Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[N:9]([CH3:23])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:24](Br)([CH3:27])([CH3:26])[CH3:25]>C1CCCCC1.[Ag-]=O>[C:24]([O:1][CH:2]([C:8]1[N:9]([CH3:23])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)Br
Reactant: CCOC(=O)C(O)c1c(-c2ccccc2)c2ccccc2n1C
Agent: O=[Ag-]
Solvent: C1CCCCC1
Product: CCOC(=O)C(OC(C)(C)C)c1c(-c2ccccc2)c2ccccc2n1C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(1-methyl-3-phenyl-1H-indol-2-yl)acetate (1c) (300 mg, 0.97 mmol), silver (I) oxide (674 mg, 2.91 mmol) and tert-butylbromide (544 μL, 4.85 mmol) in cyclohexane (10 mL) was vigorously stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired ether oxide (1d) as a white solid (35 mg, 0.1 mmol, 10%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:17])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12](=[S:14])[NH:11][C:10]=3[CH:15]=[C:6]2[O:5]1.[N+]([C:21]1[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1)([O-])=O>O1CCCC1>[F:17][C:4]1([F:3])[O:5][C:6]2=[CH:15][C:10]3[NH:11][C:12]([S:14][C:21]4[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=4)=[N:13][C:9]=3[CH:8]=[C:7]2[O:16]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: FC1(F)Oc2cc3[nH]c(=S)[nH]c3cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Aldehyde intermediate preparation: Sodium hydride (60% dispersion in mineral oil, 0.212 g, 5.3 mmol) in tetrahydrofuran (3 ml) is added dropwise over a 15 minute period to a solution of 2,2-difluoro-5,7-dihydro-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole-6-thione (0.763 g, 3.31 mmol) in tetrahydrofuran (5 ml). The mixture is stirred at room temperature for 2 hours. 5-nitro-2-furaldehyde (0.468 g, 3.31 mmol) in 7 ml of tetrahydrofuran is then added dropwise over a 15 minute period and the mixture is stirred for 2 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of dichloromethane and methanol (92/5, v/v). The fractions containing the expected product are concentrated under reduced pressure and the residue is triturated in diisopropylether and pentane and dried under vacuum to yield 5-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-ylsulfanyl)-furan-2-carbaldehyde as a brown powder. Yield=56%. Analytical LC/MS (method B): retention time=3.66 min., m/z=324.97 (positive ion mode).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][N:7]=1.[Cl:14]C1C(Cl)=CC=CN=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[C:11]([Cl:14])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)CSc1ccc(Cl)cn1
Reactant: Clc1cccnc1Cl
Product: COC(=O)CSc1ncccc1Cl
Yield: 52 %

Procedure:
was synthesized according to the procedure used for compound 14. Starting with 2,3-dichloropyridine (17, 2.09 g, 14.0 mmol) the target 18 was obtained as a colorless oil (1.6 g, 52% yield).
Reaction SMILES: Cl.[CH:2]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:43]=[CH:42][CH:41]=[CH:40][C:27]=1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[CH:2]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][N:7]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[CH:41][CH:42]=[CH:43][C:26]=4[CH3:25])=[CH:39][CH:38]=3)=[O:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CCc1ccccc1NC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a mixture of 0.245 g (1 mmol) of 5,6,11,12-tetrahydrodibenz[b,f]azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 ml of dichloromethane is added a solution of 0.281 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 4 ml of dichloromethane. The mixture is stirred overnight at room temperature, washed with water 2N HCl (3×2 ml) and 1N sodium bicarbonate (3×2 ml). The organic layer is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with 3 volumes of CH2Cl2). The filtrate is concentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCc1ccc(-c2ccc(OC)cc2)nc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1

Procedure:
The 2-(p-methoxyphenyl)-5-octylpyridine was dissolved in 100 ml of acetic acid. 8 ml of 48% hydrobromic acid was added to the reaction solution and the solution was heated for 15 hours under reflux. 100 ml of water was added to the reaction solution and the organic layer was extracted with chloroform. After washing the extract three times with water, the chloroform was removed by distillation. The residue was recrystallized from a mixture of acetone and hexane to yield 8.3 g (0.029 mol) of 2-(p-hydroxyphenyl)-5-octylpyridine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:16]1[N:17]=[C:18]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[C:28](O)[CH:29]=[C:30]([F:35])[CH:31]=3)[N:26]=2)[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12>>[N:16]1[N:17]=[C:18]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[C:28]([O:1][CH2:2][C@H:3]4[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]4)[CH:29]=[C:30]([F:35])[CH:31]=3)[N:26]=2)[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Product: Fc1cc(OC[C@H]2CCCNC2)c2nc(-c3nnc4ccccn34)ccc2c1

Procedure:
Prepared as described in Example 16 using (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate in place of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate, and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-quinolin-8-ol. MS ESI (+) m/z 378.2 (M+1) detected.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([Cl:29])[N:3]=1.N(OC(C)(C)C)=[O:31]>CC(O)C.O>[Cl:29][C:4]1[N:3]=[C:2]([OH:31])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)ON=O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(O)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A suspension of 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (291.2 g, 0.68 mol, Example 1, Step B) in 2-propanol and water (1:1, 15,560 mL) which was heated to achieve homogeneity. The solution was cooled to <15° C. and then t-butyl nitrite (357 mL, 3.0 mol) was added. The reaction was allowed to warm to room temperature and stirred until the evolution of gas subsided. The reaction was partitioned between ethyl acetate (7,300 mL) and water and the phases allowed to separate. The aqueous layer was further extracted with ethyl acetate (2×7,300 mL) and the combined organic layers were dried over magnesium sulfate, filtered and removed under reduced pressure to yield a viscous oil. Typical Yield: Quantitative.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](O)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.S(Cl)([Cl:36])=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([Cl:36])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)O)c3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonic acid (example 345) (2.0 g, 4.25 mmol) in DMF (20 mL) at 23° C. was added thionyl chloride (1.54 mL, 21.25 mmol) and the mixture was stirred at 23° C. for 2 h, then added again SOCl2 (1.54 mL, 21.25 mmol) and the mixture was stirred at 23° C. for 1 h. Diluted with EtOAc, poured into ice cold half-sat. NaHCO3-sol., separated phases, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as an off-white solid (2.0 g, 98%), which was used without further purification. MS (ISP) 489.2 [(M+H)+] and 491.1 [(M+2+H)+].
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=4)[C:14](=[O:27])[C:13]=3[C:12](Br)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32].C([O-])(=O)C.[Cl-]>COCCO.[Cu]>[Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=4)[C:14](=[O:27])[C:13]=3[C:12]([NH:33][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CCCCN
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c(NC3CCC(Cl)CC3)ccc(Br)c21
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: COCCO
Product: CCCCNc1ccc(NC2CCC(Cl)CC2)c2c1C(=O)c1ccc([N+](=O)[O-])cc1C2=O

Procedure:
10 g of 1-(p-chlorocyclohexylamino)-4-bromo-7-nitroanthraquinone, 60 ml of n-butylamine, 2.5 g of K acetate, 50 mg of copperI chloride and a trace of copper are heated under reflux until only a little starting material remains detectable in a sample. The mixture is diluted with 35 ml of ethylene glycol monomethyl ether and the product is filtered off and washed with methanol and water. 6.5 g of 1-(p-chlorocyclohexylamino)-4-butylamino-7-nitroanthraquinone are obtained.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:37])([CH3:36])[CH:33](O)[C:32]=4[C:39]=3[CH3:40])[CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CCCCCC.CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:36])([CH3:37])[CH:33]([N:3]5[CH2:2][CH2:1][C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=6[CH2:5][CH2:4]5)[C:32]=4[C:39]=3[CH3:40])[CH2:26][CH2:27]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Reactant: c1ccc2c(c1)CCNCC2
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(N3CCc5ccccc5CC3)C(C)(C)O4)CC2)cc1OC
Yield: 54 %

Procedure:
Using 2,3,4,5-tetrahydro-1H-3-benzazepine and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 57. Yield 54%. mp. 136–138° C. (hexane-methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].O.C[N+]1([O-])CC[O:25]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[O:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-2-fluoro-5-vinyl-benzyl)-carbamic acid tert-butyl ester (2.7 g, 9.5 mmol) in acetone (20 mL) was added N-methylmorpholine-N-oxide monohydrate (1.5 g, 11 mmol) and a solution of 4% aq. osmiumtetraoxide (3.7 mL, 0.5 mmol). The reaction was stirred for 1 h, saturated aqueous Na2S2O3-solution was added and stirring was continued for one hour. After extraction with EtOAc and removal of the solvent in vacuo, the residue was dissolved in acetone/water (3:1, 40 mL) and NalO4 (4.0 g, 19 mmol) was added. After stirring for 2 h at ambient temperature, the reaction mixture was filtered, washed with EtOAc, extracted with EtOAc, dried (Na2SO4) and the solvent was removed in vacuo to give the title compound which was used without further purification. tR (HPLC conditions c): 5.22 min.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[Cl:17])[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: ClCCNCCCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Clc1ccc(N2CCNCC2)cc1Cl
Yield: 27.7 %

Procedure:
This compound was prepared according to the procedure of Preparation 1. A mixture of 44.6 g (0.25 mole) of bis(2-chloroethyl)amine hydrochloride, 40.5 g (0.25 mole) of 3,4-dichloroaniline and 50.0 g (0.36 mole) of potassium carbonate in a total volume of 500 ml of n-butanol gave an oil as residue. Trituration of the oil with petroleum ether (30°-60° C.) gave 16.0 g (28%) of white solid, m.p. 62°-65° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>CCO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NC1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NC3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 35 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (60 mg, 0.16 mmol) and 4-piperidinamine (2 mL) in EtOH (3 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 125° C. for 5 hr and then at 160° C. for 90 min. The mixture was evaporated under vacuum and the resulting residue was partitioned between EtOAc and water. Organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOAc/ether (1:1) and allowed to stand at room temperature overnight. The solids that had precipitated were triturated, filtered, and dried to afford the title compound as a pale yellow solid 25 mg (35%). LCMS E-S (M+H)=438.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (t, J=4.67 Hz, 1 H) 7.98 (s, 1 H) 7.12 (s, 1 H) 5.89 (s, 1 H) 4.98 (dt, J=13.33, 6.60 Hz, 1 H) 4.30-4.41 (m, 4 H) 3.01 (t, J=11.62 Hz, 2 H) 2.85 (br. s., 1 H) 2.20 (s, 3 H) 2.12 (s, 3 H) 1.80 (d, J=10.36 Hz, 2 H) 1.44 (s, 3 H) 1.43 (s, 3 H) 1.18-1.30 (m, 3 H) 0.79-0.91 (m, 1 H)
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C)C=O>O>[Br:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
Mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (2.04 g) prepared in example 6, 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (2.69 g) and N,N-dimethylformamide (10 ml) was stirred at 50° C. for 20 hours. The reaction mixture was turned back to a room temperature, water (45 ml) was added, then extracted twice with ethyl acetate (15 ml). The organic layers were combined together, washed with water 3 times, dried over anhydrous sodium sulfate. Afer being filtrated under a reduced pressure, the residue thus obtained was purified by use of a silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (3.77 g, yield: 84%)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CC(C)=O.O>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of 2-fluoro-4-hydroxy-benzonitrile (80 g, 0.58 mol), potassium carbonate (162 g, 1.17 mol) and benzyl bromide (76.4 mL, 0.64 mol) and potassium iodide (9.6 g, 0.058 mol) in acetone (600 mL) was stirred at RT and a significant exothermic reaction was observed. Stirring continued for 18 h without cooling. Reaction progress was monitored by TLC analysis. The reaction mixture was diluted with H2O (600 mL) and extracted with EtOAc (500 mL×2). The combined organic extracts were washed with saturated aqueous NaCl solution (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was triturated in cyclohexane (300 mL) and the crystalline solid was filtered off and washed to afford 4-Benzyloxy-2-fluoro-benzonitrile (118.2 g, 90%). 1H NMR (400 MHz, CDCl3): 7.51 (1H, dd, J=8.70, 7.48 Hz), 7.40 (5H, m), 6.86-6.76 (2H, m), 5.11 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 40 °C
Yield: 83.1 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.52 mmol) prepared in Example 6 and P2S5 (227 mg, 1.02 mmol) in THF (3 mL) was heated at 40° C. for 2 h, and then diluted with toluene (20 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM solution was collected and purified by flash column chromatography to give the title compound as white solid (260 mg).
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[OH-].[NH4+:16]>O>[NH2:6][C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH2:16])=[O:3]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 59 %

Procedure:
A mixture of L-phenylalanine methyl ester hydrochloride (6.50 g, 30.1 mmol) and ammonium hydroxide solution (28% in water, 15 mL) in water (60 mL) was stirred at ambient temperature for 64 h. The aqueous layer was extracted with dichloromethane (6×100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-amino-3-phenylpropanamide as a colorless solid in 59% yield (2.92 g): 1H NMR (300 MHz, DMSO-d6) 6 7.38-7.21 (m, 5H), 7.12 (br s, 1H), 5.44 (br s, 1H), 3.63 (dd, J=9.5, 3.9 Hz, 1H), 3.28 (dd, J=13.7, 3.9 Hz, 1H), 2.72 (dd, J=13.7, 9.5 Hz, 1H), 1.41 (br s, 2H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (100 mg, 92%), MS (ISP) m/z=435.3 [(M+H)+], mp 207.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(=NC(C)C)[O-])(C)C.C(NC(=NC(C)C)O[C:36]([CH3:39])([CH3:38])[CH3:37])(C)C>C(Cl)Cl>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:18])[CH2:15][CH2:16]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Agent: CC(C)N=C([O-])NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid in DCM (0.2 M), 3 eq of tert-butyl. N,N′-diisopropylimidocarbamate were added and the mixture was stirred at RT. After 30 min, a further 1.5 eq of tert-butyl N,N′-diisopropylimidocarbamate were added and the solution stirred for an additional hour. The solution was filtered through a pad of celite and then through a pad of silica gel to give the product (83%); MS (ES+) m/z 320 (M+H)+