Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9](=[NH:13])[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.[O:16]([C:23]([N:25]=[C:26]=[S:27])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9](=[NH:13])[C:10]([C:11]#[N:12])=[C:26]([SH:27])[NH:25][C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(CSC(=N)CC#N)cc1
Reactant: O=C(N=C=S)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(CSC(=N)C(C#N)=C(S)NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of of 2-cyano-thioacetimidic acid 4-methoxy-benzyl ester (42 g, 0.19 mol) in 191 mL of ethyl acetate at 0° C. was added phenoxycarbonylisothiocyanate (34 g, 0.19 mol), and the mixture was stirred at 0° C. for 24 hours. The mixture was diluted with ether and filtered. The solids were washed with ether, collected and dried in vacuo, affording 56 g (73%) of 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid 4-methoxy-benzyl ester as a yellow solid. 1H NMR (400 MHz, CDCl3) δ12.81(s, 1H), 9.01 (s, 1H), 8.68 (s, 1H) 7.28-6.99 (m, 7H), 6.69 (d, 2H, J=8.8 Hz), 4.17 (s, 2H), 3.64 (s, 3H) ppm; MS (APCI, m/z): 400 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([CH:10]=[CH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([O-])=O>C1COCC1>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:12]([CH2:11][CH2:10][NH2:7])=[CH:13][NH:14]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])C=Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Add to a mixture of LAH (6.2 g, 163.1 mmol) and 300 mL dry THF a solution of 3-(2-nitrovinyl)-6-benzyloxy-1H-indole (9 g, 30.6 mmol) in 200 mL THF. Reflux the mixture overnight and then cool to 0° C. and quench sequentially with 6.2 mL water, 6.2 mL 15% aqueous NaOH and 18.6 mL water. After stirring 2 hours, filter through celite and concentrate to give 7.9 g (96%) of the title compound as an oil: 1H NMR (CDCl3) 8.06 (bs, 1H), 7.47–7.43 (m, 3H), 7.38–7.35 (m, 2H), 7.32–7.28 (m, 1H), 6.88–6.84 (m, 3H), 5.08 (s, 2H), 3.01–2.97 (m, 2H), 2.87–2.83 (m, 2H), 1.6 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:22]=[C:21]([NH2:31])[N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.Br[CH:33]([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH:33]([CH3:35])[CH3:34])[CH2:26]3)[N:22]=[C:21]([NH2:31])[N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12
Reactant: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCNC2)n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCCC(c2cc(Nc3ccc(Oc4ccnc5[nH]ccc45)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
50 mg (0.119 mmol) of N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-6-piperidin-3-ylpyrimidine-2,4-diamine (from example 134) are dissolved in DMF. 0.013 ml (0.143 mmol) of 2-bromopropane and 49 mg (0.358 mmol) of potassium carbonate are added, and the mixture is stirred at room temperature for 18 hours. The suspension is filtered off with suction and the filtrate is purified by preparative HPLC.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)[OH:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
Benzo[1,3]dioxole-5-carbaldehyde (1.80 g, 11.96 mmol), 5-bromobenzo[1,3]dioxole (2.65 g, 13.16 mmol), and n-butyl lithium (5.26 ml, 13.16 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give bis-benzo[1,3]dioxol-5-yl-methanol as a light brown oil (2.69 g, 83%): 1HNMR (CDCl3) 6.86-6.74 (m, 6H, Ar), 5.93 (s, 4H, 2CH2), 5.68 (d, J=3 Hz, 1H, CHOH), 2.16 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:7]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>CC(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Brc1cncc(OCC2CO2)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: OC(COc1cncc(Br)c1)Cn1cnc2ccccc21
Yield: 49.8 %

Procedure:
A solution of Example 436A (500 mg, 2.17 mmol) and 1H-Benzoimidazole (28 mg, 2.39 mmol) in 2-propanol (10 mL) was refluxed under N2 for 2 hrs. The reaction mixture was cooled, diluted with ethyl acetate(50 mL) and washed with brine (2×25 mL). The residue was concentrated and purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to 5% methanol/ethyl acetate to provide the desire product (1.08 mmol, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH:27]C(=O)OC(C)(C)C)(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:25])=[O:26])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a 20-L flask containing tert-butyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (1200 g, 2.126 mol) was added ethanol (12 L) at 20° C. The resulting mixture was stirred at room temperature and charged with hydrogen chloride gas (472 g, 12.9 mol, 6.07 equiv.). The batch was heated to 50° C. and the temperature was maintained for 3 h until reaction completion. Solvent was removed by vacuum distillation at 33-39° C. and 6 Kg of distillate was collected. Ethyl acetate (6.8 L, 6.1 Kg) was added to the batch and distilled to collect 5.1 Kg of distillate. Ethyl acetate (7.2 L, 6.48 Kg) was added to the batch and distilled to collect 5.1 Kg of distillate. Ethyl acetate (2.4 L, 2.14 Kg) was added to the batch to adjust the solvents ratio. 1H NMR indicated the mole ratio of ethyl acetate to ethanol was 1.0:0.1. The solution was heated to 65° C. n-Heptane (4.1 kg) was added to the solution at 60-65° C. over 43 min. The resulting slurry was stirred at 65° C. for 1 h. The slurry was cooled to 20° C. over 2.5 h and stirred at that temperature for 15 h. The product was collected by filtration and washed with n-heptane (2.42 L). The product was dried under reduced pressure at 45° C. for 65 h to afford the desired product (906 g, 91.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=6.2) 7.72 (m, 1 H), 7.59 (t, J=8.7 Hz, 1 H), 6.67 (t, J=5.9 Hz, 1H), 6.55 (s, 2H) 6.52 (t, J=6.0 Hz, 1 H), 3.38 (dd, J=12.7, 6.3 Hz, 2 H), 3.11 (dd, J=12.3, 6.3 Hz, 2H); C12H11BrFN7O5S (MW 464.23), LCMS (EI) m/e 485.8/487.8 (M+-C5H8O2+Na).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[OH-].[NH4+].[Cu]I>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C:2](=[O:1])[CH:7]=1
Reactant: Cc1ccnc(O)c1
Reactant: Brc1ccsc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccsc2)c(=O)c1
Temperature: 150 °C
Yield: 29.5 %

Procedure:
A mixture of 2-hydroxy-4-methylpyridine (1.5 g, 14 mmol), 3-bromothiophene (4.5 g, 28 mmol), copper (I) iodide (0.27 g, 1.4 mmol), and potassium carbonate (1.9 g, 14 mmol) in N,N-dimethylformamide (30 mL) is heated in a 150° C. oil bath for 6 hours. After cooling to room temperature, the reaction mixture is diluted with 20% aqueous ammonium hydroxide solution and extracted 3× with diethyl ether. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude oil, which is purified by flash chromatography (ethyl acetate/hexanes) to give 4-methyl-1-(3-thienyl)pyridin-2(1H)-one (0.79 g, 29%).
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[CH2:9]([O:11][C:12](=[O:40])[CH2:13][N:14]1[C:22]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([CH3:39])=[CH2:38])[CH:28]=3)(=[O:26])=[O:25])[C:17]=2[CH:16]=[N:15]1)[CH3:10].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:40])[CH2:13][N:14]1[C:22]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[C:29]([C:37]4([CH3:4])[CH2:39][CH2:38]4)[CH:28]=3)(=[O:26])=[O:25])[C:17]=2[CH:16]=[N:15]1)[CH3:10]
Reactant: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(F)(F)F)cc(C2(C)CC2)c1
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
To a solution of diiodomethane (1.0 mL, 16 mmol) in toluene (10 mL) was added diethylzinc (15% in hexane, 10 mL, 8.8 mmol) under an argon atmosphere at 0° C. and the mixture was stirred for 15 minutes. To the mixture was added [(R)-4-(3-isopropenyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (0.2 g, 0.46 mmol) in toluene (4 ml) and the mixture was stirred at 0° C. and then room temperature for 4 hours. The mixture was poured into aqueous ammonium chloride (20 mL) and extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (20 mL×3), then brine (30 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC to afford {(R)-4-[3-(1-methyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (40 mg, 18%) as a white solid. MS calcd. for C22H26F3N3O4S 485, obsd. (ESI+) [(M+H)+] 486.
Reaction SMILES: CC(C)=C[CH2:4][CH2:5]/[C:6](/[CH3:27])=[CH:7]/[CH2:8]C/C(/C)=C/CCC1(C)OC2C=CC(O)=CC=2CC1.[CH3:29][C:30]1[CH:36]=[C:35]([OH:37])[C:34]([CH3:38])=[CH:33][C:31]=1[OH:32].OC(C)(C=C)C=C>>[CH:5]([C:6]1([CH3:27])[CH2:7][CH2:8][C:33]2[C:31](=[C:30]([CH3:29])[CH:36]=[C:35]([OH:37])[C:34]=2[CH3:38])[O:32]1)=[CH2:4]
Reactant: Cc1cc(O)c(C)cc1O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC1(C)CCc2cc(O)ccc2O1
Agent: C=CC(C)(O)C=C
Product: C=CC1(C)CCc2c(C)c(O)cc(C)c2O1

Procedure:
In the second method for forming the single enantiomer chroman diol, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman for use as starting material in the present tocotrienol syntheses, a suitably monoprotected 2,5-dimethylhydroquinone is reacted with the compound 3-hydroxy-3-methyl-1,4-pentadiene to produce 2-vinyl-2,5,8-trimethylchroman-6-ol:
Reaction SMILES: [CH:1]([CH:3]([CH:13]=O)[C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=1)=O.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:1]=[C:3]([C:4]3[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=3)[CH:13]=[N:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=CC(C=O)c1cccc(C(=O)O)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(-c3cccc(C(=O)O)n3)cn2)cc1
Yield: 60.7 %

Procedure:
A solution of 6-(diformylmethyl)-pyridin-2-carboxylic acid (315 mg, 1.63 mmol), 4-methoxyphenylhydrazine hydrochloride (285 mg, 1.63 mmol) and sodium acetate (134 mg, 1.63 mmol) in acetic acid (5 mL) is heated to 110° C. for 18 h. After being allowed to cool, the solution is filtered. The solid product is washed with ethyl acetate and diethyl ether, and dried under vacuum to afford the title product (294 mg, 0.99 mmol, 61%) as a beige powder. m.p. 122-123° C. 1H NMR (300 MHz, DMSO-d6): δ 9.11 (1H, s), 8.38 (1H, s), 7.99 (2H, d, J=4.7 Hz), 7.86 (1H, t, J=4.4 Hz), 7.80 (2H, d, J=9.1 Hz), 7.08 (2H, d, J=9.1 Hz), 3.80 (3H, s), 1H missing. MS (ES+): m/e 297 (18), 296 (100). MS (ES−): m/e 295 (14), 294 (100).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([CH2:18][O:19][CH3:20])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:21]>CCOC(C)=O>[ClH:21].[CH3:1][O:2][CH2:3][CH2:4][C:5]1([CH2:18][O:19][CH3:20])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: COCCC1(COC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCC1(COC)CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(2-methoxyethyl)-4-(methoxymethyl)piperidine-1-carboxylate (400 mg) in EtOAc (7 ml) was added 1 N HCl (7 ml) under ice bath cooling, and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo to give 4-(2-methoxyethyl)-4-(methoxymethyl)piperidine hydrochloride (260 mg) as a white powder. The obtained crude product was used in next reaction without further purification.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([C:15]1[CH:22]=[C:21]([O:23]C2CCCCO2)[CH:20]=[C:19]([B:30]2[O:34][C:33](C)(C)C(C)(C)[O:31]2)[C:16]=1C=O)[CH3:14].Cl>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:33]1[O:34][B:30]([OH:31])[C:19]2[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]([CH2:13][CH3:14])[C:16]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: CCc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CC)c21
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
To a suspension of zinc dust (5.35 g, 82.3 mmol) in THF (10 mL) was added trimethylsilyl chloride (1.1 g, 10.15 mmol) at 40° C. The mixture was heated to 55° C. and stirred for 45 minutes. After cooling down to 37° C., ethyl bromoacetate (7.58 mL, 74.87 mmol) was slowly added to the reaction mixture at 37-40° C. After addition, the resulting mixture was allowed to cool to room temperature over 30 minutes. This solution was added to a solution of 2-ethyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (2.07 g, 5.39 mmol) in THF (6 mL) at 0° C. The mixture was stirred for 10 minutes before treating with 3 N HCl and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and lyophilized to give (4-ethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester(0.380 g, 27%). 1H NMR (400 MHz, DMSO-d6δ 9.30 (s, 1H), 9.02 (s, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 5.40 (m, 1H), 4.00 (m, 2H), 3.00 (m, 1H), 2.50 (m, 2H), 2.20 (m, 1H), 1.20 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Temperature: 150 °C
Yield: 88.9 %

Procedure:
tert-Butyl [2-(4-bromophenyl)ethyl]carbamate (0.52 g, 1.73 mmol) was dissolved in dry DMF (17 mL) under nitrogen atmosphere. Zinc cyanide (0.41 g, 3.46 mmol) and tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) was added. The reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The procedure was repeated two more times with equal amount of starting material and the resulting three mixtures were combined. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (40+M column, isocratic run DCM/MeOH (99.5:0.5, 960 mL), gradient run DCM/MeOH (99.5:0.5-92:8, 240 mL), isocratic run DCM/MeOH (92:8, 720 mL)) affording the title compound (1.14 g, 88.9%). 1H NMR (500 MHz, CDCl3): δ 1.44 (s, 9H), 2.88 (t, 2H), 3.40 (q, 2H), 4.58 (bs, 1H), 7.32 (d, 2H), 7.61 (d, 2H); Mass Spectrum: M+H+ 247.
Reaction SMILES: C(N1CCC[C@@H](CN(C2C=CC=CC=2)C(=O)CC)C1)(OC(C)(C)C)=O.[CH2:26]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[CH2:43][CH3:44])[CH2:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:26]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([CH2:40][N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[CH2:43][CH3:44])[CH2:35]1)[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(=O)N(CC1CCCN(CCc2ccccc2)C1)c1ccccc1
Agent: CCC(=O)N(C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Product: CCC(=O)N(C[C@H]1CCCN(CCc2ccccc2)C1)c1ccccc1

Procedure:
Following the procedures described in Example 5, (S)-N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 31 was converted to (S) N-(1-Phenethyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 32 (LRMS 350).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:25])[CH2:8][CH:9]([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH3:24])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:24][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([CH3:23])=[CH:22][C:13]=1[CH:9]1[CH2:10][C:11](=[O:12])[C:6]([C:1](=[N:30][O:29][CH2:27][CH3:28])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:25])[CH2:8]1
Reactant: CCCC(=O)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O

Procedure:
A mixture of 2-butyryl-5-(1,4-dimethylnaphth-2-yl)-3-hydroxycyclohex-2-en-1-one (0.25 g), ethoxyamine hydrochloride (1.3 equiv) and sodium acetate trihydrate (1.3 equiv) were stirred in ethanol (30 ml) at room temperature for 4 hr. The mixture was then immediately extracted with ether. The dried (MgSO4) organic extract was evaporated to give 5(1,4-dimethylnaphth-2-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1>C(O)(=O)C.[C].[Pd]>[CH3:14][N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CN1CCN(Cc2ccccc2)C(c2ccccc2)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCNC(c2ccccc2)C1=O
Yield: 9.9 %

Procedure:
4-Benzyl-1-methyl-2-oxo-3-phenylpiperazine (15 g, 0.535 moles) was dissolved in acetic acid (120 ml) and added 5% palladium-carbon (50% wet, 1.5 g). Reaction mass was hydrogenated at 100 psi. After completion of the reaction, reaction mixture was filtered and acetic acid was distilled under reduced pressure. Residue was dissolved in DM water (75 ml). pH was adjusted to 11.0–12.0 with 50% aqueous sodium hydroxide solution. The product was extracted with methylene chloride (2×75 ml) and washed with DM water (75 ml). The methylene chloride layer was concentrated under reduced pressure to obtain 10.1 g of 1-methyl-2-oxo-3-phenylpiperazine.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:40])([CH3:39])[C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:26][CH2:27][NH:28][C:29](=[O:38])[C:30]([CH3:37])([NH:32][C:33](=[O:36])[CH2:34]Cl)[CH3:31])[CH2:13][CH2:14][NH:15][C:16](=[O:25])[C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)([CH3:19])[CH3:18])=[O:8])=[O:4].[K+].[CH2:42]([O:44][C:45]([S-:47])=[S:46])[CH3:43]>C(#N)C>[CH2:42]([O:44][C:45](=[S:47])[S:46][CH2:2][C:3](=[O:4])[NH:5][C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][N:12]([CH2:26][CH2:27][NH:28][C:29](=[O:38])[C:30]([NH:32][C:33](=[O:36])[CH2:34][S:47][C:45]([O:44][CH2:42][CH3:43])=[S:46])([CH3:37])[CH3:31])[CH2:13][CH2:14][NH:15][C:16](=[O:25])[C:17]([CH3:19])([NH:20][C:21](=[O:24])[CH2:22][S:46][C:45]([O:44][CH2:42][CH3:43])=[S:47])[CH3:18])([CH3:40])[CH3:39])[CH3:43]
Reactant: CC(C)(NC(=O)CCl)C(=O)NCCN(CCNC(=O)C(C)(C)NC(=O)CCl)CCNC(=O)C(C)(C)NC(=O)CCl
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=S)SCC(=O)NC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)NC(=O)CSC(=S)OCC)CCNC(=O)C(C)(C)NC(=O)CSC(=S)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a mixture of N-[2-(bis-{2-[2-(2-chloro-acetylamino)-2-methyl-propionylamino]-ethyl}-amino)-ethyl]-2-(2-chloro-acetylamino)-2-methyl-propionamide (1.00 g; 1.54 mmol) and 20 mL acetonitrile was added O-ethyl xanthic acid potassium salt (0.761 g; 4.75 mmol). After stirring the mixture at room temperature for 5 hr, additional O-ethyl xanthic acid potassium salt (0.370 g; 2.31 mmol) was added. After stirring for an additional 5 hours at room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure to to afford 1.20 g (87%) of the tris(ring-opened AzTC)amine as a red solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Reactant: CON(C)C(=O)c1ccc(C)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Under an argon atmosphere, a solution of 10.40 g of N-methoxy-N-methyl-p-toluamide in 100 ml of tetrahydrofuran was ice-cooled and 4-methylbenzylmagnesium chloride (solution prepared by dissolving 10.60 g of α-chloro-p-xylene and 1.94 g of magnesium in 85 ml of tetrahydrofuran) was added dropwise. After stirring for one hour, 100 ml of 10% hydrochloric acid was slowly added. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the crude crystal was washed with diisopropyl ether and then dried under reduced pressure to obtain 8.43 g of the desired compound as a colorless crystal having a melting point of 93 to 100° C.