Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH2:20][OH:21])[CH2:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)CCC(CO[Si](C)(C)C(C)(C)C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)CCC(CO)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In tetrahydrofuran (10 ml), (2RS)-6-(N-tert-butoxycarbonylaminomethyl)-2-(tert-butyldimethylsilyloxymethyl)-1,2,3,4-tetrahydronaphthalene (1.09 g) was dissolved. To the resulting solution, tetra-butylammonium fluoride (a 1.0M tetrahydrofuran solution, 4.0 ml) was added, followed by stirring at room temperature for 2 hours. After concentration under reduced pressure, the concentrate was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1˜2:1), whereby a colorless solid (0.77 g, 98%) was obtained. A portion of the solid was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: ClC([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)CCC[NH-].[H-].[Na+].[OH2:30]>O1CCCC1>[CH3:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:10]2[CH:11]=[C:7]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:30])[CH:8]=[N:9]2)=[CH:17][CH:16]=1
Reactant: O
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(Cl)CCC[NH-])cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(N3CCCC3=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-chloro-N-[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]butylamide obtained in Example 29-(2) (0.224 g) in tetrahydrofuran (2.0 mL), sodium hydride (55% in mineral oil, 0.111 g) was added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=100:1), and the resulting crystal was washed with diisopropyl ether to give the titled compound (0.127 g) as a light-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[CH:39]=[CH:38][NH:37][C:34]3=[N:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][C:12]([C:31]2[CH:32]=[C:33]3[CH:39]=[CH:38][NH:37][C:34]3=[N:35][CH:36]=2)=[CH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CC=C(c2cnc3[nH]ccc3c2)CC1
Temperature: 80 °C
Yield: 9.6 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohex-1-enyl ester (730 mg, 20 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (490 mg, 20 mmol), Pd(dppf)Cl2 (80 mg) and 2.0M Na2CO3 (3 ml, 6 mmol) in DMF (20 ml) was heated at 80° C. under N2 for 3 hours, and then concentrated. The residue was suspended in water, filtered and the solid was purified by FC to give [4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester (600 mg) in 96% yield. FIA-MS: m/e=314.05 (M+H). A suspension of the above cyclohexene (300 mg) and 10% Pd/C (200 mg) in a 1:1 mixed solvent of EtOAc and MeOH (30 ml) was shaken under 50 psi H2 for 20 h. Filtration gave [4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-cyclohexyl]-carbamic acid tert-butyl ester (280 mg). FIA-MS: m/e=316.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[O:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[O:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)no1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)no1
Temperature: 40 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A mixture of methyl 3-(benzyloxy)isoxazole-5-carboxylate (1.68 g, 7.2 mmol) and lithium hydroxide monohydrate (0.839 g, 20 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was stirred at 40° C. for 4 h. 1 M hydrochloric acid solution was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid (1.58 g, 100%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.[CH:43]1(B(O)O)[CH2:45][CH2:44]1.[OH-].[K+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:43]1([C:2]2[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH3:12])[C:8]3[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[N:7]=3)[CH:3]=2)[CH2:45][CH2:44]1
Reactant: OB(O)C1CC1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C2CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 100 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0. 113 mmol), cyclopropyl boronic acid (20 mg, 0.34 mmol), and tetrakis(triphenylphosphine) palladium(0) (13. 1 mg, 0.011 mmol) were combined in dry tetrahydrofuran (2 mL) followed by addition of 0.58 mL of a 1 N aqueous potassium hydroxide solution in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20% EtOAc/Hex) to afford 70.5 mg (100%) as an oil. LC/MS (HPLC method 2): tR=3.738 min, 624.24(MH)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([NH:20][CH:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:20]([CH:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:40]1=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CC(CNCc2ccccc2)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CC2CN(Cc3ccccc3)C(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 32 %

Procedure:
t-Butyl 2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate (0.64 g; 1.5 mmol) was dissolved in toluene (40 ml). Triethylamine (457 μL; 3.3 mmol) and triphosgene (0.49 g; 1.65 mmol) were added. The reaction mixture was stirred at RT for 4.5 h. It was then washed with water (1×), saturated NaHCO3 solution (1×) and again with water (1×). The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was chromatographed on an SiO2 cartridge (EtOAc/n-heptane 1:3). t-Butyl 2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.22 g, 0.48 mmol) was obtained as a yellow oil. MS: 453.20 (M+H); Rt: 1.94 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=O)[CH:12]=1.[Cl-].[Li+].CO>ClCCl>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]2[C:15]([CH3:17])=[CH:16][C:11]([OH:10])=[CH:12][C:13]2=[O:14])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cnc(Cl)cc1N
Reactant: Cc1cc(O)cc(=O)o1
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 160 °C
Yield: 6 %

Procedure:
A well-powdered mixture of 4-amino-5-methyl-2-chloropyridine (0.5 g, 3.5 mmol), 4-hydroxy-6-methyl-pyrone (0.665 g, 5.3 mmol), and lithium chloride (0.025 g, 0.6 mmol) was heated at 160° C. for 20 min in a sealed tube. The resulting melt was cooled and the product was isolated by silica gel flash chromatography using 3% methanol in dichloromethane. Appropriate fractions were combined, concentrated under reduced pressure and the resulting solid was triturated with ethyl acetate, cooled and filtered. The solid was washed with ethyl acetate and dried to give 0.053 g of the title compound as a yellow powder. ES-MS: m/z=251 (M+H).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18.6 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [BH4-].[Li+].CO.[F:5][C:6]1[C:7]2[O:32][N:31]=[C:30]([N:33]3[CH:37]=[C:36]([C:38](OCC)=[O:39])[CH:35]=[N:34]3)[C:8]=2[CH:9]=[C:10]2[C:23]=1[N:22]1[CH2:24][C@@H:25]([CH3:29])[O:26][C@@H:27]([CH3:28])[C@@H:21]1[C:12]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14][C:13]1=[O:20])[CH2:11]2>O1CCCC1.O>[F:5][C:6]1[C:7]2[O:32][N:31]=[C:30]([N:33]3[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[N:34]3)[C:8]=2[CH:9]=[C:10]2[C:23]=1[N:22]1[CH2:24][C@@H:25]([CH3:29])[O:26][C@@H:27]([CH3:28])[C@@H:21]1[C:12]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14][C:13]1=[O:20])[CH2:11]2
Reactant: CCOC(=O)c1cnn(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN2c3c(cc4c(-n5cc(CO)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium borohydride (0.434 mL, 0.87 mmol) was added to an ice cooled solution of methanol (0.035 mL, 0.87 mmol) in tetrahydrofuran (10 mL). The solution was warmed to room temp and stirred for 1 hour. 1.5 ml of this solution was added to a solution of ethyl 1-[(2R,4S,4aS)-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-1H-pyrazole-4-carboxylate (Example 37, 60 mg, 0.11 mmol). The reaction was stirred at room temp for 12 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were washed twice with brine, dried over MgSO4 and concentrated. The residue was purified by reverse phase HPLC to give product as a solid. Yield: 20 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:12][C@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A mixture of 4-nitrobenzaldehyde (30.22 g, 0.2 mol), 1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (40.06 g, 0.2 mol) and sodium tri(acetoxy)borohydride (85 g, 0.4 mol) in 1,2-DCE (1 L) was stirred at room temperature over-weekend. The reaction mixture was treated portion-wise with NaHCO3 solution (400 mL) over a period of ˜2 h. After a further 30 mins, the organic layer was separated, washed with brine, dried and concentrated to give a viscous pale yellow oil. Purification by column chromatography eluting with 0%, 10% and then 20% EtOAc/hexane yielded the title compound as a yellow crystalline solid (61.1 g).
Reaction SMILES: CN(C)[C:3](Cl)=[O:4].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([NH:25][NH2:26])=[O:24])[CH2:19][CH2:18]1>N1C=CC=CC=1>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[O:24][C:3](=[O:4])[NH:26][N:25]=2)[CH2:19][CH2:18]1
Reactant: CN(C)C(=O)Cl
Reactant: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Solvent: c1ccncc1
Product: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)o1
Temperature: 85 °C
Yield: 39.7 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@@H:16]1[CH2:28][CH:29]=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH2:28][C@@H:29]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:30])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: O[C@@H](CC1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Add phenyllithium (11.3 mL, 20.4 mmol, 1.8 M in cyclohexane-ether) dropwise to a −78° C. solution of (S)-(1,4-dibenzyl-piperazin-2-yl)-acetaldehyde (4.2 g, 13.6 mmol) in THF (60 mL). Stir 30 min at −78° C. and 4 h at ambient temperature. Add ice, brine, and extract with ether. Wash the extracts with brine, dry with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 3.98 g (76%) of the title compound: mass spectrum (ion spray): m/z=387 (M+1). HR-MS calculated for C26H31N2O: 387.2436. Found 387.2442.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH3:20].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][NH2:20])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: N
Solvent: CO
Solvent: O
Product: NCCOC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
A mixture of 28.2 g (0.1 mole) of 2-[bis(p-fluorophenyl)methoxy]ethyl chloride and 17 g (1 mole) of ammonia in 187.5 ml of methanol is shaken in an autoclave for a period of 6 hours at 135° C. The reaction mixture is poured into water and extracted with diethyl ether. The extract is acidified with 2N hydrochloric acid. The acid aqueous layer is separated off, made alkaline with 2N sodium hydroxide and extracted with diethyl ether. The extract is dried over potassium carbonate and the ether is distilled off. The residue is distilled, yielding 15.4 g of 2-[bis(p-fluorophenyl)-methoxy]ethylamine, boiling point 130° C/0.2 mm.Hg. The base is dissolved in diethyl ether and an ethereal solution of maleic acid is added. The precipitate is filtered off and crystallised from a mixture of ethanol and diethyl ether. 2-[Bis(p-fluorophenyl)methoxy]ethylamine hydrogen maleate is obtained. Its melting point is 126°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[CH2:14][S:15]([CH2:18][CH2:19][Cl:20])(=[O:17])=[O:16].S(=O)(=O)(O)O>C(Cl)CCl>[Cl:1][C:2]1[C:10]([NH:11][CH2:14][S:15]([CH2:18][CH2:19][Cl:20])(=[O:17])=[O:16])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(CO)CCCl
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=C(O)c1cc(Cl)cc(NCS(=O)(=O)CCCl)c1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
20.6 g (0.1 mole) of 2,5-dichloro-3-aminobenzoic acid and 18.7 g (0.12 mole) of hydroxymethyl-(β-chloroethyl)-sulfone were suspended in 100 ml of ethylene chloride, 1 ml of concentrated sulfuric acid was added thereto and the mixture was stirred for 3 hours at 40° C. The mixture was then cooled and the product which had crystallized out was filtered off and recrystallized from acetonitrile. This gave 30.8 g (89% of theory) of 2,5-dichloro-3-[(β-chloroethyl)-sulfonylmethylamino]-benzoic acid in the form of colorless crystals of melting point 156° C (with decomposition).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH2:20][C:21]#[N:22])[CH:16]=[CH:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24]>N.CCO.[Ni]>[NH2:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:23])[C:5](=[O:24])[N:4]([CH2:3][C:2]([CH3:1])([CH3:25])[CH3:26])[C:12]3=[CH:11][CH:10]=2)[CH:14]=1
Reactant: Cc1ccc(CC#N)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Cc1ccc(CCN)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Raney 2800 Nickel (30 mg, suspended in water) was added to a 25 mL receiver flask. The black solid was rinsed with EtOH and a solution of 82-2 (38 mg, 0.11 mmol) dissolved in 2M ammonia in EtOH (2 mL) was added. The flask was purged with hydrogen and the reaction was stirred at room temperature under a balloon of hydrogen. After 3 hours, the flask was purged with nitrogen and the mixture was filtered, rinsed with EtOH and concentrated. Purified by reverse phase (Sunfire C18, 25-85% CH3CN/0.1% TFA in water) and the fractions containing product were passed through an SCX cation exchange column, washed with acetonitrile, and eluted with 2M ammonia in EtOH to give 82-3 as a colorless oil. HRMS (M+H)+: observed=353.2, calculated=353.5.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+](=[CH2:13])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][C:2]1([CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:1]1
Reactant: C=[N+]=[N-]
Reactant: C=C(C)CCC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)CCC1(C)CC1
Temperature: 0 °C

Procedure:
To an ice cold solution of ethyl 4-methyl-4-pentenoate (1.11 g, 7.8 mmol) in 0.5 M diazomethane in Et2O, was added palladium(II) acetate by portionwise addition (4 portions of 5 mg each were added in 15 min intervals). A total of 4 portions were added. The reaction mixture was filtered on a pad of celite and concentrated under 60 mm Hg with gentle warming. This crude product was treated a second time with diazomethane and palladium(II) acetate, filtered and concentrated. The resulting oil was filtered on a pad of florisil (60–100 mesh), washed with Et2O (2×10 mL), concentrated under 60 mm Hg to give ethyl 3-(1-methylcyclopropyl)propanoate as a colorless oil.