.01 mole) of 3-chloro-2,2',4,4',6,6'-hexanitrobiphenyl was carried out as above. After extracting the crude reaction product with methanol until the extracts were light colored, the somewhat gummy residue was dissolved in acetone, an equal volume of methanol was added and the solution was heated, with magnetic stirring, on a hot plate. A light yellow crystalline material separated, was filtered off and dried. It weighed 1.7 g, 25% of the theoretical yield. Recrystallized from acetone methanol formed faintly yellow rod-like crystals, mp 255°-256°. Anal. Calcd for C19H7N9O18 : C, 35.1; H, 1.1; N, 19.4. Found: C, 34.9, 34.2; H, 1.6, 1.2; N, 19.2, 18.8.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:23](Br)([CH3:25])[CH3:24]>CN(C)C=O>[CH:23]([N:3]1[N:2]=[N:1][C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4]1)([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nnc(-c2cnc3ccccn3c2=O)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of 0.9 g (0.0042 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 25 ml of dimethylformamide, 1.15 g (0.0084 moles) of anhydrous potassium carbonate and 1.1 ml (0.0126 moles) of isopropyl bromide was stirred at 90° C. for 1 hour. The hot yellow solution was filtered, the filtrate evaporated. To the crystalline residue 25 ml of water was added, and the crystals were collected. 0.6 g (55.8%) of the title compound was obtained, in the form of white crystals, m.p.: 146°-148° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]1([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:24](Cl)=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>O1CCCC1>[CH:1]([NH:4][C:24](=[O:25])[CH:23]([O:22][C:21]1[CH:32]=[CH:33][C:18]([C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)=[CH:19][CH:20]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)NC(C)C
Reaction time: 5 h

Procedure:
To a solution of 5 g of isopropylamine and 5 ml of triethylamine in 100 ml of absolute tetrahydrofuran is slowly added dropwise with stirring at -5° C a solution of 13 g of α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid chloride in 25 ml of absolute tetrahydrofuran. The reaction mixture is left to stand for 5 hours at room temperature, then evaporated in vacuo to dryness. The residue is partitioned between methylene chloride and 2N hydrochloric acid. The organic phase is washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid isopropylamide of the formula ##STR23## (m.p. 86°-88° C after recrystallisation from petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]([OH:26])[CH:12]=3)=[CH:4][CH:3]=1.[CH2:27](O)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:11](=[C:12]([CH3:27])[C:13]([OH:26])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COc3cc(O)ccc32)cc1
Reactant: CCO
Product: COc1ccc(C2c3ccc(O)c(C)c3OCC2c2ccc(O)cc2)cc1

Procedure:
2.5 g of the product of step 8, 10% Pd/Al2O3 0.4 g and 50 ml of ethanol were combined in a 2-neck 100 ml round bottom flask. The reaction was hydrogenated at low pressure using standard conditions for 3 hours. The reaction was filtered through Celite to remove the catalyst, rinsed through with ethanol (100 ml). The filtrate was concentrated to ˜15 ml before being poured into chilled, stirred water (300 mL). A pale orange precipitate formed which then formed a brown oil. The mixture was then extracted with diethyl ether, the combined organic layers washed with water (3×100 ml), brine (1×100 ml), dried over anhydrous magnesium sulphate and filtered. The solvent was removed in vacuo to give red/brown oil. The product was recrystallised from diethyl ether (˜15 ml), to give brown solid which was rinsed with chilled diethyl ether to give off-white crystals. 4 crops of (IV), ˜1 g. The 1H NMR spectrum and numbering scheme being shown below.