Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C1COCC1.CN(C=O)C.O>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)(=[O:33])=[O:32])=[C:3]2[CH:16]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
Alternatively, to a stirred solution of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (3.76 g, 11.93 mmol) in THF (60 mL) and DMF (30 mL) was added sodium tert-butoxide (2.87 g, 29.8 mmol) and 3-chlorobenzenesulfonyl chloride (3.36 mL, 23.86 mmol). The reaction mixture was stirred at RT under nitrogen for ca. 30 min and was then diluted with water (ca. 30 mL) and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate/DCM, to afford the title compound (4.06 g). Alternatively, to a stirred solution of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (7 g, 22.21 mmol) in THF (100 mL) and DMF (50 mL) was added sodium tert-butoxide (5.34 g, 55.5 mmol) and 3-chlorobenzenesulfonyl chloride (6.25 mL, 44.4 mmol). The reaction mixture was then stirred at RT under nitrogen for ca. 30 min. The reaction mixture was quenched with saturated NH4Cl solution (ca. 200 mL) and extracted with DCM (ca. 80 mL×5). The combined organics were dried and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM, to afford material (8.24 g). 200 mg of the material was re-purified with a gradient of 0-30% ethyl acetate in DCM, to afford the title compound (115 mg).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([NH:13][C@H:14]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:15]1OC(=O)C)(=[O:12])[CH3:11].[CH2:37]([SH:46])[CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl>[C:10]([NH:13][C@H:14]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:15]1[S:46][CH2:37][CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: SCC=Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1SCC=Cc1ccccc1
Reaction time: 48 h
Yield: 52.2 %

Procedure:
Boron trifluoride etherate (200 μl, 1.3 mmol) is added to a solution of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-α-D-mannopyranose (389 mg) and cinnamyl mercaptan (150 mg) in chloroform (10 ml), and the solution is kept under nitrogen for 2 days. Another portion of boron trifluoride etherate (200 μl) is added and the solution is kept under nitrogen for another 2 days. Chloroform (15 ml) is added and the solution is washed with aqueous sodium hydrogencarbonate and water, dried, and evaporated in vacuo to a residue, which is purified by preparative chromatography (EtOAc--CHCl3, 10:90, v/v, as a developing phase) to give the title compound (250 mg, 52%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]=[C:8]2[O:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(C(F)(F)F)cc4)nccc23)c1
Yield: 18.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(4-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-41, 100 mg, 0.32 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 177 mg, 0.65 mmol), oxalyl chloride (123 mg, 0.98 mmol), DMF (1 drop) and DIPEA (124 mg, 0.96 mmol) in CH2Cl2 (5 mL) to afford 33 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.30 (d, J=7.8 Hz, 1H), 8.21 (t, 1H), 8.08 (d, J=6.9 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.73 (d, J=6.3 Hz, 1H), 7.54 (m, 4H), 7.37 (d, J=8.4 Hz, 2H), 4.32 (d, J=5.7 Hz, 2H), 1.14 (s, 9H); MS (m/z): 556.29 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:26]N(C=O)C>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17](=[O:19])[C:8]3[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=3)[O:2][CH:26]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Reactant: Oc1cccc(O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2ccc(Br)cc2)coc2cc(O)ccc12
Yield: 57.8 %

Procedure:
This compounds was synthesised in the same manner as described above. Resorcinol (0.66 g, 6 mmol), 4-bromophenylacetic acid (1.29 g, 6 mmol), BF3Et2O (4 ml), PCl5 (1.9 g, 9.1 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(4-bromo-phenyl)-7-hydroxy-chromen-4-one as a white crystalline solid (1.1 g, 57.8%); Rf 0.85 ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(2,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.70 (1H, br s), 10.79 (1H, br s), 10.19 (1H, br s), 8.18 (0.45H, s), 8.13 (0.55H, s), 7.43-7.36 (1H, m), 7.29-7.21 (2H, m) 7.08-7.05 (1H, m), 4.02 (2H, s), 3.44-3.37 (2H, m), 3.31 (3H, s), 3.26-3.20 (2H, m); HRMS calcd for C19H17F2N3O4+H+: 390.1265. Found 390.1255.
Reaction SMILES: C([Li])CCC.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[O:24].C1(C)C=CC=CC=1>O1CCCC1.O>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([CH3:21])[S:19][C:20]=3[CH:23]([OH:24])[C:22]([O:26][CH2:27][CH3:28])=[O:25])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: Cc1nc(-c2ccc3c(c2)CCCO3)cs1
Reactant: CCOC(=O)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1sc(C)nc1-c1ccc2c(c1)CCCO2
Reaction time: 0.5 h
Yield: 24 %

Procedure:
Under a nitrogen atmosphere, butyl lithium (1.6M, 840 μL, 1.34 mmol) was added at −78° C. to a solution of 4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-methyl-1,3-thiazole (13a) (260 mg, 1.12 mmol) in anhydrous tetrahydrofuran (5 mL). After 30 minutes, ethyl glyoxylate 50% in toluene (500 μL, 2.5 mmol) was added at −78° C. and the mixture was stirred for 2 hours, hydrolyzed with water and concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired alcohol (13b) as a white solid (90 mg, 0.27 mmol, 24%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]=[N+]=[N-])=[CH:5][CH:4]=1)#[N:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CN)cn1
Reaction time: 8 h

Procedure:
The compound obtained in (a) was dissolved in 45 ml of THF and 1.2 ml of water and, while stirring, 11.2 g of triphenylphosphine were added in portions. The reaction mixture was left to stand at RT overnight.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[C:5]([NH2:15])[NH:4][N:3]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=O.C(O)(=[O:32])C>>[C:22]([O:21][C:19]1[N:4]2[N:3]=[C:2]([CH3:1])[C:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])=[C:5]2[N:15]=[C:17]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:18]=1)(=[O:32])[CH3:23]
Reactant: CC(=O)O
Reactant: Cc1ccccc1Cc1c(C)n[nH]c1N
Reactant: CCOC(=O)CC(=O)c1ccncc1
Product: CC(=O)Oc1cc(-c2ccncc2)nc2c(Cc3ccccc3C)c(C)nn12
Temperature: 25 °C
Yield: 69 %

Procedure:
A solution of 3-methyl-4-(2-methylbenzyl)-1H-pyrazol-5-amine (3.005 g, 14.93 mmol) and ethyl 3-oxo-3-(pyridin-4-yl)propanoate (3.17 g, 16.42 mmol) in acetic acid (50 mL) was stirred under reflux for 48 h. After cooled to room temperature, the mixture was concentrated. The residue was diluted with ethyl acetate (30 mL). The resulting precipitate was filtered, washed with ethyl acetate, dried in vacuo to give the titled product (4.02 g, 69%); LC/MS: MS (ES+) m/e 331 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.91 (s, 3H), 2.09 (s, 3H), 2.36 (s, 3H), 3.99 (s, 2H), 6.08 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 7.04-7.21 (m, 3H), 7.77 (d, J=4.8 Hz, 1H), 8.76 (d, J=4.8 Hz, 1H), 11.95 (s, 1H), 12.16 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@H]1CCCN[C@H]1c1ccccc1
Solvent: CO
Product: OC1CCCNC1c1ccccc1

Procedure:
cis-3-Hydroxy-2-phenylpiperidine (Description 3b) and (-)dibenzoyltartrate were dissolved in methanol and crystallized by addition of ethyl acetate. The solid was recrystallised from hot methanol to give the hemi dibenzoyltartrate salt, mp 223°-224° C. This was liberated from the salt as described above to give the single enantiomer (+)-cis-3-hydroxy-2-phenylpiperidine, mp 93°-95° C. [α]23D =+98.5° (c=1, MeOH). The mother liquors were converted to the free base as described in Description 3b and crystallization using (+)dibenzoyltartrate in an analogous manner to that described above gave (-)-3-hydroxy-2-phenylpiperidine, mp 93°-95° C. [α]23D =-97.2° C. (c=1, MeOH).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCOC(C)=O>CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step C (14.0 g, 59.4 mmol) in 180 mL of dimethylformamide at 0° C. was added triethylamine (26.3 mL, 190 mmol), followed by methanesulfonyl chloride (10.5 mL, 137 mmol). The reaction was stirred overnight, allowing it to warm to room temperature. The solution was poured into EtOAc, washed with saturated NH4Cl solution, saturated aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: C1CCNCC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCCCC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (100 mg) and piperidine (22.7 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (81.0 mg).
Reaction SMILES: Br[C:2]1[CH:17]=[C:16]([S:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1.C[C:27]12CC3(C)P(C4C=CC=CC=4)[C:33](C)([CH2:35][C:29]([CH3:45])(O3)O1)[O:34]2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:27][O:34][C:33]1[N:11]=[CH:8][CH:7]=[C:29]2[C:45]([C:2]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=3[O:4][C@H:5]3[CH2:10][CH2:9][C@H:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]3)=[CH:22][N:21]([CH3:25])[C:35]=12
Reactant: CN(C)[C@H]1CC[C@H](Oc2ccc(S(=O)(=O)N3CCCC3)cc2Br)CC1
Reactant: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1nccc2c(-c3cc(S(=O)(=O)N4CCCC4)ccc3O[C@H]3CC[C@H](N(C)C)CC3)cn(C)c12
Temperature: 100 °C

Procedure:
A mixture of Example 144B (60 mg, 0.14 mmol) and Example 59A (40.1 mg, 0.14 mmol) was degassed under argon. To this mixture was added dioxane (8 mL) followed by degassing with argon. To this mixture was added potassium phosphate, dibasic (109 mg, 0.626 mmol) and water (2.000 mL) followed by degassing with argon. To this mixture was added 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (6.91 mg, 0.024 mmol) and then immediately tris(dibenzylideneacetone)dipalladium (0) (8.92 mg, 9.74 μmol) followed by degassing with argon. The reaction mixture was heated at 100° C. for 1 hour. The mixture was cooled to ambient temperature and partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound (0.042 g, 59% yield)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20](CCO)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:26](O)[CH3:27]>O>[Cl:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:26][CH2:27][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: CCO
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCC1CCN(c2ccc(Cl)nn2)CC1
Solvent: O
Product: O=Cc1ccc(OCCC2CCCCN2c2ccc(Cl)nn2)cc1
Temperature: 25 °C

Procedure:
4- {2-[1-(6-Chloro-3-pyridazinyl)piperidinyl]ethoxy}benzaldehyde (Intermediate IIa) was prepared from 4-hydroxybenzaldehyde and 2-[1-(6-Chloro-3-pyridazinyl)-4-piperidinyl]ethanol using a Mitsunobu Reaction and following the general methods described in U.S. Pat. No. 4,992,433. The aldehyde (60 mg, 0.17 mmol) was dissolved in ethanol (5 ml) with stirring at room temperature and a solution of ethoxyanine in water (0.5 ml, 50% EtONH2) was added. The reaction was stirred at room temperature for 2 days and then concentrated on a rotary evaporator and the residue was purified by chromatography (silica gel 18g) using chloroform as eluent. The first compound to elute was the O-ethyloxime (1) which was obtained as a pale cream solid (30mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.ClC1C=C(C=CC=1)C(OO)=[O:37]>>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:37])=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCCc1nc2c(C)cc[n+]([O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 42.8 %

Procedure:
A solution of 7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (9 mg) and m-chloroperoxybenzoic acid (6 mg) CHCl3 (2 mL) was heated to reflux for 2 hours. Concentration and purification (SiO2, 80:20:1 CH2Cl2 /MeOH/NH4OH) gave 4 mg of the title compound as a solid. 1H NMR (300 MHz, CD3OD) δ 8.07 (d, 1H, J=6 Hz), 7.60-7.43 (m, 4H), 7.19, (d, 1 H, J=6 Hz), 7.09 (s, 4H), 6.14 (s, 2H), 2.82 (t, 2H, J=7.5 Hz), 2.63 (s, 3H), 1.81-1.67 (m, 2H), 0.98 (t, 3H, J=7.5 Hz).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.N[N:14]1[CH:18]=[N:17][N:16]=[CH:15]1>C1(C)C(C)=CC=CC=1>[S:9]1[CH:10]=[CH:11][C:7]([C:5]2[C:18]3[N:14]([CH:15]=[N:16][N:17]=3)[N:2]=[CH:3][CH:4]=2)=[CH:8]1
Reactant: Nn1cnnc1
Reactant: CN(C)C=CC(=O)c1ccsc1
Solvent: Cc1ccccc1C
Product: c1cc(-c2ccsc2)c2nncn2n1

Procedure:
As for Example 16, a mixture of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one, 4-amino-1,2,4-triazole and xylene is refluxed for 16 hours to give the product of the Example.
Reaction SMILES: C1COCC1.CO.O[Li].O.C[O:12][C:13]([C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:37])[NH:35][CH3:36])[C:29]([CH3:38])=[CH:28]3)[CH:16]=1)=[O:14]>O>[CH3:38][C:29]1[N:30]([C:34](=[O:37])[NH:35][CH3:36])[C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:24][C:21]1[CH:20]=[CH:19][N:18]=[C:17]3[CH:16]=[C:15]([C:13]([OH:14])=[O:12])[S:23][C:22]=13)=[CH:33][CH:32]=2
Reactant: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)OC)sc34)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)O)sc34)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A solution of THF (5 mL), MeOH (1 mL) and H2O (1 mL) was used to dissolve LiOH.H2O (0.042 g, 1.0 mmol) and then added 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (0.35 g, 0.89 mmol) added. The solution was stirred at 25° C. for 2 h, quenched with several drops of 1N HCl then concentrated. The precipitate was rinsed with H2O (2×5 mL) and Et2O (2×5 mL), dried under high vacuum for 2 h and used as is to afford 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (0.25 g, 73%) as yellow solid. HPLC: Rt 3.43 min. (95% area). LCMS (ACPI) M+H+ m/z: 382.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:7]=2[CH2:6]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH:4]=[C:5]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[O:9][C:8]4[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:7]=4[CH2:6]3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1cccc2c1CC(=CCCBr)c1cccnc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution the product of step 2 (1.1 g) in DMF (15 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g) and potassium carbonate (0.53 g) and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (0.86 g) and minor one (0.05 g). Major isomer
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C@H:9]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][C:20](=[O:22])[N:19](CC3C=CC(OC)=CC=3)[S:18]2(=[O:33])=[O:32])[CH:12]=1)=[O:7])(=[O:3])[CH3:2].C([SiH](C)C)(C)(C)C>C(O)(C(F)(F)F)=O.CC#N.O>[C:1]([NH:4][C@@H:5]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:6]([NH:8][C@H:9]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][C:20](=[O:22])[NH:19][S:18]2(=[O:33])=[O:32])[CH:12]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCNC(=O)[C@H](Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: C[SiH](C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CCCCCNC(=O)[C@H](Cc1cccc(N2CC(=O)NS2(=O)=O)c1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
A solution of the title H compound, (S)-2-acetylamino-N-((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide (124 mg, 0.183 mmol) in TFA (3 mL) containing t-butyidimethylsilane (0.091 mL, 0.548 mmol) is heated at 80° C. for 30 min, then concentrated under nitrogen stream to give an oil containing a fine dark suspension. The product is taken up in 60% MeCN in water and water (1 mL) is added. The mixture filtered through a 0.1 micron Acrodisc filter and the filtrate is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in five aliquots and eluted at 30 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac to yield (S)-2-acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide as a white foam: [M+1]+=558.