Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][N+:17]([O-:19])=[O:18].C(C1C=CC=C(C(C)(C)C)C=1[O-])(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:16]2[N+:17]([O-:19])=[O:18])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CBr
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Temperature: -19 °C
Reaction time: 0.25 h
Yield: 319.7 %

Procedure:
A stirred mixture of 9.4 g of 4A bead molecular sieves, 9.4 g of dry Celite, (trademark), 5.62 g (30 mmol) of N-benzylmaleimide, and 120 mL of dry toluene under nitrogen was cooled to -19° C. and treated with 2.7 mL (3.9 mmol, 1.3 equivalents) of bromonitromethane. Tetrabutylammonium 2,6-di-t-butylphenoxide, the title product of Example 1, 23.38 g, was added, via a solid addition funnel, over 1.75 hours to the stirred reaction mixture at -19° C. After 15 minutes of further stirring, the reaction mixture was warmed to -1° C. and treated with 60 mL of 2N hydrochloric acid with vigorous stirring. The mixture was stirred for 1 hour and filtered through a Celite pad. The filtered solids were washed two times with 100 mL of toluene and the combined toluene solutions were washed two times with 60 mL of 2N hydrochloric acid, two times with 50 mL of water and once with brine. The resulting solution was stirred with 3.0 g of Darco (trademark) KBB overnight and filtered. The recovered Darco was washed two times with 50 mL of toluene, the toluene solutions were combined and the toluene was removed under vacuum to yield 14.95 g of a partially solidified orange-brown oil. This material was dissolved in 30 mL of toluene at 50° C. The toluene was removed by distillation under reduced pressure at 50° C., using a heated oil bath, while maintaining a constant volume by adding a total of 120 mL of isopropanol. This resulting slurry was stirred at 50° C. for 3 hours. Heating of the mixture was discontinued and the mixture was allowed to slowly cool to room temperature overnight. The mixture was then cooled to 0° C. for 3 hours and filtered. The filtered solids were washed with 10 mL of cold isopropanol followed by hexanes, and dried under vacuum giving 3.07 g (42% yield) of the title compound as a light tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Mg]Br.[O:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[O:27][C:26](=[O:28])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[N:23]=3)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[NH:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:21][CH2:20]2)=[O:27])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=c1oc(N2CCC3(CC2)OCCO3)nc2ccccc12
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-5-chloropyridine (573 mg, 4.51 mmol) in tetrahydrofuran (25 mL) at 0° C. under nitrogen was added methylmagnesium bromide (3.0 M in ether, 1.50 mL, 4.51 mmol) dropwise via a syringe. After stirring at 0° C. for 10 min, 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-3,1-benzoxazin-4-one (1.30 g, 4.51 mmol) was added. After stirring 15 h at room temperature, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium chloride and the layers separated. The organic phase was washed with water, dried (magnesium sulfate), filtered, and concentrated in vacuo to give, after recrystallization from EtOAc, 880 mg (47%) of the title compound.
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5](OCC)=[O:6].[NH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20]>CN(C=O)C.[Cl-].[Na+].O>[N+:17]([C:15]1[CH:14]=[CH:13][C:12]2[O:20][CH2:4][C:5](=[O:6])[NH:10][C:11]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a stirred suspension of KF (4.9 g, 84.35 mmol) in DMF (25 mL) was added ethyl bromoacetate and the mixture was stirred at rt. After 25 minutes, to the mixture was added 2-amino-4-nitrophenol (5 g, 32.44 mmol) and the mixture was stirred at 60° C. After 25 h, the mixture was cooled to rt, poured into cold brine (200 mL), extracted with EtOAc (100 mL×3). The combined organics were washed with brine (200 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in MeOH, filtered, and washed the solid with MeOH to give 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one as a brown solid: Spectrum (ESI) m/e=193.0 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16](/[CH:30]=[CH:31]/[C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2.[NH4+].[Cl-]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:18]2[CH:17]=[C:16](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: c1cscn1
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of thiazole (0.38 g (0.10 mL, 1.4 mmol) in THF (2.0 mL) was added n-butyl lithium (1.6M solution in hexanes, 0.5 mL, 0.8 mmol) and stirred for 30 min. To this solution was added 0.176 g (1.3 mmol) of zinc chloride in 3.0 mL of tetrahydrofuran and stirred for 45 min. The resulting turbid solution was transferred, via cannula, to a flask containing a mixture of 0.17 g (0.35 mmol) of ethyl (E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-yl)ethenyl]benzoate (Compound A9) and 15 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium(0) in 3.0 mL of tetrahydrofuran. The reaction mixture was stirred for 1 h at ambient temperature and 1.5 h at 55° C. The reaction mixture was treated with aqueous NH4Cl, and extracted with EtOAc (2×). The combined organic layer was washed with brine and dried (MgSO4). The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexane) to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[CH:14]3[CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+].Cl.CO>CO.O.O1CCCC1>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Yield: 70.1 %

Procedure:
To a suspension of 9-(4-nitrobenzyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta(e][1,4]diazepin-10(1H)-one (10.2 g, 30 mmol) and bromocresol green in a mixture of methanol (100 mL)-tetrahydrofuran (THF) (30 mL) was added sodium cyanoborohydride (2.08 g, 33 mmol). To this mixture, 10% hydrogen chloride/methanol was slowly added dropwise at the same temperature until the color of the reaction mixture had ceased to change. This reaction mixture was diluted with water and extracted with 3 portions of ethyl acetate. The pooled organic layer was washed serially with water and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) and crystallized from ethyl acetate-diethyl ether to provide 7.09 g (yield 70%) of the title compound. m.p. 154°-155° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[F:24])[N:14]=[C:13]3[O:25][N:26]=[C:27]([CH3:28])[C:12]=23)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+].Cl>CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([F:24])=[C:17]([C:15]2[N:14]=[C:13]3[O:25][N:26]=[C:27]([CH3:28])[C:12]3=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:29])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[N:16]=2)[CH:22]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2onc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c12
Temperature: 70 °C
Yield: 27 %

Procedure:
4-[6-(5-Chloro-2-fluoro-phenyl)-3-methyl-isoxazolo[5,4-d]pyrimidin-4-ylamino]-nicotinic acid methyl ester (525 mg) was suspended in methanol (4 ml) added 1M sodium hydroxide solution (4 ml) and heated to 70° C. for 30 min. Removed methanol under vacuum and acidified solution to pH 4 with 6M hydrochloric acid. Filtered solid, washed with water and oven dried to give 137 mg product.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH3:30])[CH:23]=1>CCOCC>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH3:30])[CH:23]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: Cc1cc(F)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reaction time: 7 h
Yield: 115.3 %

Procedure:
22.6 g Potassium tert. butoxide, 33.2 g 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester and 300 mL MTB ether were stirred for 1 h at reflux. A solution of 20.3 g 4-Fluoro-2-methyl-benzonitrile, dissolved in 250 mL MTB ether was added within 20 min to the suspension and heating to reflux was continued for 7 h. The reaction was quenched with water. The organic layer was separated and washed with water and concentrated to give 54.8 g (yield 92%) of 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (500 MHz, d6-DMSO) δ 1.40 (s, 9H), 1.47-1.55 (m, 2H), 1.88-1.95 (m, 2H), 2.43 (s, 3H), 3.13-3.22 (m, 2H), 3.63-3.70 (m, 2H), 4.66-4.73 (m, 1H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: ON=Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a suspension of 4-chlorobenzaldehyde (70 g, 0.50 mol) and hydroxylamine hydrochloride (38.06 g, 0.55 mol) in a mixture of water (125 ml), methanol (150 ml) and ice (215 ml) was added an aqueous solution of sodium hydroxide (43.82 g NaOH in 100 ml water). Ice was occasionally added to keep the temperature below room temperature. The resulting almost clear solution was stirred for two hours before it was extracted with methyl t-butyl ether (500 ml). The remaining aqueous layer was acidified with 6 N HCl (95 ml) to pH around 5. The suspension was extracted with dichloromethane (500 ml). The organic phase was dried and concentrated to give the title compound as a white solid (63.39 g): NMR (CDCl3, 200 MHz): δ=8.09 (s, 1H), 7.66 (br s, 1H), 7.49 (m, 2H), 7.34 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1>C(Cl)Cl.O=[Mn]=O>[N:10]1[C:11]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: OC1CCCc2cccnc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline (13.96 g, 93.6 mmol) in dry CH2Cl2 (400 mL) was added solid <5 micron activated 85% MnO2 (manganese IV oxide) (82.22 g, 804 mmol). The resulting black suspension was stirred 18 h, at which point the mixture was filtered through a cake of celite and washed with CH2Cl2 (3×50 mL). The combined washings were concentrated to provide 11.27 g (82%) of the title compound as a pale yellow solid, which was used in subsequent reactions without further purification. This material displayed spectra identical to those reported above.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].CO[C:12](OC)([CH3:14])[CH3:13]>>[CH3:13][C:12]1([CH3:14])[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1
Reactant: Oc1cccc(O)c1O
Reactant: COC(C)(C)OC
Product: CC1(C)Oc2cccc(O)c2O1

Procedure:
The pyrogallol is particularly suitable for reaction with 2,2-dimethoxypropane to form 2,2-dimethyl-4-hydroxy-1,3-benzodioxole, and then reaction of this with methyl isocyanate to produce the pesticide 2,2-dimethyl-1,3-benzodioxol-4-yl methylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:38].[BH4-].[Na+].Cl>C1COCC1.O>[NH2:1][C:2]1[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][C:5]([CH2:6][CH:7]([CH2:8][OH:9])[CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(CC(CO)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.00 g (5.425 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyric acid (intermediate product 68) in 100 mL THF was added 1.054 g (6.500 mmol) CDl and the mixture was stirred for 2 hours at RT. This solution was added dropwise under a nitrogen atmosphere over 5 minutes to an ice-cooled solution of 0.728 g (19.250 mmol) sodium borohydride in 50 mL water and the mixture was stirred for 16 hours at RT. The reaction mixture was acidified with 1 N aqueous HCl to pH 2 and exhaustively extracted with EtOAc. The combined org. phases were washed with sat. aqueous NaCl solution, dried over sodium sulphate and evaporated i. vac.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH3:7][C:8]1([CH3:19])S[C@@H:11]2[CH2:13][C:14](=[O:15])[N:10]2[C@H:9]1[C:16]([OH:18])=[O:17].[OH-].[Na+].[S:22](=[O:25])(O)[O-:23].[Na+]>CCOCC.O.C(O)(=O)C>[CH3:7][C:8]1([CH3:19])[S:22](=[O:25])(=[O:23])[C@@H:11]2[CH2:13][C:14](=[O:15])[N:10]2[C@H:9]1[C:16]([OH:18])=[O:17]
Reactant: O=S([O-])O
Reactant: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Reaction time: 0.25 h
Yield: 26 %

Procedure:
To a mixture of 7,600 ml. of water and 289 ml. of glacial acetic acid was added, portionwise, 379.5 g. of potassium permanganate. This mixture was stirred for 15 minutes, and then it was cooled to 0° l C. To it was then added, with stirring, a mixture which had been prepared from 270 g. of penicillanic acid, 260 ml. of 4 N sodium hydroxide and 2,400 ml. of water (pH 7.2), and which had then been cooled to 8° C. The temperature rose to 15° C. during this latter addition. The temperature of the resulting mixture was reduced to 5° C. and the stirring was continued for 30 minutes. To the reaction mixture was then added 142.1 g. of sodium bisulfite, in portions, during 10 minutes. The mixture was stirred for 10 minutes at 10° C., and then 100 g. of supercel (a diatomaceous earth) was added. After a further 5 minutes of stirring, the mixture was filtered. To the filtrate was added 4.0 liters of ethyl acetate, and then the pH of the aqueous phase was lowered to 1.55 using 6 N hydrochloric acid. The ethyl acetate layer was removed and combined with several further ethyl acetate extracts. The combined organic layer was washed with water, dried (MgSO4) and evaporated almost to dryness in vacuo. The slurry thus obtained was stirred with 700 ml. of ether at 10° C., for 20 minutes, and then the solid was collected by filtration. This afforded 82.6 g. (26% yield) of the title compound having a melting point of 154°-155.5° C. (dec.).
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.C(O)(=O)C.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH:4]1([N:19]2[CH2:20][CH2:21][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18]2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
MeOH (0.3 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (2 g, 11.47 mmol) and acetic acid (1.051 mL, 18.35 mmol) were added to a stirred solution of tert-butyl piperazine-1-carboxylate (1.068 g, 5.735 mmol) in THF (40 mL) under nitrogen. Sodium cyanoborohydride (0.541 g, 8.60 mmol) was added portionwise over a period of 10 mins. The resulting mixture was stirred at 60° C. for 24 h. The reaction mixture was evaporated to dryness and mixed with water (80 mL) and 1M HCl (25 mL). This solution was washed with EtOAc (2×50 mL), the aqueous layer was basified with K2CO3, and extracted with EtOAc (2×30 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over MgSO4, filtered and evaporated to afford tert-butyl 4-cyclopropylpiperazine-1-carboxylate (0.792 g, 61.1%) as a colourless oil which crystallised on standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Reaction time: 120 h
Yield: 71 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (1.87 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (8.05 mL), and acetic acid (5.72 mL) were dissolved in methanol (60 mL). To the resultant solution, sodium cyanoborohydride (1.89 g) was added at room temperature, followed by stirring for 5 days. Diethyl ether was added to the residue obtained by removal through evaporation of the reaction solvent under reduced pressure, and insoluble matter was filtered off. The filtrate was partitioned by addition of aqueous 1N sodium hydroxide thereto. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid (1.62 g, 71%).
Reaction SMILES: [Na].[C:2](OCC)(=O)CC(OCC)=O.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:2][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Add sodium metal (3.5 g) portion-wise over 1 hour to a 3 neck flask containing 79 mL of diethyl malonate heated to 90° C. under nitrogen. Lower the temperature to 60° C. and add 2-chloro-3-nitropyridine (1a-1, 25.0 g) portion-wise over 15 min. The reaction color turns to dark red. Keep the solution for 3 h at 60° C. and then allow to stand at rt overnight. Tlc indicates remaining starting material. Heat the solution to 80° C. for an additional 3 h (completion of the reaction). Remove the diethyl malonate under reduced pressure and take-up the dark brown residue in a mixture of conc. H2SO4 (18 mL) and H2O (32 mL). Heat the mixture for 7 h at 105° C. (decarboxylation) and then allow to stand at rt overnight. Wash the mixture with 3×150 mL of Et2O and 2×200 mL of EtOAc, and discard the washings. Basify the aqueous phase to pH 8-9 with NaOH and extract with 3×200 mL EtOAc. Filter the combined organic extracts over Celite® (diatomaceous earth) (Celite Corporation, 137 West Central Avenue, Lompor, Calif. 93436) and remove the solvent under reduced pressure. The residue crystallizes to give 2a-1 (15.0 g, 68%), mp 29-31° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-].[K+].CN(C=O)C>C(OCC)(=O)C.O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(CCl)OCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Chloroacetaldehyde diethyl acetal (2.00 g), potassium benzoate (1.91 g), potassium bromide (0.30 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration, the organic layer was washed with water (30 mL) and was dried over anhydrous sodium sulfate. Subsequent filtration and vacuum concentration yielded the target compound (0.97 g) in a yield of 31%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O>[Pd].C(O)C>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)cc1N
Reaction time: 3.5 h
Yield: 105.9 %

Procedure:
4-Amino-3-nitrophenol (1.09 g, 7.072 mmol) was dissolved into ethanol (50 ml). Palladium on charcoal (10%, 220 mg) was added and the mixture was stirred for 3.5 h under hydrogen atmosphere. The reaction mixture was filtered over Celite® and concentrated to afford 138a (930 mg, 100% yield) as a dark brown solid.