Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH3:33])[S:27]([CH3:30])(=[O:28])=[O:29])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(NS(C)(=O)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(C)S(C)(=O)=O
Yield: 89.5 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}methanesulfonamide (60.4 mg, 0.124 mmol) in N,N-dimethylformamide (1.2 mL) was added sodium hydride (60%, 6.0 mg, 0.15 mmol. After the resultant mixture was stirred at room temperature for 30 min, methyl iodide (0.010 mL, 0.16 mmol) was added. The resultant mixture wad stirred at room temperature for 30 min, diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (55.6 mg, 0.111 mmol, 90%).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[OH:9].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([NH:4][C@@H:5]([C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:17][CH2:18]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:9])[OH:10])=[O:37])=[CH:30]2
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CCC(=O)O)CC2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-(D-glutamyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and 5-chloroindole-2-carboxylic acid (43%).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH3:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CNC2
Temperature: 40 °C
Reaction time: 168 h
Yield: 60.3 %

Procedure:
1.5 g of 10% palladium on carbon was added to a solution of 12.5 g of 2-benzyl-5-methoxyisoindoline prepared above in 150 ml of methanol and the mixture was stirred under hydrogen gas stream at 40° C. under atmospheric pressure for 7 days. After removing the catalyst by filtration, the filtrate was concentrated and purified by vacuum distillation to give 4.7 g of 5-methoxyisoindoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:10][CH2:9]1.O.[NH2:29]N.C(O)C>C(OCC)(=O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:29])[CH2:12][CH2:13]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCN3CCN(c4ccccc4F)CC3)cccc21
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCCN1CCN(c2ccccc2F)CC1
Temperature: 90 °C
Yield: 47.5 %

Procedure:
A mixture of 3-[4-(2-fluorophenyl)piperazin-1-yl]propylphthalimide (1.87 g, 5.09 mmol) and hydrazine hydrate (305 mg, 6.11 mol) in 10L of ethanol was heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature and then diluted with 4 mL of ethyl acetate and 60 mL of diethyl ether. The mixture was filtered and the solvents were removed by evaporation to give 3-[4-(2-fluorophenyl)piperazin-1-yl]propylamine (574 g, 2.42 mmol).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7].[C:31]1([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+].C(O)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:41]2[CH2:42][CH2:43][N:38]([CH2:37][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:39][CH2:40]2)[CH2:10][C@@H:9]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7]
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2ccccc2)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
Titanium(IV)isopropoxide (16.5 g) was added to a mixture of intermediate 3 (21.5 g) and 1-(phenylmethyl)piperazine (8.81 g) in DCM (35 ml). The mixture was stirred for 3 hours at RT. Sodium cyanoborohydride (2.85 g) and ethanol (70 ml) were added and the resulting reaction mixture was stirred overnight at RT. Water (5 ml) and DCM were added. The biphasic mixture was filtered over dicalite, and the filter residue was washed with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN and the precipitate was filtered off and dried, yielding 7.93 g (26.9%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine (compound 16; mp. 143.8° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-4-methylbenzene: ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][O:12][CH:13]([F:15])[F:14])C1C=CC=CC=1>C1COCC1.[Pd]>[C:20]([O:19][C:17]([NH:16][C@@H:10]([CH2:11][O:12][CH:13]([F:14])[F:15])[C:9]([OH:24])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)O
Yield: 100.1 %

Procedure:
A solution of the compound of Formula XIII(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid benzyl ester (1.76 g, 5.09 mmol) in THF was stirred with 10% Pd/C (360 mg) under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and concentrated to give the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid (1.3 g, 100%) as a sticky, colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 6.21 (wt, 1H), 5.35 (d, 1H), 4.59 (m, 1H), 4.35 (m, 1H), 4.21 (m, 1H) and 1.42 (s, 9H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[SH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH:10]1([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:3][N:4]=2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Reactant: Sc1ccccn1
Product: O=C(Nc1ncc(Sc2ccccn2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercaptopyridine.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:30]1[C:38]([NH2:39])=[C:37]2[C:33]([NH:34][CH:35]=[N:36]2)=[N:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:39][C:38]1[N:30]=[CH:31][N:32]=[C:33]2[C:37]=1[N:36]=[CH:35][N:34]2[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1)n1cnc2c(N)ncnc21
Yield: 39.7 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate C9, 68 mg, 0.142 mmol), 9H-purin-6-amine (57.6 mg, 0.426 mmol) and K2CO3 (29.5 mg, 0.213 mmol) to give the title compound (30 mg, 37.1%). The resulting mixture was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) The resulting product was further purified by Preparative HPLC (method 2) to give the chemically pure compound (10 mg, 13%) and a batch with lower purity (9 mg, 12%).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:32])=[C:13]([C:27](OCC)=[O:28])[C:14](=[O:26])[N:15]2[CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:32])=[C:13]([C:27]([NH:37][CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:28])[C:14](=[O:26])[N:15]2[CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CCN2CCOCC2)c1=O
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(CCN2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-(2-morpholin-4-ylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 5 and was obtained as an off-white solid: 1H NMR (CDCl3) δ 10.01 (1H, br d, J=5 Hz), 8.70 (1H, s), 8.61 (1H, s), 7.39 (2H, d, J=7.7 Hz), 7.30 (2H, t, J=7.7 Hz), 7.21 (1H, m), 4.89 (2H, m), 4.52 (1H, m), 4.26 (4H, m), 4.07 (2H, m), 3.50 (2H, m), 3.18 (2H, m), 3.09 (2H, m), 2.43 (2H, m), 2.06 (2H, m), 1.81 (2H, m); HRMS calcd for C26H30N4O4+H+: 463.2345. Found: 463.2343.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])CC(C)C)[CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH3:32]>>[C:1]([S:4][CH:5]([CH2:10][C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:16])[CH:6]([CH2:19][CH:20]([CH3:25])[CH3:21])[C:7]([NH2:32])=[O:9])(=[O:3])[CH3:2]
Reactant: N
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)CC(SC(C)=O)C(CC(C)C)C(N)=O

Procedure:
The title compound, m.p. 235°-240° C., was prepared from the compound of Example 5 and ammonia by an analogous procedure to that described in Example 11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][N:20]=1)[C:12](N(OC)C)=[O:13].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:12]=[O:13])[CH:18]=[CH:19][N:20]=1
Reactant: CON(C)C(=O)c1ccnc(-c2c(F)cccc2F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccnc(-c2c(F)cccc2F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a stirred solution of (2-(2,6-difluoro-phenyl)-N-methoxy-N-methyl-isonicotinamide (Example 33) (268 mg, 0.963 mmol) in toluene (1.2 mL) at −78° C. was added DIBAL (1M in toluene; 1.01 mL, 1.01 mmol) dropwise. The mixture was stirred −78° C. for 2 hours then warmed to 0° C. and the reaction was quenched by the addition of 1M aqueous HCl. The mixture was neutralized using saturated aqueous NaHCO3 solution and then extracted into CHCl3 (×3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The product was purified by SiO2 chromatography providing the title compound (127 mg).
Reaction SMILES: [Cl-:1].O[CH2:3][CH2:4][NH+:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.Cl.N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl.O>[Cl-:22].[Cl:1][CH2:3][CH2:4][NH+:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=S1(=O)CC[NH+](CCO)CC1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S1(=O)CC[NH+](CCCl)CC1
Temperature: 25 °C

Procedure:
4-(2-Hydroxyethyl)thiomorpholin-4-ium 1,1-dioxide chloride, the HCl salt of 41-1, (6.0 g, 27.82 mmol) was treated with pyridine (2.43 g, 30.60 mmol) and then warmed with a solution of thionyl chloride (4.96 g, 41.72 mmol) in chloroform (20 mL) to 60° C. After 1.5 hours the reaction was cooled to 25° C. and water was added. The chloroform was drawn off and the aqueous layer was condensed under reduced pressure to a clear syrup which crystallized upon standing. The crystals were filtered off, washed with 95% ethanol, methanol and then dried to afford 41-2. 1H-NMR (CD3OD): 4.01(t, 2H); 3.90(m, 4H); 3.71(t, 2H); 3.59(t, 4H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]O)=[CH:36][CH:35]=1)#[N:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(CO)cc1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
Diethyl azodicarboxylate (524 mg, 3.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (900 mg, 3.0 mmol), as prepared in step (c) of the Example 1, 4-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (790 mg, 3.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a white solid (0.95 g, 76%). 1H-NMR (300 MHz, CDCl3) δ 2.26 (s, 3 H), 5.03 (s, 2 H), 6.57 (t, 1 H, J=2.2 Hz), 6.59 (s, 1 H), 6.67 (s, 1 H), 7.38 (t, 1 H, J=5.8 Hz), 7.49 (d, 2 H, J=4.2 Hz), 7.60 (m, 2 H), 7.67 (d, 2 H, J=3.5 Hz) and 7.96 (d, 1 H, J=3.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12].[C:20]([O:23][C:24](=O)C)(=[O:22])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:20](=[O:22])[O:23][CH3:24])=[O:12])[CH2:14][CH2:15]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2N)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCN(C)CC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of Intermediate 69B (540 mg, 2.04 mmol) in DCM (20 mL) was added TEA (0.570 mL, 4.09 mmol), acetic anhydride (0.289 mL, 3.06 mmol), and DMAP (2 mg, 0.016 mmol). The reaction mixture was stirred overnight, then washed with saturated aqueous NaHCO3, dried, and concentrated. The reaction mixture was purified by flash chromatography, (SiO2, 24 g, 0-10% MeOH/DCM) to give Intermediate 69C (600 mg, 96%) as a yellow solid. HPLC: Rt=0.517 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=307 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH3:7][S:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)(=[NH:10])=[O:9]>N1C=CC=CC=1>[CH2:3]([O:2][C:1](=[O:5])[N:10]=[S:8]([CH3:7])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:9])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CS(=N)(=O)Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCOC(=O)N=S(C)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 105.7 %

Procedure:
Ethyl chlorocarbonate (8.1 mL; 84.6 mmol) was added dropwise to a stirred solution of (rac)-1-[(S-methylsulfonimidoyl)methyl]-3-nitrobenzene (13.9 g; 65.1 mmol) in pyridine (615 mL) at 0° C. The batch was slowly warmed to room temperature. After 24 hours the batch was concentrated and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated to give the desired product (19.7 g) that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=2)[CH2:31][S:32][CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[O:27])[CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=2)[CH2:31][S:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])[CH:8]=1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)ncn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(2-(6-(3-methylbenzylamino)pyrimidin-4-yl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (180 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (5 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 84 mg (51%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 9.42 (s, 1H), 8.84 (s, 1H), 7.80 (s, 1H), 7.71 (m, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.24 (m, 6H), 6.90 (s, 1H), 5.42 (s, 2H), 4.64 (m, 1H), 3.82 (s, 2H), 3.26 (m, 4H), 2.59 (m, 2H), 1.67 (m, 6H). MS (ES, m/z): 596 [M+H]+.
Reaction SMILES: Cl.C(N=C=N)C.[C:7]([O:11][C:12]([N:14]([C@H](CC1C=CC2C(=CC=CC=2)C=1)C(O)=O)[CH3:15])=[O:13])([CH3:10])([CH3:9])[CH3:8].ON1C2N=CC=CC=2N=N1.CN(CC1CCN(C(=O)[C@H](NC)CC2C=CC=CC=2)CC1)C.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:13])[NH:14][CH3:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=N
Agent: CN[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At 0° C., N-3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (416 mg, 2.17 mmol) was added to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propioni acid (715 mg, 2.17 mmol) and 1-hydroxy-7-azabenzotriazole (296 mg, 2.17 mmol) in dichloromethane (20 ml) and N,N-dimethyformamide (10 ml). The reaction mixture was stirred for 20 min at 0° c. A solution of (2R)-1-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(methylamino)-3-phenylpropan-1-one (659 mg, 2.17 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.56 ml, 3.26 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml). The aqueous solution was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography 60 on silica (80 g), using ethyl acetate/heptane/triethylamine (1:1:0.08) as eluent, to give 1.05 g of N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-(dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C(N(CC)CC)C.[Na].O[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]([NH2:29])=[O:28]>C1C=CC=CC=1.O>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[C:27]([NH2:29])=[O:28])[CH2:3]1
Reactant: CN1CCC(O)C1
Reactant: NC(=O)c1ccc2ccccc2c1O
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC(Oc2c(C(N)=O)ccc3ccccc23)C1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
In another vessel, 79 g (0.69 mole) of methanesulfonychloride was added dropwise to a solution of 69.7 g (0.69 mole) of 1-methyl-3-pyrrolidinol and 77 g (0.76 mole) of triethylamine in 500 ml of dry benzene while cooling with an ice bath. The mixture was stirred 15 minutes and filtered. The filter cake was washed with 500 ml benzene and the benzene filtrates were combined and concentrated on the rotary evaporator to about 200 ml. The residue was added dropwise to the above prepared dimethylsulfoxide solution containing the sodium salt of 1-hydroxy-2-naphthalenecarboxamide while stirring at 75° C. The temperature was maintained at 75° C. for 18 hr with external heat. The resulting solution was cooled and an equal volume of water was added. The mixture was extracted with three portions of chloroform. The washes were combined and concentrated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted twice with ethyl acetate. The ethyl acetate washes were combined, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-isooctane. Yield of solid was 55 g (32%). A portion was recrystallized twice from ethyl acetate-isooctane, m.p. 122°-129° C.