Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][C:21]1[CH:61]=[CH:60][C:24]([O:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:28][CH2:27]2)=[CH:23][CH:22]=1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C@H:26]2[CH2:27][CH2:28][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:52]5[NH:53][C:4](=[O:7])[O:5][N:3]=5)=[CH:44][CH:45]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:30][CH2:31]2)=[CH:60][CH:61]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(O)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogen carbonate (0.55 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.22 g) was added, and the mixture was stirred at 90° C. for 23 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.028 g, 14%).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:17]1(=NO)CCCCC[CH2:18]1>>[C:9]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:1]1.[C:1]1(=[N:7][OH:8])[CH2:18][CH2:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ON=C1CCCCC1
Reactant: ON=C1CCCCCC1
Reactant: O=C1CCCCCN1
Product: O=C1CCCCCCN1
Product: ON=C1CCCCCCC1

Procedure:
For example, cyclohexanone oxime gives ε-caprolactam, cycloheptanone oxime gives 7-heptane lactam, cyclooctanone oxime gives 8-octane lactam, and cyclododecanone oxime gives laurolactam
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[CH:21]1([Zn+])[CH2:23][CH2:22]1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][NH2:18])=[C:11]([F:19])[C:10]=1[O:9][C:4]1[CH:3]=[C:2]([CH:21]2[CH2:23][CH2:22]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: [Zn+]C1CC1
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (0.460 g, 1.260 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.029 g, 0.025 mmol) in THF (10 ml) was added cyclopropylzinc bromide (0.5 M solution in THF) (6.30 ml, 3.15 mmol) and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give ({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amine (0.281 g, 0.861 mmol, 68% yield). 1H NMR (400 MHz, METHANOL-d4) d ppm 7.20-7.44 (m, 3H), 6.76 (s, 1H), 6.54 (s, 1H), 3.86 (s, 2H), 1.74-2.05 (m, 1H), 0.83-1.08 (m, 2H), 0.40-0.76 (m, 2H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([C:28]5([OH:27])[CH2:30][CH2:29]5)=[O:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (70 mg, 68%), MS (ISP) m/z=413.5 [(M+H)+], mp 164° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 1-hydroxy-cyclopropane-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>C(O)(C)C>[CH3:17][O:18][C:19]([C:21]1([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[C:7]4[CH2:8][CH2:9][CH2:10][C:6]=4[N:5]=[C:4]([CH2:11][CH:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[N:3]=3)=[CH:30][CH:31]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1)=[O:20]
Reactant: Clc1nc(CC2CCCC2)nc2c1CCC2
Reactant: COC(=O)C1(c2ccc(N)cc2)CCCC1
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(CC4CCCC4)nc4c3CCC4)cc2)CCCC1
Yield: 62.6 %

Procedure:
A mixture of 4-chloro-2-cyclopentylmethyl-6,7-dihydro-5H-cyclopentapyrimidine (0.38 g, 1.6 mmol) and 1-(4-amino-phenyl)-cyclopentane carboxylic acid methyl ester (0.35 g, 1.6 mmol) in anhydrous isopropanol (8 mL) was heated at reflux under nitrogen for 8 to 18 hours. Thereafter, volatiles were evaporated under reduced pressure. The residue was triturated with ether and filtered. The solid was dissolved in ethyl acetate, washed with 5% sodium bicarbonate, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow powder (0.42 g, 63% yield).
Reaction SMILES: [OH-:1].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].O.Cl>CS(C)=O>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:1])([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 8 h

Procedure:
87.6 g of finely powdered sodium hydroxide was added in portions over an 8-hour period to a stirred solution of 165.0 g of 2-nitro-4-(trifluoromethyl)chlorobenzene in 220 ml of dimethyl sulfoxide at room temperature. The mixture was allowed to stand overnight, then poured into 1.5 liters of cold water. The resulting mixture was acidified to pH 1 with concentrated hydrochloric acid. An oil formed; it was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent under reduced pressure. The residue was mixed with cold sodium hydroxide solution and the mixture was extracted with petroleum ether. The water layer was acidified with concentrated hydrochloric acid. The resulting oil was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent to give 2-nitro-4-(trifluoromethyl)phenol (6A).
Reaction SMILES: [CH:1]1([N:4]([CH3:25])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][OH:56].C(N(CC)CC)C.CN(C)[CH:66]=[O:67]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:55][O:56][C:66]([C:9]1[CH:8]=[CH:7][C:6]2[CH:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:25])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[CH:10]=1)=[O:67]
Reactant: CN(C1CC1)C1CCC(C)(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CO
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Temperature: 70 °C
Yield: 85 %

Procedure:
A solution of trifluoro-methanesulfonic acid 5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Intermediate 54, 0.37 g, 0.98 mmol), palladium acetate (0.05 g, 0.22 mmol)and 1,3-bis(diphenylphosphino)propane (0.096 g, 0.23 mmol) in a mixture of dimethylformamide (4 mL), methanol (4 mL) and triethyl amine (2 mL) was heated at 70° C. under an atmosphere of carbon monoxide overnight. The volatiles were distilled of in vacuo and the residue was diluted with water and extracted with diethyl ether (×3). The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-5% ethyl acetate in hexane as the eluent, to afford the title compound (0.236 g, 85%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[C:9]1([NH:15][C:16](=S)[NH:17][NH2:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:20]1(C)C=CC=C[CH:21]=1>O1CCCC1>[NH:15]([C:16]1[C:2]([C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])=[C:20]([CH3:21])[NH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNC(=S)Nc1ccccc1
Reactant: Cc1ccccc1
Reactant: CC(C)OC(=O)CCl
Solvent: C1CCOC1
Product: Cc1[nH]nc(Nc2ccccc2)c1C(=O)OC(C)C
Reaction time: 0.5 h

Procedure:
35.7 g of isopropyl 2-chloroacetate is added to a suspension of 33.5 g of 4-phenylthiosemicarbazide in 150 ml of tetrahydrofuran. After the mixture has been stirred for 30 minutes it is boiled for a further 30 minutes and then allowed to cool. The precipitated solid is isolated by suction filtering, washed with acetone and the residue is heated in a water/acetone mixture (1:1). After the separated sulfur has been poured off, the whole is allowed to cool and is neutralized with aqueous NaHCO3, solution and the precipated solid is isolated; m.p. 138°-139° C. (from toluene).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.36 mmol) in dioxane (5 mL) was added 2,4-difluorophenylboronic acid (113 mg, 0.72 mmol), K3PO4 (152 mg, 0.72 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (115 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(Cc2ccccc2)c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
A mixture of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6.05 g, 39.24 mmol), benzyl bromide (5.14 mL, 43.17 mmol) in DMF (50 mL) was cooled with an ice-water bath, then the solids of NaH (1.89 g, 47.09 mmol) were added in one portion, the mixture was stirred at 0° C. for 1.5 h, then quenched with saturated ammonium chloride aqueous solution, diluted with EtOAc, the organic phase was washed with water and saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified with column chromatography to give the desired title product (5.537 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=7.30 (m, 3H), 6.95 (m, 2H), 6.57 (d, 1H, J=3.0 Hz), 6.53 (d, 1H, J=3.0 Hz), 5.03 (s, 2H), 4.25 (q, 2H, J=7.0 Hz), 2.44 (s, 3H), 1.34 (t, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16](I)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16]([C:35]3[CH:36]=[CH:37][S:33][CH:34]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(I)n21
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(-c3ccsc3)n21
Yield: 54.2 %

Procedure:
To a solution of tert-butyl(2-{6-iodo-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate (100 mg, 0.177 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, (67.9 mg, 0.531 mmol) of 3-thienylboronic acid, 7.2 mg (0.009 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium, complex with dichloromethane and 172 mg (0.531 mmol) of cesium carbonate, were subsequently added. The mixture was heated at 80° for 1 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash chromatography on silica gel column (DCM/EtOAc/EtOH 6/4/0.5), and further purification by HPLC/MS preparative method 1, 50 mg (54%) of tert-butyl(2-{1-oxo-6-(thiophen-3-yl)-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate were obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[N:11][O:12][C:8]=2[CH:7]=1>S(=O)(=O)(O)O.CCOCC.C(Cl)Cl>[Cl:5][C:6]1[C:21]([N+:1]([O-:4])=[O:2])=[CH:20][C:9]2[C:10]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[N:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C(C)Oc1noc2cc(Cl)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(C)Oc1noc2cc(Cl)c([N+](=O)[O-])cc12
Reaction time: 1 h

Procedure:
Nitric acid (70%, 3.0 mL, 47 mmol) is slowly added to a mixture of methyl 2-[(6-chloro-1,2-benzisoxazol-3-yl)oxy]propionate (6.0 g, 23.5 mmol) in concentrated sulfuric acid (50 mL) while maintaining the temperature below 10° C. The reaction mixture is stirred for 1 hour on an ice/water bath and poured onto ice. The resultant aqueous mixture is diluted with ether, stirred for several minutes and the ether is allowed to evaporate overnight. The resultant mixture is filtered to obtain a solid which is dissolved in methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a solid which is recrystallized from an ether/hexanes solution to give the title product as a solid, mp 98°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26]C)[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:26])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28]
Reactant: COc1c2c(c3n(c1=O)CCC(=O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CN1CC(=O)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H, 11H)-tetrone (25 mg, 0.05 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) in dioxane (1 mL) was stirred at room temperature for 1.5 hour. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound. 1H NMR (400 MHz, CDCl3) δ 13.47 (s, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.19 (m, 1H), 7.12 (t, J=8.2 Hz, 1H), 5.56 (br s, 1H), 4.94 (br m, 1H), 4.23 (br m, 2H), 4.16-3.98 (m, 2H), 3.60 (br d, J=8.1 Hz, 1H), 3.51 (br d, J=10.2 Hz, 1H), 3.24 (br signal, 1H), 2.89 (s, 3H), 2.59 (br signal, 1H). (ES MS M+1=448.0)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]1[CH2:13][CH2:12][CH2:11]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: BrC1CCC1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCC2)c1
Temperature: 25 °C

Procedure:
To a cooled (0 C) stirred solution of 4-bromo-1H-pyrazole (5.360 g, 36.47 mmol) in DMF (50 mL) was added sodium hydride (1.925 g, 80.23 mmol) slowly. The mixture was allowed to stir in the ice bath 30 min and bromocyclobutane (3.433 ml, 36.47 mmol) was added. The vessel was sealed and the reaction mixture heated at 95 C for 23 h. The mixture was allowed to cool to rt and diluted with 200 mL EtOAc, washed with 500 mL water, then 2×100 mL water, sat NaHCO3, then the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a CH2Cl2 in hexanes gradient. (I2 stain for visualization). The title compound was collected as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5](C=O)[N:6]=1.C(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:30])C.[C:50]1(C)C=C[CH:53]=[CH:52][CH:51]=1>>[F:1][C:2]1[N:3]([C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=[C:5](/[CH:50]=[CH:51]/[C:52](=[O:30])[CH3:53])[N:6]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(=O)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole and acetyl triphenyl phosphorane were reacted in toluene at 100° over 18 hours to give E-2-fluoro-4-(3-oxobut-1-enyl)-1-triphenylmethylimidazole. This was hydrogenated in a mixture of EtOAC and EtOH, using 5% w/w palladium on carbon as catalyst, to give 2-fluoro-4-(3-oxobutyl)-1-triphenylmethylimidazole. This was treated in EtOH with O-methylhydroxylamine hydrochloride and pyridine. Evaporation of solvent and trituration with water gave 2-fluoro-4-(3-methoxyiminobutyl)-1-triphenylmethylimidazole as a mixture of isomers, the major Z-isomer having the following n.m.r. spectrum in CDCl3 : 1.84 (s, 3H); 2.4-2.7 (m, 4H); 3.86 (s, 3H); 6.37 (s, 1H); 7.1-7.4 (m, 15H).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([C:4]#[CH:5])[CH3:3].[Li+].[NH2-].Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N>[CH3:1][C:2]([CH3:3])([NH2:6])[C:4]#[C:5][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCOCCCc1ccccc1
Reactant: C#CC(C)(C)N
Agent: N
Agent: [Li+]
Agent: [NH2-]
Product: CC(C)(N)C#CCCOCCCc1ccccc1
Reaction time: 1.5 h
Yield: 13.8 %

Procedure:
1,1-Dimethylpropargylamine (8.5 g) was added dropwise to a suspension of lithamide [from lithium (1.7 g)] in liquid ammonia (100 ml) at -33°. The mixture was stirred for 90 min and a solution of [3-(2-bromoethoxy)propyl]benzene (21.5 g) in ER (30 ml) was added dropwise. The suspension was stirred for 4 h and ammonia was allowed to evaporate overnight. The residue was treated with H2O (100 ml) and extracted with ER (3×100 ml). The dried extract was evaporated and the residue was distilled to give the title compound as a colourless oil (3.0 g) b.p. 160°-165°/0.2 mmHg. T.l.c. (ER) Rf 0.3.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10](OC)(OC)OC)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:20][Si:21]([O:43][Si:44]([CH3:47])([CH3:46])[CH3:45])([O:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[O:22][Si:23]([O:34]C(=O)C)([O:29][Si:30]([CH3:33])([CH3:32])[CH3:31])O[Si](C)(C)C)(=O)C.C(O[Si:52]([CH3:59])([CH3:58])[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55])(=O)C>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([Si:52]([CH3:58])([CH3:59])[O:53][Si:54]([CH3:55])([CH3:56])[CH3:57])([Si:52]([CH3:59])([CH3:58])[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[O:34][Si:23]([O:29][Si:30]([CH3:33])([CH3:32])[CH3:31])([O:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[O:22][Si:21]([O:38][Si:39]([CH3:40])([CH3:41])[CH3:42])([O:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[O:20][Si:10]([CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([Si:52]([CH3:59])([CH3:58])[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[Si:52]([CH3:59])([CH3:58])[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reactant: CC(=O)O[Si](C)(C)O[Si](C)(C)C
Reactant: CC(=O)O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](OC(C)=O)(O[Si](C)(C)C)O[Si](C)(C)C
Product: C=C(C)C(=O)OCCC[Si](O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](CCCOC(=O)C(=C)C)([Si](C)(C)O[Si](C)(C)C)[Si](C)(C)O[Si](C)(C)C)([Si](C)(C)O[Si](C)(C)C)[Si](C)(C)O[Si](C)(C)C

Procedure:
This monomer was prepared in a manner similar to that described in Example 1. The reactants were γ-methacryloxypropyltrimethoxysilane (2 moles), 1,3-Bis(acetoxy)-1,1,3,3-TETRA(trimethylsiloxy)disilox ane (1 mole) and acetoxypentamethyldisiloxane (4 moles). This material is designated SM-16.