Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:11])[C:8]=1[C:9]#[N:10].CCO[CH2:15][CH3:16]>[N+](C1C=CC=CC=1)([O-])=O.C1(=O)CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:8]=1[C:9]([NH2:10])=[C:15]1[C:16]([CH2:4][CH2:3][CH2:8][CH2:7]1)=[N:11]2
Reactant: CCOCC
Reactant: COc1cccc(N)c1C#N
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=C1CCCCC1
Product: COc1cccc2nc3c(c(N)c12)CCCC3
Temperature: 125 °C

Procedure:
6-Methoxyanthranilonitrile (14.0 g) was dissolved in nitrobenzene (150 ml) and cyclohexanone (18.45 g), and freshly fused zinc chloride (25.6 g) was added. The reaction mixture was warmed at 125° C. for 1.5 hr, cooled to room temperature, and poured into ether (1 l). The solid was collected, washed with ether, and distributed between 2-butanone and ammonium hydroxide. The organic phase was washed with brine, dried, filtered, and evaporated. The residue was recrystallized two times from ethyl acetate to give 13.7 g (63.8%), mp 187°-188° C.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:46])([F:45])[CH2:6][CH2:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:37](=[O:38])[CH2:36][O:35][C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:33]2)=[CH:27][CH:26]=1)[C:9]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH:15]([C:21]([O:23]C)=[O:22])[CH2:16]2)=[O:10].Cl>C1COCC1.O>[F:46][C:5]([F:4])([F:45])[CH2:6][CH2:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:37](=[O:38])[CH2:36][O:35][C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:33]2)=[CH:27][CH:26]=1)[C:9]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH:15]([C:21]([OH:23])=[O:22])[CH2:16]2)=[O:10]
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(CCC(F)(F)F)c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)c2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1Cc2cccc(NC(=O)C(CCC(F)(F)F)c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32 mg (0.76 mmol) of lithium hydroxide monohydrate were added to a solution of 112 mg (0.19 mmol) of methyl 4-[(5,5,5-trifluoro-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}pentanoyl)amino]-2,3-dihydro-1H-indene-2-carboxylate (Example 143A) in 2 ml of THF and 1 ml of water, and the mixture was stirred at room temperature overnight. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue obtained was purified by preparative HPLC. This gave 74 mg (0.13 mmol, 68% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](F)[C:12]([Cl:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([OH:27])[CH:21]=[N:22][C:23]=1[CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:14]=[C:13]([O:27][C:20]2[CH:21]=[N:22][C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:18]([Cl:17])[CH:19]=2)[C:12]([Cl:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1Cl
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
tert-Butyl 2,5-dichloro-4-fluorobenzoate (Preparation 218, 251 mg, 0.61 mmol) was added to a solution of 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 69, 161 mg, 0.61 mmol) and potassium carbonate (393 mg, 1.82 mmol) in dimethylsulfoxide (5 mL). The reaction mixture was stirred at room temperature for 18 hours then diluted with sodium hydroxide (1M, 5 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with heptane:dichloromethane (from 95:5 to 60:40) to afford the title compound as a colourless oil (116 mg, 30%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.O.[C:20](=O)(O)[O-].[Na+]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C@@H:5]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3][C:2](=[O:1])[CH3:20])[CH3:18]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (7.00 g, 27.4 mmol) in tetrahydrofuran (100 mL) was added methyl Grignard reagent (3M in diethyl ether, 9.60 mL, 28.8 mmol) dropwise for 20 minutes at −78° C., and stirred for 1 hour. After stiffing for 2 hours at 0° C., to the mixture was added saturated sodium bicarbonate water dropwise, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (7.60 g, 26.5 mmol, 97%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][C:23](O)=[O:24])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][OH:24])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A mixture of 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid (140 mg, 0.414 mmol) and LAH (0.414 mL, 0.414 mmol) in THF (5 mL) was stirred at 0° C. for 2 h. The reaction was quenched with water (1 mL) dropwise and then stirred at rt for 10 min. The mixture was diluted with EtOAc (5 mL) and filtered. The filtrate was washed with water, dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (64 mg, 48% yield) as a clear oil. LCMS, [M+Na]+=347.1. 1H NMR (500 MHz, CDCl3) δ 7.29-7.16 (m, 3H), 7.10-6.96 (m, 3H), 6.96-6.87 (m, 2H), 6.76 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 3.77 (s, 2H), 3.62 (t, J=7.3 Hz, 2H), 2.07-1.88 (m, 4H), 1.73-1.57 (m, 4H), 1.38 (t, J=7.3 Hz, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]([CH2:21][CH2:22][OH:23])([CH2:19]O)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)NC(=O)CC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:1]1([NH:7][C:8]2[C:9]3[CH:26]=[N:25][N:24]([CH2:27][CH3:28])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:21][CH2:22][O:23][CH2:19]3)[O:16][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CCO)C3)cnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C1CCC(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCOC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
2-{3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl}ethanol (150 mg, 0.00038 mole) (example 11), triphenylphosphine (132 mg, 0.00050 mole) and succinimide (42 mg, 0.00042 mole) were taken in dry tetrahydrofuran. Diisopropyl azodicarboxylate (0.115 ml, 0.00058 mole) was added dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1.[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH2:28].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1c2ccc(Cl)cc2CCc2c(OC3CCOCC3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2c(OC3CCOCC3)cccc21

Procedure:
For the synthesis of the title compound, 0.45 g (0.0013 mol) of 8-chloro-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.17 g (0.0013 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)2, 0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O. Purification is carried out by column chromatography (flash; SiO2; hexane 70%/ethyl acetate 30%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
20 g of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) of example 3 were dissolved in 200 ml tetrahydrofuran. The mixture was cooled to about −78° C. and 55 ml n-butyllithium (1.6 M) were added. After about 0.5 hours, 11.8 ml of pivaloyl chloride were added. After 1 hour, the mixture was quenched with 210 ml ammonium chloride solution and extracted with 70 ml ethyl acetate. The mixture was concentrated to dryness to obtain 26/g of (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl). 1H-NMR (CDCl3): 1.40 (9H, s, C(CH3)3); 1.91 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.47 (1H, m, 3-CHH); 2.55 (1H, m, 3-CHH); 2.74 (1H, dd, 1-CHH); 3.18 (1H, dd, 1-CHH); 4.67 (1H, m, 5-CH); 7.34 (2H, m, aromatic); 7.36 (1H, m, aromatic); 7.46 (2H, m, aromatic); 7.58 (4H, m, aromatic). m/z: 336 (MH+, 100%).
Reaction SMILES: C[Al](C)C.[CH3:5][NH2:6].[OH:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][CH3:23])[CH:10]=[C:9]1[C:24]([O:26]C)=O>C1(C)C=CC=CC=1>[OH:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][CH3:23])[CH:10]=[C:9]1[C:24](=[O:26])[NH:6][CH3:5]
Reactant: CN
Reactant: COC[C@@H]1C=C(C(=O)OC)[C@H](O)CN1C(=O)OC(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CNC(=O)C1=C[C@@H](COC)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
A dry 2 necked round bottomed flask was equipped with a magnetic stirrer and it was flushed with nitrogen twice. Then trimethylaluminum (0.191 ml, 0.38 mmol) was added followed by toluene (0.5 ml). The solution was cooled down to −10° C. and methanamine (0.183 ml, 0.37 mmol) was added slowly. The reaction mixture was stirred at that temperature for 20 minutes. A solution of (2S,5S)-1-tert-butyl 4-methyl 5-hydroxy-2-(methoxymethyl)-5,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate 254, 100 mg, 0.33 mmol) in toluene (0.5 ml) was added slowly at room temperature. After stirring overnight the reaction was quenched with 1M HCl and allowed to stir for 15 minutes to complete the hydrolysis. The reaction mixture was extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (MeOH/DCM) afforded the title compound as a clear oil (53 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1cccc(NC(=O)Nc2ccc(OC)c(-c3c(Cl)cnn3C)c2)c1
Yield: 27 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Methoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 7.5 mg (27%) of Compound 30 (Note: Compound 30 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=389 (M+H37Cl, 39), 387 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.91 (s, 1H), 1H), 7.49 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.28 (s, 1H), 7.12 (t, J=2 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 6.81 (dd, J1=8 Hz, J2=4 Hz, 1H), 6.37 (dd, J1=8 Hz, J2=4 Hz, 1H), 3.63 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][O:14][C:15]1[C:16]([N+]([O-])=O)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O>CN(C=O)C>[CH3:13][O:14][C:15]1[C:16]2[S:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:18][C:17]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cccc(OC)c2s1
Temperature: 70 °C

Procedure:
550 mg (3.97 mmol) of potassium carbonate and 350 mg (3.31 mmol) of methyl mercaptoacetate are added to a solution of 600 mg (3.31 mmol) of 3-methoxy-2-nitrobenzaldehyde in 8 ml of DMF. The reaction mixture is heated at 70° C. for 4 h. After cooling, water is added. The resulting precipitate is filtered off, washed with water and dried under reduced pressure. This gives 387 mg (45.7% of theory) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1.N1CCCCC1.[OH-].[K+]>C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:27]1[C:26]2[C:30](=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[NH:29][C:28]1=[O:32])([OH:16])=[O:15]
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O
Temperature: 95 °C
Yield: 96.6 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (591 mg), 6-methoxy-2-oxindole (333 mg) and piperidine (0.1 mL) in ethanol (4 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for and additional hour. The reaction mixture was cooled and concentrated, dissolved in water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 730 mg (99%) of 4-(2-carboxyethyl)-3-methyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:34]3[CH:33]=[C:32]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:37]=[CH:36][CH:35]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(-c4ccccc4)c3)o2)c1
Temperature: 100 °C

Procedure:
Bromo-derivative (99) (70 mg, 0.19 mmol) was coupled to biphenyl-3-boronic acid (42 mg, 0.21 mmol) acid using Method E, except that the reaction was heated at 100° C. The crude product was purified by column chromatography eluting with a stepped gradient of 0-10% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH:10]([C:17]([O:19]C)=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH:10]([C:17]([OH:19])=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C(=O)OC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: C1CCOC1
Product: CCCCc1nn(C(C(=O)O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 50 %

Procedure:
The hydrolysis of 5-n-butyl-2-[α-(carbomethoxy)benzyl]-2,4-dihydro-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one using methanolic sodium hydroxide in THF was carried out as described in Example 7. After work-up, the residue was flash chromatographed over silica gel (gradient elution with 4-30% MeOH/CH2Cl2) to give the title compound in 50% yield. This material was re-acidified with 1N HCl to pH 1.5, and the compound re-isolated to give a foam, homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 510 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH2:8]C)[NH:5][C:4]=1[C:10]([OH:12])=[O:11])#[N:2].CC1NC(C=O)=C(C#N)C=1>>[C:1]([C:3]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4]=1[C:10]([OH:12])=[O:11])#[N:2]
Reactant: CCc1cc(C#N)c(C(=O)O)[nH]1
Agent: Cc1cc(C#N)c(C=O)[nH]1
Product: Cc1cc(C#N)c(C(=O)O)[nH]1

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 31 starting from 5-methyl-2-formyl-1H-pyrrole-3-carbonitrile (preparation: J. Med. Chem. 1998, 41(6) 808-820).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[S:26][C:27]([NH2:30])=[CH:28][N:29]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[S:26][C:27]([NH:30][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][N:29]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1cnc(N2CCOCC2)s1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1cnc(N2CCOCC2)s1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-thiazol-5-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-morpholin-4-yl-thiazol-5-ylamine. LCMS calcd for C18H15F3N4O3S (m/e) 424, obsd 425 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[CH2:10][C@H:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:45][C:46]1[N:50]2[C:51](=[O:60])[N:52]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[CH2:53][C:49]2=[CH:48][N:47]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[CH2:10][C@H:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([N:57]2[CH2:56][CH2:55][CH:54]([N:52]3[CH2:53][C:49]4=[CH:48][N:47]=[C:46]([CH3:45])[N:50]4[C:51]3=[O:60])[CH2:59][CH2:58]2)=[O:14])=[CH:6][CH:7]=1
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Reactant: O=C(C[C@@H](C(=O)O)C1CCCCC1)Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)[C@H](CC(=O)Nc3ccc(Cl)cc3)C3CCCCC3)CC1)C2
Yield: 29.1 %

Procedure:
To a solution of (2R)-4-((4-chlorophenyl)amino)-2-cyclohexyl-4-oxobutanoic acid (0.27 g) obtained in Example 5b) and HOBt (0.20 g) in acetonitrile (10 ml) was added WSC (0.25 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.26 g), DBU (0.27 g) and triethylamine (0.27 g) were added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=10/1), and the product was washed with ethyl acetate-hexane to obtain the title compound as colorless powder (0.13 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=1)=[O:9]
Reactant: O=C(c1ccc(O)c(-c2ccccc2)c1)c1ccccc1Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(C(=O)c3ccccc3Cl)cc2-c2ccccc2)cc1O
Yield: 68.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-chloro-phenyl)-(6-hydroxy-biphenyl-3-yl)-methanone (0.300 g, 0.972 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.436 g, 1.84 mmol) in THF. Purification by preparative HPLC (C18, eluting with CH3CN/H2O containing 0.1 % TFA), followed by crystallization from EtOAc/hexane gave 0.34 g (69%) of the title compound as a tan solid, mp 101-102° C. 1H NMR (DMSO-d6) δ 6.82 (d, 1H), 6.85 (dd, 1H), 7.14-7.16 (m, 2H), 7.27-7.33 (m, 3H), 7.52-7.54 (m, 1H), 7.58-7.65 (m, 5H), 7.71 (d, 1H), 7.81 (dd, 1H). IR (KBr) 3400, 3050, 1675, 1390 and 1190 cm-1. mass spectrum (EI) m/z 508 (M +). Anal. Calcd. for C26H17ClO7S 0.5H2O: C,60.29; H,3.50; N,0.00. Found: C,60.35; H,3.68; N,0.14.