Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=1)(=O)=O>CN(C)C=O>[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][N:24]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=3)[CH2:23][CH2:22]2)[N:12]=1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Temperature: 100 °C
Yield: 64 %

Procedure:
N,N-Diisopropylethylamine (0.8 mL; 5 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (0.2 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.22; 1 eq) in dimethylformamide (1.5 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography, eluting with a gradient from dichloromethane to dichloromethane/MeOH (98/2) affording the title compound in 64% yield (0.21 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:35])[CH:31]1[CH2:34][NH:33][CH2:32]1>>[CH3:29][N:30]([CH3:35])[CH:31]1[CH2:34][N:33]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:32]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: CN(C)C1CNC1
Product: CN(C)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 236 using 2-chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1) and N,N-dimethylazetidin-3-amine. The crude product was purified by preparative HPLC (Condition 14). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed. The aq. phase was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title product as white crystals. HPLC (Condition 10) tR=6.01 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.99 (s, 6H) 2.95-3.04 (m, 1H) 3.53 (dd, J=9.19, 5.28 Hz, 2H) 3.69-3.77 (m, 2H) 7.36 (d, J=8.99 Hz, 2H) 7.87 (d, J=8.99 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.54-8.57 (m, 1H) 8.63 (d, J=2.74 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.23 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-])=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.CO.[BH4-].[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O.[Ni](Cl)Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH2:12])=[C:8]([O:10][CH3:11])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(C2CC2)ncc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc(C2CC2)ncc1N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a mixture of 2-cyclopropyl-4-methoxy-5-nitropyridine (805 mg, 4.15 mmol), nickel(II) chloride, 6H2O (2956 mg, 12.44 mmol), and methanol (25 mL), cooled to 0° C., was added sodium borohydride (941 mg, 24.87 mmol) portion wise over 1 minute. After 5 minutes, the reaction was diluted with DCM (50 mL), saturated sodium bicarbonate (50 mL), and water (50 mL), and filtered through Celite©. The layers of the filtrate were separated and the aqueous layer was further extracted with DCM (50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), eluted through a phase separator, and concentrated to afford 6-cyclopropyl-4-methoxypyridin-3-amine (448 mg, 63%) as a yellow oil. MS (m/z) 165.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([I:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14]CC)=[O:13])[O:7][CH2:6][CH2:5]2.O[Li].O>CO.C1COCC1.O>[F:1][C:2]1[C:3]([I:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[O:7][CH2:6][CH2:5]2
Reactant: CCOC(=O)C1OCCc2c1ccc(F)c2I
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1OCCc2c1ccc(F)c2I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-fluoro-5-iodo-3,4-dihydro-1H-isochromene-1-carboxylate (1.6 g, 4.5 mmol) in 25 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (700 mg, 18.3 mmol), and the mixture was stirred at ambient temperature for 30 min. The solvents were removed under vacuum, and the residue was added 50 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 6-fluoro-5-iodo-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: CCOCC.[CH2:6]([Mg]Cl)[CH2:7][CH3:8].[C:11]([N:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:17]1=[O:27])(=[O:15])[CH:12]=[CH:13][CH3:14]>C1COCC1>[CH3:14][C@H:13]([CH2:6][CH2:7][CH3:8])[CH2:12][C:11]([N:16]1[C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][O:18][C:17]1=[O:27])=[O:15]
Reactant: CC=CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: CCC[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC[C@@H](C)CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
To the copper (1) bromide dimethylsulfide complex (13.34 g, 64.87 mmol) in dry THF (150 mL) at −30° C. under Nitrogen was added a 2M ether solution of Propylmagnesiumchloride (64.87 mL, 129.7 mmol) and stirred for 20 minutes. (R)-3-But-2-enoyl-4-phenyl-oxazolidin-2-one (15.0 g, 64.87 mmol) in THF (60 mL) was added over a 15 minute period at −35° C. and let slowly warm up to room temperature over 4 hours. The mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The suspension was extracted into ether, washed with 5% ammonium hydroxide solution and then with brine and dried over MgSO4. The solution was concentrated under reduced pressure to afford the titled compound (13.34 g; 100% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (m, 6H) 1.2 (m, 3H) 1.6 (s, 1H) 2.0 (m, 1H) 2.7 (dd, J=16.1, 8.5 Hz, 1H) 3.0 (dd, J=15.9, 5.4 Hz, 1H) 4.3 (dd, J=8.9, 3.8 Hz, 1H) 4.7 (t, J=8.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 7.3 (m, 5H). MS, m/z (relative intensity): 276 [M+1H, 100%].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:19][N:18]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:26]([O:28]CC)=[O:27])=[N:3]1.CO.[OH-].[Li+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:19][N:18]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:26]([OH:28])=[O:27])=[N:3]1
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)C3CN(c4cccnn4)C3)cc2)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(=O)O)cc1-c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1
Temperature: 60 °C

Procedure:
Ethyl 1-methyl-5-(4-(1-(pyridazin-3-yl)azetidine-3-carboxamido)phenyl)-1H-pyrazole-3-carboxylate (368 mg, 0.905 mmol) was taken up in tetrahydrofuran (3.38 mL), and methanol (3.38 mL) then 1N aqueous lithium hydroxide (1.35 mL, 1.350 mmol) was added. The mixture was heated at 60° C. for 2 hours. The mixture was concentrated to dryness, suspended in water and treated with 1N aqueous HCl to pH 2. The solution was extracted with ethyl acetate and the organic layers were dried with sodium sulfate, filtered, and concentrated to give a colorless syrup that solidified upon standing. This solid was triturated with ether and collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.67 (s, 1H), 10.32 (bs, 1H), 8.60-8.55 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.42 (dd, J=9.0, 4.5 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H), 6.80 (s, 1H), 4.34-4.13 (m, 4 H), 3.91 (s, 3 H), 3.83-3.74 (m, 1H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]([C:9]#[C:10][CH2:11][CH:12]([O:61][Si:62]([C:75]([CH3:78])([CH3:77])[CH3:76])([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([O:43][Si:44]([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:30][C:31]#[C:32][CH:33]([O:35][Si](C(C)(C)C)(C)C)[CH3:34])=[CH:20][CH:19]=1)[CH3:8])(C)C.[NH+]1C=CC=CC=1>C(O)C>[CH3:58][C:57]([Si:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[O:43][CH:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([O:61][Si:62]([C:75]([CH3:76])([CH3:77])[CH3:78])([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:11][C:10]#[C:9][CH:7]([OH:6])[CH3:8])=[CH:19][CH:20]=1)[CH2:30][C:31]#[C:32][CH:33]([OH:35])[CH3:34])([CH3:60])[CH3:59]
Reactant: CC(C#CCC(CCCCOc1ccc(OCCCCC(CC#CC(C)O[Si](C)(C)C(C)(C)C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(O)C#CCC(CCCCOc1ccc(OCCCCC(CC#CC(C)O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of the alkyne 12b (526 mg, 457 μmol) in absolute ethanol (6.0 mL) was added pyridinium p-toluenesulfanate (273 mg, 1.09 mmol) in one portion. The reaction mixture was stirred at 55° C. overnight (~14 h). The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by MPLC (3:1 hexane:ethyl acetate) to give the alcohol 14 (387 mg, 92%); IR (neat, thin layer): 3405, 3070, 3048, 2935, 2858, 1963, 1893, 1827, 1589, 1507, 1471, 1428, 1365, 1228, 1155, 1002, and 823 cm-1 ; Anal. Calcd for C58 H74O6Si2 : C, 75.44%; H, 8.08%. Found: C, 75.16%; H, 7.89%; tlc: Rf =0.14 in 3:1 hexane:ethyl acetate; [α]RTD =-7.9°, c=5.47 in ethyl acetate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4cnn(CC)c4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1cc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cn1
Yield: 75.4 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (52 mg), 1N aqueous sodium hydroxide solution (2 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was heated under reflux for 30 min. After cooling, 1N hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine; dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from tetrahydrofuran-hexane gave {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (37.6 mg, yield 77%). melting point: 165-166° C.
Reaction SMILES: C([O:4][CH:5]1[C:6]([O:54][CH:55]([O:57][CH2:58][CH3:59])[CH3:56])([CH3:53])[CH2:7][CH2:8][CH:9]([O:47][CH:48]([O:50][CH2:51][CH3:52])[CH3:49])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:40][CH:41]([O:43][CH2:44][CH3:45])[CH3:42])([CH3:39])[CH2:24][CH:25]2[O:38][CH:26]2[CH:27]([CH3:37])[CH:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:51]([O:50][CH:48]([O:47][CH:9]1[CH2:8][CH2:7][C:6]([O:54][CH:55]([O:57][CH2:58][CH3:59])[CH3:56])([CH3:53])[CH:5]([OH:4])[CH:17]=[CH:16][CH:15]([CH3:18])[CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:40][CH:41]([O:43][CH2:44][CH3:45])[CH3:42])([CH3:39])[CH2:24][CH:25]2[O:38][CH:26]2[CH:27]([CH3:37])[CH:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:29][CH3:30])[O:13][C:11](=[O:12])[CH2:10]1)[CH3:49])[CH3:52]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of (8E,12E,14E)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (145 mg, 0.17 mmol) in methanol (2.5 mL) was added potassium carbonate (95 mg, 0.69 mmol) at room temperature, followed by stirring at the same temperature for two hours and 30 minutes. The reaction mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=40:60) to give the title compound (128 mg, 93%) as a colorless oil.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7](OCC1C=CC=CC=1)=[O:8])[CH2:3][C:4](=O)O.[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:36])[CH:33]=2)[CH:28]=[CH:27][N:26]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:20]([O:19][C:17](=[O:18])[NH:1][C@H:2]1[CH2:3][CH2:4][N:36]([CH2:35][C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][N:26]=[C:25]3[NH2:24])=[CH:30][CH:31]=2)[C:7]1=[O:8])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: NCc1ccc2ccnc(N)c2c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(N)c3c2)C1=O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 0.3 g of Boc-L-Asp(H)-OBn (WO 96/40679) dissolved in 2 mL methanol was added 176 mg of 1-amino-7-(aminomethyl)isoquinoline. After stirring for 30 minutes, a solution of 80 mg sodium cyanoborohydride and 90 mg zinc chloride in 2 mL methanol was added. The mixture was stirred for an additional two hours. After this time, 7 mL of an aqueous 0.2 N sodium hydroxide solution was added and the resulting mixture was concentrated. The residue was treated with 100 mL dichloromethane and 10 mL water, filtered and an additional 100 mL water was added to the filtrate. The organic layer was separated and washed with aqueous 5% sodium hydrogencarbonate and brine. All aqueous layers were washed twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/dichloromethane/methanol=10/10/1 to dichloromethane/methanol=10/1 to give 146 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]CC2C=CC=CC=2)[CH2:10][C@@H:9]1[C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C@H:21]1[O:25][C:24]([CH3:26])([CH3:27])[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Yield: 100 %

Procedure:
Combine (2R,4R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.22 mmol), 10% palladium on carbon (12 mg) and methanol (10 mL) and stir overnight under 1 atmosphere of hydrogen. Add filter agent, filter, and concentrate under reduced pressure to provide the desired compound (0.100 g, 98%) as a foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([N:28](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[CH3:45][S:46]([OH:49])(=[O:48])=[O:47]>[OH-].[OH-].[Pd+2].C1COCC1>[CH3:45][S:46]([OH:49])(=[O:48])=[O:47].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH2:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
Part B: To the THF solution of crude 1-[N-[(1,3-benzodioxol-5-yl) sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanol was added water (500 mL) followed by methane sulfonic acid (531 g, 5.5 moles). The solution was stirred to insure complete mixing and added to a 5 gallon autoclave. Pearlman's catalyst (200 g of 20% Pd(OH)2 on C/50% water) was added to the autoclave with the aid of THF (500 mL). The reactor was purged four times with nitrogen and four times with hydrogen. The reactor was charged with 60 psig of hydrogen and stirring at 450 rpm started. After 16 hours, HPLC analysis indicated that a small amount of the mono-benzyl intermediate was still present. Additional catalyst (50 g) was added and the reaction was allowed to run overnight. The solution was then filtered through celite (500 g) to remove the catalyst and concentrated under vacuum in five portions. To each portion, toluene (500 mL) was added and removed under vacuum to azeotropically removed residual water. The resulting solid was divided into three portions and each washed with methyl t-butyl ether (2 L) and filtered. The residual solvent was removed at room temperature in a vacuum oven at less than 1 torr to yield the 2714 g of the expected salt.
Reaction SMILES: [CH:1]1([C:4]([CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[O:5])[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([C:4]([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C=CC(=O)C2CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CCC(=O)C2CC2)cc1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of 11.83 g of 4-cyanophenylvinyl cyclopropyl ketone in 200 ml of absolute ethanol containing 0.3 g of 10% palladium-on-carbon catalyst was hydrogenated at an initial pressure of 45 pounds per sq. in. for one hour. The catalyst was filtered off, and the product isolated from the filtrate and recrystallized from methanol to give 8.9 g of 4-cyanophenylethyl cyclopropyl ketone, m.p. 76° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCCCCC>C(OCC)(=O)C>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate (5.06 g, 14.6 mmol) in ethyl acetate (80 ml) was added a 4 N solution of hydrogen chloride in ethyl acetate (40 ml), and the mixture was stirred at room temperature for 5 hours. Hexane (200 ml) was added to the reaction mixture and a precipitated solid was collected by filtration. The obtained solid was added to an aqueous saturated sodium bicarbonate solution (300 ml), followed by stirring at room temperature for 2 hours. The obtained powder was collected by filtration to yield 2.77 g (77.0%) the desired product.
Reaction SMILES: [C:1]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[C:1]([NH:20][CH2:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C1(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
Tritylamine (180 mg, 0.00068 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.170 g, 0.000568 mol, this was prepared by using procedures analogous to that described for the synthesis of example 1, steps 1-2) in 1,2-dichloroethane (4.0 mL, 0.051 mol) and followed by sodium triacetoxyborohydride (0.36 g, 0.0017 mol) and the mixture was stirred overnight. The mixture was poured into pre-cooled water, and extracted with ethyl acetate. The organic layer was separated, dried (NaSO4), and concentrated in-vacuo. The product was purified by CombiFlash eluting with hexane/EtOAc (max EtOAc 20%). LC-MS: 543.3 (M+H)+; 243.2.