Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:9])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O.[C:49]1([S:55]([N:58]2[C:62]3=[N:63][CH:64]=[C:65]([NH2:73])[C:66]([NH:67][CH:68]4[CH2:72][CH2:71][O:70][CH2:69]4)=[C:61]3[CH:60]=[CH:59]2)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:49]1([S:55]([N:58]2[C:62]3=[N:63][CH:64]=[C:65]([NH:73][C:6]([C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:9])=[O:8])[C:66]([NH:67][CH:68]4[CH2:72][CH2:71][O:70][CH2:69]4)=[C:61]3[CH:60]=[CH:59]2)(=[O:56])=[O:57])[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(=O)O[C@H](C)C(=O)O
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@H](C)C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCOC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
(R)-2-acetoxypropanoic acid (0.306 g, 2.32 mmol) was dissolved in methylene chloride (20 mL, 200 mmol;). Triethylamine (0.42 mL, 3.0 mmol;) was added, followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.972 g, 2.56 mmol;) dissolved in N,N-dimethylformamide (2 mL, 20 mmol;). After 15 minutes, 1-benzenesulfonyl-N-(tetrahydro-furan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.728 g, 2.03 mmol) was added and the reaction was stirred 64 h at room temperature. The volatiles were removed under reduced pressure and the residue was dissolved in 100 ml EtOAc. This was shaken with 50 ml saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc (2×50 ml). The combined organics were dried with MgSO4, filtered and concentrated. This material was then dissolved in a minimum volume of CH2Cl2 and injected onto a 40 g silica gel column which had been equilibrated with heptane. It was then eluted with a gradient of 0% to 100% ethyl acetate in heptane. The product containing fractions were combined and evaporated under reduced pressure to give the title compound as a clear oil (0.596 g, 62%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=7.6 Hz, 2H), 7.88 (s, 1H), 7.60-7.43 (m, 4H), 7.21 (d, J=7.2 Hz, 1H), 6.62 (d, J=4.1 Hz, 1H), 5.11-4.95 (m, 2H), 4.59-4.48 (m, 1H), 4.01-3.74 (m, 4H), 2.33-2.21 (m, 1H), 2.19 (d, J=3.3 Hz, 3H), 2.03-1.95 (m, 1H), 1.59 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([N+:19]([O-])=O)[CH:10]=[C:11]([C:13](=[O:18])[NH:14][O:15][CH2:16][CH3:17])[CH:12]=1)=[O:6])[CH3:2].[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>[Pd].C(O)C>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:19][C:9]2[CH:10]=[C:11]([C:13](=[O:18])[NH:14][O:15][CH2:16][CH3:17])[CH:12]=[C:7]([C:5](=[O:6])[NH:4][O:3][CH2:1][CH3:2])[CH:8]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CCONC(=O)c1cc(C(=O)NOCC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCONC(=O)c1cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc(C(=O)NOCC)c1
Reaction time: 1 h

Procedure:
A solution of 2.0 g. (0.0067 mol) of 3,5-bis-ethoxycarbamoylnitrobenzene in 150 ml. of 2B ethanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. Reduction was complete in 1 hour, the catalyst was filtered, and to the colorless filtrate was added 1.42 g. (0.0064 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyranone. The mixture was heated under reflux for 45 minutes, cooled and the product filtered to yield 5-acetyl-4-hydroxy-3-[1-(3,5-bis-ethoxycarbamoylphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 234°-235° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[C:20]([C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1)#[N:21]>>[O:19]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[N:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[C:20]#[N:21])[CH2:30][CH2:31]2)=[O:16])=[CH:17][CH:18]=1)([CH3:8])[CH3:9]
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C#N)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)N4CCCS4(=O)=O)cc3)CC2)c(C#N)c1
Yield: 79.7 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (100 mg) described in Preparation Example 39 and 4-(3-cyano-5-methylpyridin-2-yl)piperazine (51 mg) described in Preparation Example 107 and by the reaction and treatment in the same manner as in Example 87, the title compound (94 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[Cl:23])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1ccccc1)c1ccc(C2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC(c1ccccc1)c1ccc(C2CCCCC2)cc1
Temperature: 70 °C
Yield: 97 %

Procedure:
76 g (0.286 mol) of 4-cyclohexylphenylphenylcarbinol are introduced in portions into a mixture of 143 ml (2 mols) of thionyl chloride and 200 ml of benzene at 70° C. The reaction mixture is heated to 70° C. for 15 hours and then evaporated. The oil which remains is stirred with petroleum ether, whereupon it solidifies to a crystal sludge. 79 g (96% of theory) of 4-cyclohexylphenyl-phenylchloromethane of melting point 75° C. are obtained. ##STR7##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].C(=O)(O)[O-].[Na+]>ClCCl>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])([O-:17])=[O:16]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of aniline (17 g, 180 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (100 mL) was added a solution of 3-nitrobenzoyl chloride (30 g, 160 mmol) in dichloromethane (60 mL). The mixture was stirred for 15 min at 0° C. then overnight at room temperature. It was then poured into saturated sodium bicarbonate (1 L) and stirred vigorously for 15 min. The precipitate was collected, washed with water and dried (40 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[CH:3]=1.CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[F:33][C:32]([F:35])([F:34])[S:29]([O:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=2)(=[O:30])=[O:28]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (prepared using similar method described in Example 1, 500 mg, 1.9 mmol), DIPEA (490 mg, 3.8 mmol) and DMAP (5 mg, 0.02 mmol) in DCM (2 mL) was added Tf2O (1.07 g, 3.8 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at 25° C. for 5 hours. The mixture was diluted with H2O extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified by column (PE:EA=5:1) to obtain the product of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (600 mg, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.39 (s, 1H), 7.64 (s, 1H), 7.18˜7.20 (m, 3H), 6.77˜6.82 (m, 1H). MS (M+H)+: 395/397.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].C(OC([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=O)(C)(C)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:47]3[CH2:48][CH2:49][N:44]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:45][CH2:46]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: CS(=O)(=O)Cl
Product: Cc1ccccc1-c1cc(N2CCN(S(C)(=O)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 58 %

Procedure:
In a similar manner to Example 6, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 17; 65.0 mg) was reacted with 1-(t-butoxycarbonyl)piperazine (57.5 mg) and methylsulfonyl chloride (50 μL) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(methylsulfonyl)piperazine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (46.7 mg, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:37])[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)([OH:29])[C:25]([F:28])([F:27])[F:26])=[C:19]([Cl:38])[CH:18]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:37])[C:24]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=3)([OH:29])[C:25]([F:26])([F:27])[F:28])=[C:19]([Cl:38])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorosulfonyl-benzoic acid ethyl ester (CAS Reg. No. 10486-51-8, 15 mg) was added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 20 mg) in pyridine (0.8 ml). The solution was stirred for 30 min at room temperature. The mixture was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (18 mg) as a light yellow foam. MS (m/e)=577.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[N:32]([CH3:45])[N:33]=[C:34]3[C:39]=2[CH:38]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]3[Cl:44])[CH:9]([C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[N:32]([CH3:45])[N:33]=[C:34]3[C:39]=2[CH:38]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:36]=[C:35]3[Cl:44])[CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:29][CH:30]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the faster-eluting enantiomer of the product from Step B (4 mg, 0.006 mmol) in DCM (1 mL) was added TFA (1 mL, 13 mmol), and the solution was stirred for 30 minutes at RT. The solution was concentrated, then the residue was purified by reverse phase HPLC eluting with acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the enantiopure title compound as a white solid. This was the most potent glucagon receptor antagonist of the four stereoisomeric compounds. 1H NMR (600 MHz, CD3OD): δ 8.44 (s, 1 H); 7.60 (d, J=8.3 Hz, 2H); 7.52 (d, J=8.0 Hz, 2H); 7.40 (d, J=8.3 Hz, 2H); 7.39 (s, 1H); 7.32 (d, J=8.0 Hz, 2H); 5.02 (d, J=11.9 Hz, 1H); 4.07 (s, 3H); 4.02 (td, J=11.3, 3.4 Hz, 1H); 3.51 (t, J=7.0 Hz, 2H); 2.54 (t, J=7.0 Hz, 2H); 1.76-1.61 (m, 2H); 1.19-1.02 (m, 2H); 0.78 (t, J=7.3 Hz, 3H); LC1 2.44 min. (M+H)− 606.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:22])=[CH:15][CH:16]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CNC(C)=O)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminomethyl-benzamide and acetyl chloride, the title compound was prepared as white crystals (17% yield). MS: m/e=441(M+H+).
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-furan-2-yl)-ethanone (2.00 g, 14.27 mmol) in dry CH2Cl2 (29 mL) was treated at 0° C. with Et3N (2.58 mL, 18.55 mmol) followed by DMAP (178 mg, 1.43 mmol) and Ms-Cl (1.33 mL, 17.13 mmol). After stirring at rt for 3 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-furan-2-yl)-ethanone as a brown oil. Part of this crude material (2.33 g, 14.72 mmol) was dissolved in dry DMF (50 mL) and treated with NaN3 (2.90 g, 44.16 mmol) at 80° C. for 24 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the aq. layer extracted with EA (1×). The combined org. extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1-(5-azidomethyl-furan-2-yl)-ethanone as a brown oil. LC-MS-conditions 02: tR=0.81 min; [M+AcCN+H]+=207.50.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26])[CH:17]=[CH:16]2.[OH-].[Na+].C1COCC1.CO>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([OH:27])=[O:26])[CH:17]=[CH:16]2
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OC(Cc3ccccc3)C(=O)O)ccc2c1

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl 2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.200 g, 0.433 mmol), prepared in the previous step, and 1N NaOH (0.65 mL, 0.65 mmol) in 1.5:1.5:1 THF:MeOH:water (40 mL) with the exception that this reaction was complete after 18 hours (overnight) at ambient temperature. The title compound was isolated as a pale-yellow solid (0.194 g, 100%) and used without further purification, mp 171–173° C. Elemental Analysis for C30H25NO3.0.05 H2O Calc'd: C, 80.35; H, 5.64; N, 3.12. Found: C, 80.38; H, 5.67; N, 3.00.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)(O)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3]CC1C=CC=CC=1)=O.C(CC(Cl)=S)(=O)C.[C:33]([S:36][CH2:37]C(N1CC=C[C@@]1(CC1OC=CC=1)C(O)=O)=O)(=[O:35])[CH3:34]>>[C:33]([S:36][CH2:37][C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:3])(=[O:35])[CH3:34]
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(=O)N1CC=C[C@@]1(Cc1ccco1)C(=O)O
Agent: CC(=O)CC(=S)Cl
Product: CC(=O)SCC(=O)N1CC(Cc2ccco2)=C[C@H]1C(=O)O

Procedure:
4-[(2-Furyl)methyl]-3,4-dehydro-L-proline from part (a) is reacted with 2-acetylthioacetyl chloride according to the procedure of Example 3 (b) to yield (2S)-1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[ClH:17]>C(O)C>[ClH:7].[ClH:17].[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:6][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClCCCN1CCCCC1
Reactant: CC(C)CCN
Agent: Cl
Solvent: CCO
Product: CC(C)CCNCCCN1CCCCC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 23.2 ml of isoamylamine and 16.17 g of 1-(3-chloropropyl)piperidine was heated to 120° C. for 2 hours. The reaction mixture was then dissolved in 100 ml of ethanol. To this ethanol solution was added 17 ml of conc. hydrochloric acid. The mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected, washed with ethanol, and dried to give 14.70 g of 1-[3-(3-methylbutylamino)propyl]piperidine dihydrochloride as a white crystalline product.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[OH-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-2-methyl-1-propanol (7.1 mmol) in tetrahydrofuran (THF) (25 mL) was added dropwise to a slurry of 60% sodium hydroxide/oil (3 g, 75 mmol) in THF (75 mL). The mixture was stirred at room temperature for 1 hour and then cooled in an ice bath. A solution of benzyl bromide (5.9 mL, 50 mmol) was added dropwise. After stirring for 2 hours at 0° C., the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated to an oil which was subjected to flash chromatography on silica gel eluting with 5% methanol/chloroform. Fractions containing the desired product were combined and concentrated to yield an oil. Yield: 4.2 g (47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:14])[CH3:15])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)O)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c12
Reaction time: 12 h
Yield: 87 %

Procedure:
A solution of 6-bromo-3-ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.3 g, 0.901 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.292 g, 1.92 mmol) in DMSO (4 mL) and was stirred at room temperature for 15 min. Then PyBOP (0.75 g, 1.44 mmol) was added to it and stirring was continued for 12 hr. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (0.35 g, 81.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:9](N1CCCCC1C(=O)NC1C=CC(C#CC2C(C3C=C(C)C=CC=3O)=NN(C)C=2)=CC=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([OH:79])=[C:54]([C:56]2[C:60]([C:61]#[C:62][C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([CH:72]4[CH2:77][O:76][CH2:75][CH2:74][NH:73]4)=[O:71])=[CH:65][CH:64]=3)=[CH:59][N:58]([CH3:78])[N:57]=2)[CH:55]=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:9]([N:73]1[CH2:74][CH2:75][O:76][CH2:77][CH:72]1[C:70](=[O:71])[NH:69][C:66]1[CH:65]=[CH:64][C:63]([C:62]#[C:61][C:60]2[C:56]([C:54]3[CH:55]=[C:50]([Cl:49])[CH:51]=[CH:52][C:53]=3[OH:79])=[N:57][N:58]([CH3:78])[CH:59]=2)=[CH:68][CH:67]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)cc2)c1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3)cc2)c(-c2cc(Cl)ccc2O)n1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1

Procedure:
Using the same procedure for the preparation of 3D, reaction of compound 7D with BOC-D-Phg-OH (2D) afforded the title compound 8D, which was purified by silica column chromatography eluting with dichloromethane/EtOAc (9/1, 8/1, 7/1) to give pure 8D as white powder in similar yield. 1H NMR (CDCl3, 500 MHz) δ 10.68 (s, 1H), 8.72 (s, 1H), 8.61 (s, 1H), 7.92 (d, 2H, J=7.0 Hz), 7.63 (s, 1H), 7.57 (d, 2H, J=8.0 Hz), 7.43 (m, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.97 (dd, 1H, J=9.0, 1.0 Hz), 5.48 (d, 1H, J=6.0 Hz), 5.40 (d, 1H, J=5.5 Hz), 5.29 (s, 1H), 4.82 (d, 1H, J=12.0 Hz), 3.96 (s, 3H), 3.78 (d, 1H, J=10.5 Hz), 3.65 (t, 1H, J=12.5 Hz), 3.60 (t, 1H, J=10.0 Hz), 3.43 (dd, 1H, J=11.5, 2.0 Hz), 3.07 (t, 1H, J=11.5 Hz), 1.45 (s, 9H). LCMS (ESI) m/z 692.34 (MNa+), 670.33 (MH+), 614.24 (100), 570.23. HPLC: tR=5.35 min.
Reaction SMILES: [N:1]1([C:6]2[CH:20]=[CH:19][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]([N:25]=[C:26]=[S:27])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH2:21]([NH:25][C:26]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14]1)=[S:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=S
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Solvent: ClCCl
Product: CCCCNC(=S)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-[4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinamine (4.06 g, 15.0 mmol) and butyl isothiocyanate (1.81 mL, 1.73 g, 15.0 mmol) are combined in methylene chloride (75 mL) and stirred at room temperature. After 24 hr, an additional portion (0.90 mL, 0.86 g, 7.5 mmol) of butyl isothiocyanate is added, and the mixture is stirred for 48 hr. The mixture is washed twice with 1N aqueous sodium hydroxide, once with brine, dried over magnesium sulfate, and evaporated. Trituration of the residue with ether and recrystallization from ethanol-ether affords the title compound.