Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:18]2([OH:21])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CN1CCC(O)(c2ncc(Br)cn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under nitrogen. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes before dropwise addition of 1-methylpiperidin-4-one (0.9 mL, 0.01 mol). The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was allowed to warm to room temperature, then diluted with 5% aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulphate, then the solvent removed under reduced pressure. The resulting crude material (1.55 g) was sonicated in ethyl acetate (10 mL) and DCM (1 mL), then heptane was added. The solid that formed was filtered to afford the title compound (580 mg, 29.4%) as a brown solid. LCMS Method F: MH+: m/z 272/274, RT 1.20 minutes.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[C:24]1([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][O:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCCOC=C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCCN(CCCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
(R)-1-[3-[[2,2-Diphenylethenyl]oxy]propyl]-3-piperidine carboxylic acid ethyl ester (0.60 g, 0.0015 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.4 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 0.52 ml) was added with cooling followed by dichloromethane (250 ml). The mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with acetone, collected by filtration and dried in vacuo to give the title compound (0.30 g, 50%), m.p. 176°-180°.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH:14]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][C:10]=1[O:25][CH3:26])C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][C:10]=1[O:25][CH3:26]
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)c(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2cc(OC)c(O)cc2O1
Reaction time: 96 h
Yield: 94 %

Procedure:
A solution of 7.5 mmol of ethyl 7-(benzyloxy)-6-methoxy-4-oxo-4H-chromen-2-carboxylate in 60 ml of ethyl acetate and 30 ml of glacial acetic acid is hydrogenated in the presence of 1.2 g of 10% palladium on carbon at 3 bar and 50° C. After 4 days, the hydrogenation is terminated and the mixture is diluted with ethyl acetate. The mixture is filtered through kieselguhr and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the organic phase is washed with water and saturated sodium chloride solution. The mixture is dried over sodium sullfate and concentrated, giving ethyl 7-hydroxy-6-methoxy-2-chromancarboxylate in a yield of 94% as a colorless oil which is directly reacted further.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)=O.[NH2:10][C:11]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:12]=1[S-:13].[Na+].[OH-].[Na+].[Sn](Cl)Cl>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:11]=2[N:10]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1[S-]
Reactant: O=C(O)c1ccccn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1ccc2sc(-c3ccccn3)nc2c1
Temperature: 125 °C

Procedure:
PPA (500 g) is added to picolinic acid (24.6 g, 0.2 mol) and sodium 2-amino-4-nitrothiophenoxide (47 g, 0.2 mol). The mixture is heated at 120-130° C. for 6 hours. The resulting mixture is cooled and NaOH is added dropwise (pH=10). The product is filtered off and washed with water. The 2-(2-pyridyl)-5-nitrobenzothiazole is recrystallized from 9/1 isopropyl ether/methanol and is added to a solution of tin dichloride (61.6 g, 0.273 mol) in conc. HCl (50 ml) at 0° C. This mixture is heated at 95° C. for 120 minutes. It is cooled and NaOH is added dropwise (pH=10). The resulting mixture is extracted with chloroform and the combined organic phases are extracted with 0.5M HCl. The acidic aqueous phases are combined, basified with NaOH (pH=10) and extracted with ethyl acetate. The extracts are washed with water and evaporated. The solid obtained is recrystallized from isopropyl ether. Yield: 3.6 g; Rf (9/1 chloroform/methanol): 0.45; IR (KBr): 3400, 3325, 3215, 1590, 1430, 1320, 780 cm−1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[OH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.CC(C)([O-])C.[K+]>>[CH3:30][C:10]1[CH:11]=[CH:12][C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[O:17])=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:7]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(OC2CCN(C)CC2)n1
Temperature: 140 °C
Yield: 71.4 %

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.13 g), 4-hydroxy-N-methylpiperidine (0.087 g) and potassium tert-butoxide (1M in tert-butanol, 1.5 ml) was stirred and heated to 140° C. for 1 hour. The mixture was partitioned between water and methylene chloride and the organic phase was washed with brine, dried over sodium sulphate and evaporated. There was thus obtained the title compound as a solid (0.11 g); NMR Spectrum: (DMSOd6) 1.45 (m, 2H), 1.88 (m, 2H), 1.97 (m, 2H), 2.05 (s, 3H), 2.15 (s, 3H), 2.23 (m, 2H), 3.5 (m, 4H), 5.7 (m, 4H), 4.77 (m, 1H), 6.28 (d, 1H), 6.89 (m, 1H), 7.1 (m, 1H), 7.21 (m, 1H), 7.24 (s, 1H), 7.47 (m, 1H), 7.9 (m, 1H), 7.98 (d, 1H), 8.25 (m, 1H), 8.9 (s, 1H), 10.24 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)c1c(C)c2ccccc2n1-c1ccccc1

Procedure:
Prepared in analogy to that of Example 1(a) from 3-methyl-1H-indole-2-carboxylic acid ethyl ester, iodobenzene, CuI, N,N′-dimethylethylenediamine, and potassium phosphate. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.7-7.0 (m, 9H), 4.15 (q, 2H, J=7.1 Hz), 2.67 (s, 3H), 1.10 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26]C2CCCCO2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:33]C2CCCCO2)[CH2:15][C:14]1=[O:40])=[O:4].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.O.O1CCCC1>>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([OH:33])[CH2:15][C:14]1=[O:40])=[O:4]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC)OC1CCCCO1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC

Procedure:
At 40°, 300 mg. of (5Z,13E)-(8R,11R,12R,15S)-1-(N-methylcarbamoyloxy)-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-9-one was agitated with 9 ml. of a mixture of glacial acetic/water/tetrahydrofuran (65/35/10) for 6 hours. The mixture was then evaporated to dryness under vacuum. After purifying the residue by chromatography on silica gel (ether/ethyl acetate 7+3), 145 mg. of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.Cl.[CH2:28]([OH:30])[CH3:29]>>[CH2:28]([O:30][C:19](=[NH:20])[C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[CH:22][CH:21]=1)[CH3:29]
Reactant: CCO
Reactant: N#Cc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.4 %

Procedure:
A mixture of 4-(1-benzyl-piperidin-4-ylidenemethyl)-benzonitrile (14 g, 48.6 mmol), chloroform (10 mL) and 6 M hydrogen chloride in ethanol (300 mL) was stirred at room temperature for 48 hours. The solution was concentrated in vacuo, the remaining solid was repeatedly dissolved in ethanol (400 mL) and concentrated in vacuo to yield 16.4 g (92.4%) of the title compound, which was used in the next steps without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18]1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1CCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOC(=O)N1CCC(C=O)C1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of dimethyl sulfoxide (13.03 ml) in dichloromethane (25 ml) was dropwise added to a solution of oxalyl chloride (9.1 ml) in dichloromethane (100 ml) below -65° C. with stirring. The mixture was stirred at the same temperature for 30 minutes. A solution of 1-allyloxycarbonyl-3-hydroxymethylpyrrolidine (17.0 g) in dichloromethane was added to the mixture at the same temperature. The mixture was stirred below -65° C. for 30 minutes, followed by dropwise addition of triethylamine (38.5 ml) below -65° C. The cooling bath was then removed and the reaction mixture was allowed to warm up to ambient temperature, washed with water (250 ml×2), 1N hydrochloric acid (150 ml), saturated sodium hydrogen carbonate (150 ml) and brine (150 ml) in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of methanol and dichloromethane (1:99 V/V) to give 1-allyloxycarbonyl-3-formylpyrrolidine (13.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]>CO.C(Cl)(Cl)Cl.[Pt](=O)=O>[Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(/C=C/c4ccccc4)cc3Cl)c2n1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(CCc4ccccc4)cc3Cl)c2n1
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Methyl 3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.37 g) was dissolved in methanol/chloroform=1/4 (24 ml), and platinum(IV) oxide (169 mg) was added. The mixture was stirred under a hydrogen atmosphere at normal pressure for 4 hours. Platinum(IV) oxide (169 mg) was added, and the mixture was further stirred under a hydrogen atmosphere at normal pressure for 6 hr. The reaction mixture was filtered through Celite and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate/chloroform=1/3). The fraction containing the objective compound was concentrated under reduced pressure to give the objective compound (1.92 g) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:33]=[CH:32][C:18]([O:19][CH2:20][C:21]3[NH:22][C:23]4[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:36](Br)[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:33]=[CH:32][C:18]([O:19][CH2:20][C:21]3[N:25]([CH2:36][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:38])[C:24]4[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=4[N:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4ccc(C#N)cc4[nH]3)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4cc(C#N)ccc4n3CC(=O)c3ccccc3)cc2)CC1
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)-phenoxymethyl]-5-cyanobenzimidazole (915 mg) in dimethylformamide (15 ml) was added 60% sodium hydride (90 mg) with ice-cooling, and the mixture was stirred at the same temperature for 20 min. Phenacyl bromide (426 mg) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by HPLC (hexane:ethyl acetate=2:3) to give the title compound (385 mg).
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(O[Na])(C)(C)C.OP([O-])(O)=O.[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:1]([N:8]1[C:16]2[C:11](=[C:12]([N:21]3[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(Cl)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C

Procedure:
The compound was prepared according to Method 2 from N-tert-butyldimethylsilyl-4-chloroindole (100 g, 376 mmol, 1 equiv.), tert-butyl 1-piperazinecarboxylate (84 g, 451 mmol), Palladium(II)acetate (1.26 g., 5.62 mmol, 2%), 2-(dicyclohexylphosphino) biphenyl (3.95 g., 11.28 mmol, 4 mol %) tert-BuONa (50 g, 520 mmol, 1.4 equiv.) in toluene. The solution was cooled to room temperature and KH2PO4 (150 mL, 13% aqueous solution) was added and pH was adjusted (pH=8-9) followed by extraction with toluene (2×100 mL), dried (MgSO4) and evaporated. The residue was crystallized from heptane to yield 124.4 g (79.6%). 1H NMR (CDCl3)δ 7.20 (d, J=8.4 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.06 (t, 1H), 6.60-6.57 (m, 2H), 3.65 (t, 4H), 3.16 (t, 4H), 1.48 (s, 9H), 0.91 (s, 9H), 0.58 (s, 6H); 13C NMR (CDCl3) δ 155.0; 145.5; 142.2; 129.9; 124.9; 122.0; 109.3; 107.2; 102.9; 79.8; 77.3; 51.5; 28.5; 26.4; 19.5; −3.8; MS (ESI) 416.4 (M+H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:8]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:9]([CH3:14])[CH2:10][N:11]=[N+]=[N-])(=O)=O.CCN(C(C)C)C(C)C>CO.[Pd]>[Si:16]([O:15][C@@H:8]1[C@@H:9]([CH3:14])[CH2:10][NH:11][CH2:6][C@H:7]1[NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of (2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentyl methanesulfonate (0.59 g, 1.3 mmol) in MeOH (10 mL) was deoxygenated with nitrogen for 20 min. DIPEA (0.55 mL, 3.2 mmol) was added, followed by 10 wt % Pd on carbon (0.1 g, 0.1 mmol). The mixture was hydrogenated under hydrogen gas at 1 atm. for 2 h. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give the sub-title compound (0.43 g, 98%). LCMS calc. for C17H37N2O3Si (M+H)+: m/z=345.3. found: 345.2. 1H NMR (500 MHz, CDCl3) δ 4.35 (bs, 1H), 3.32 (dt, J=13.1, 6.3 Hz, 1H), 3.25 (d, J=12.3 Hz, 1H), 3.04 (t, J=8.8 Hz, 1H), 2.94 (ddd, J=13.1, 4.1, 1.5 Hz, 1H), 2.33 (dd, J=12.6, 10.5 Hz, 1H), 2.24 (dd, J=13.1, 10.9 Hz, 1H), 1.76 (bs, 1H), 1.55 (tdd, J=8.9, 6.7, 4.2 Hz, 1H), 1.41 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=10.3 Hz, 6H) ppm.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[C:30](#[N:34])[CH2:31][C:32]#[N:33]>>[C:32]([C:31]([C:30]#[N:34])=[CH:1][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:33]
Reactant: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=O)cc4ccccc34)O1)N2C
Reactant: N#CCC#N
Product: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=C(C#N)C#N)cc4ccccc34)O1)N2C

Procedure:
This compound is prepared according to the method employed for Example 10, from 0.39 g (1 mmol) of the compound of Example 2 and from 0.13 g (2 mmol) of malononitrile.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:52]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C1COCC1.O.CCOC(C)=O>[CH2:19]([O:18][C:16]([NH:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:14][CH2:13][C:12]([N:62]1[CH2:61][CH2:60][N:59]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:64][CH2:63]1)=[O:15])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (39 g, 0.107 mol) in THF (214 mL) was added LiOH (2 N, 107.4 mL). The reaction mixture was stirred at RT overnight, concentrated to dryness, and dissolved in DMF (100 mL). To the resulting solution were added HBTU (48.9 g, 0.13 mmol) and Boc-piperazine (24 g, 0.13 mol). The reaction mixture was stirred at RT for 1 h and diluted with water (200 mL) and EtOAc (500 mL). The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-tert-butyl 4-(4-(benzyloxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentanoyl)piperazine-1-carboxylate (33.3 g, 56.5%). LRMS (M+H) m/z 550.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)([O-])=O.[CH3:20][C:21]([Mg]Br)=[CH:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH3:20][C:21]1[NH:1][C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:22]=1[CH3:23]
Reactant: O=[N+]([O-])c1cnccc1N1CCc2ccccc2C1
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)ccnc2c1C
Temperature: -20 °C
Reaction time: 5 h
Yield: 38.7 %

Procedure:
2-(3-Nitropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (5 g, 19.58 mmol) prepared in Preparation 1 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 80 ml, 117.5 mmol) was added at −78° C. to the solution, which was then stirred for 5 hours at −20° C. 20 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol=10/10/1, (v/v/v)) to give the titled compound as a pale yellow solid (2.1 g, 25.3%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Br-].[CH:17]1([CH2:23][Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:17]1([CH2:23][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: [Zn+]CC1CCCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 4-chloro-3-(trifluoromethyl)benzoate (238 mg, 1.0 mmol) and bis(tri-t-butylphosphine)palladium (0) (51 mg, 0.10 mmol) in THF (2 mL) was added (cyclohexylmethyl)zinc(II) bromide (6 mL, 3.00 mmol) at room temperature. The reaction mixture was heated at reflux for 2 h, quenched with saturated NaHCO3 solution, and filtered through Celite®. The filtrate was extracted with ethyl acetate. The combined organics were dried and concentrated, and the residue was purified by silica gel column chromatography to give the title compound (280 mg) as a colorless oil. LCMS m/z=301.4. 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.62-1.72 (m, 6H), 2.71 (d, J=6.7 Hz, 2H), 3.94 (s, 3H), 7.39 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.0, 1.5 Hz, 1H), 8.30 (d, J=1.4 Hz, 1H).