Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C@:6]1([CH3:28])[C:10](=[O:11])[O:9][C@@H](C2C=CC=CC=2)[N:7]1C(OCC1C=CC=CC=1)=O.C[Si](C)(C)[O-].[K+].CO>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C@:6]([CH3:28])([C:10]([OH:11])=[O:9])[NH2:7]
Reactant: C[C@@]1(Cc2cccc(I)c2)C(=O)O[C@@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@](N)(Cc1cccc(I)c1)C(=O)O
Temperature: 75 °C
Yield: 107 %

Procedure:
A mixture of benzyl (2S,4R)-4-(3-iodobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate (1.47 g) and potassium trimethylsilanolate (1.2 g) was suspended in THF (50 ml) and heated to 75° C. for 2.5 h. MeOH (10 ml) was added and the solvents were removed under reduced pressure. The residue was dissolved in MeOH and applied to two 10 g SCX-2 cartridges eluting with MeOH and then with 0.2M ammonia in MeOH. The ammoniacal solutions were evaporated to dryness to give the title compound (910 mg) LCMS RT=1.93 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41]([OH:43])=O)=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C.[F:57][C:58]1[CH:63]=[CH:62][C:61]([C@H:64]([NH2:66])[CH3:65])=[CH:60][CH:59]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:41]([NH:66][C@@H:64]([C:61]2[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=2)[CH3:65])=[O:43])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)N[C@H](C)c4ccc(F)cc4)n3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (110 mg, 0.18 mmol) was suspended in THF (2 ml), cooled to 0° C., then 4-methylmorpholine (55.3 mg, 0.55 mmol) and ethylchloroformate (27.7 mg, 0.26 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h, then (R)-1-(4-fluorophenyl)ethylamine was added. The reaction was warmed to RT and stirred for 1 h, then concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-5% MeOH/DCM) to provide (R)-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-(1-(4-fluorophenyl)ethyl)picolinamide (100 mg, yield: 76%). MS (M+H)+: 724.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:25][C:24]([CH:31]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:25][C:24]([CH2:31][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: Cc1cccc(N2CCN(CCNCc3cc(CC(C)C)n(C(C)(C)C)n3)CC2)c1C
Yield: 90.8 %

Procedure:
Compound 17 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6](/[CH:8]=[N:9]/[C:10]([CH3:13])([CH3:12])C)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21]C(C#C)=[CH:19][CH:18]=1)#[N:16].C(NC(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:13]=[C:10]([C:12]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)/N=C/c1cc(Br)ccc1I
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2cc3ccc(Br)cc3cn2)cc1

Procedure:
The product from Example 62D (3.6 mmol), 4-cyanophenylacetylene (4.3 mmol), CuI (0.2 mmol), PdCl2(PPh3)2 (0.1 mmol), and diisopropylamine (5.3 mmol) can be combined in toluene (15 mL) and processed as described in Example 62E to provide the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A solution of 4-mercaptophenol in dry acetone was treated successively with excess of potassium carbonate and ethyl bromoacetate. The reaction mixture was refluxed overnight. After allowing the reaction mixture to cool to rt, it was filtered through celite and washed with acetone. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated in-vacuo. The residue was purified by flash chromatography (silica, hexanes:ether, 3:1 to 1:1) to provide the desired thioether.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C(#N)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:42])[F:43])=[CH:38][CH:37]=2)=[O:41])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in acetonitrile (10 ml) were added triethylamine (0.089 ml, 0.64 mmol) and 4-trifluoromethylphenyl isocyanate (0.061 ml, 0.43 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (139 mg, 65%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: OC(c1cccc(-c2ccccn2)c1)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cccc(Cc3ncc[nH]3)c2)nc1

Procedure:
2-[3-(1H-Imidazol-2-ylmethyl)-phenyl]-pyridine was prepared from rac-(1H-imidazol-2-yl)-(3-pyridin-2-yl-phenyl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 236.3 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@:9]([O:36][C:37]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[S:39][CH:38]=2)([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])(=[O:26])=[O:25])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][CH2:6][N:5]1[C:46](=[O:57])[C:47]1[C:52]([C:53]([F:56])([F:55])[F:54])=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:2][CH3:3]>O.C(#N)C>[CH2:1]([C@@H:4]1[C@:9]([O:36][C:37]2[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[S:39][CH:38]=2)([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:25])=[O:26])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][CH2:6][N:5]1[C:46](=[O:57])[C:47]1[C:52]([C:53]([F:54])([F:56])[F:55])=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(c2ccccc2S(=O)(=O)NCCCC(=O)OCC)CC1
Solvent: CC#N
Solvent: O
Product: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(c2ccccc2S(=O)(=O)NCCCC(=O)O)CC1

Procedure:
In an analogous procedure to representative example 65 step 2, ethyl 4-(2-(1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)phenylsulfonamido)butanoate was saponified to provide A58 as a white solid after lyophilization from water/acetonitrile: 1H NMR (300 MHz, CDCl3 8.80 (d, J=4.4 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.98-7.84 (m, 1H), 7.60-7.30 (m, 4H), 6.99 (d, J=7.8 Hz, 1H), 6.72-6.50 (m, 1H), 5.61-5.30 (m, 4H), 3.90-3.67 (m, 1H), 3.43-0.70 (m, 25H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:22])[C:20]=1[OH:21])[CH:16]=O>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:16][C:15]3[CH:14]=[C:13]([Cl:12])[C:20]([OH:21])=[C:19]([Cl:22])[CH:18]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C1Cc2ccc(Br)cc2N1
Product: O=C1Nc2cc(Br)ccc2C1=Cc1cc(Cl)c(O)c(Cl)c1

Procedure:
The title compound is synthesized in an identical manner to example 2 except 6-bromo-oxindole was used in place of 5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride and 3,5-dichloro-4-hydroxy-benzaldehyde was used in place of 3,5-dibromo-4a-hydroxy-benzaldehyde. 1H NMR (DMSO-d6) δ7.05 (s, 1H); 7.12 (d, 1H); 7.43 (d, 1H); 7.56 (s, 1H); 7.76 (s, 2H); 10.78 (bs, 1H); 10.91 (bs, 1H). Electrospray MS (−ve) 384.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27](OC)=[O:28])[CH2:24][CH2:25]2.N12CCN(CC1)CC2.C1(C)C=CC=CC=1>CO>[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:28])[CH2:24][CH2:25]2
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)C1CCC2OC2C1
Agent: C1CN2CCN1CC2
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)C1CCC2OC2C1
Yield: 90.4 %

Procedure:
To a 3-neck 100 mL flask equipped with an argon inlet, stir bar and distillation apparatus was added 1-octadecanol (5.03 g, 19 mmol, obtained from Sigma-Aldrich), methyl 3,4-epoxycyclohexanecarboxylate (ERL-4140, 8.69 g, 56 mmol, obtained from Dow Chemical Company), 1,4-diazabicyclo[2.2.2]octane (DABCO™, 1.02 g, 9.1 mmol, obtained from Sigma-Aldrich) and toluene (15 mL). The reaction mixture was refluxed until methanol ceased collecting in the receiving flask and the completion of the reaction was confirmed by 1H NMR spectroscopy. The still pot from the distillation was diluted with toluene (15 mL) and washed with brine (3×15 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed in vacuo. The excess methyl 3,4-epoxycyclohexane carboxylate was removed via Kugelrohr distillation under reduced vacuum to give 6.78 g (87%) of a white solid (mp=32-34° C.) of octadecyl 3,4-epoxycyclohexanecarboxylate. 1H NMR (CDCl3, δ): 4.06 (td, J=6.7, 1.9 Hz, 2H), 3.25-3.14 (m, 2H), 2.55-2.45 (m, 1H), 2.31-1.26 (m, 38H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:15][Cl:16])[CH2:7][N:8]2[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([BH3-])#N.Cl>C1C=CC=CC=1>[Cl:16][CH2:15][CH:6]1[C:5]2[C:9](=[CH:10][C:2]([NH:1][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:8]([S:11]([CH3:14])(=[O:12])=[O:13])[CH2:7]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)N1CC(CCl)c2ccc(N)cc21
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Agent: [BH3-]C#N
Solvent: c1ccccc1
Solvent: O
Product: CS(=O)(=O)N1CC(CCl)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc21
Reaction time: 0.67 h
Yield: 87 %

Procedure:
A mixture of 6-amino-3-(chloromethyl)-1-(methanesulfonyl)indoline (29) [Tercel, M., Denny, W. A. and Wilson, W. R., Bioorg. Med. Chem. Lett., 1996, in press] (73 mg, 0.28 mmol), 4-nitrobenzaldehyde (51 mg, 0.34 mmol) and toluenesulfonic acid monohydrate (5 mg, 0.3 mmol) in benzene (30 mL) was heated to reflux and most of the benzene slowly distilled off over 40 min. The remaining orange-brown solution was cyanoborohydride (35 mg, 0.56 mmol) then 2N HCl (0.5 mL) were added and the mixture was stirred at 20 C for 40 min, then evaporated. The residue was diluted with water, extracted with EtOAc (×2), and the extracts dried (Na2SO4) and evaporated. Dry column chromatography, eluting with EtOAc/petroleum ether (1:2), gave 3-(chloromethyl)-1-(methanesulfonyl)-6-[(4-nitrobenzyl)amino]indoline (30) as a yellow oil (96 mg, 87%). 1H NMR (CDCl3) a 8.19 (d, J=8.8 Hz, 2 H, ArH o to NO2), 7.52 (d, J=8.8 Hz, 2 H, ArH m to NO2), 7.00 (d, J=8.2 Hz, 1 H, H-4), 6.73 (d, J=2.2 Hz, 1 H, H-7), 6.22 (dd, J=8.2, 2.2 Hz, 1 H, H-5), 4.47 (s, 2 H, NCH2Ar), 4.03 (dd, J=10.8, 8.8 Hz, 1 H, CHHN), 3.92 (dd, J=10.8, 4.6 Hz, 1 H, CHHN), 3.69 (dd, J=10.4, 4.1 Hz, 1 H, CHHCl), 3.67-3.60 (m, 1 H, H-3), 3.53 (dd, J=10.4, 7.9 Hz, 1 H, CHHCl), 2.83 (s, 3 H, NSO2CH3). 13C NMR a 148.7, 147.2, 146.8, 143.4, 119.9 (C-6,8,9,1,4), 127.8, 123.9 (C-2 and 6, 3 and 5), 125.7, 107.9, 98.6 (C-4,5,7), 54.6 (C-2), 47.5, 46.8 (CH2Cl, NCH2Ar), 41.9 (C-3), 34.5 (SO2CH3). MS (DEI, 35Cl) m/z 395 (35%, M+), 346 (100%, M-CH2Cl); HRMS calcd. for C17H18ClN3O4S 395.07066, found 395.06880.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH:17]([NH:33]C(OC(C)(C)C)=O)[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH:17]([NH2:33])[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
4N HCl-dioxane (5 ml) was added to a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (100 mg) in ethanol (5 ml ), the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 78 mg of the titled compound (Yield: 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:6]1[C:5]([CH2:3][OH:2])=[CH:9][C:8]([C:10]([F:13])([F:11])[F:12])=[N:7]1
Reactant: COC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Into a 500 mL flask was weighed 3.84 g (12.6 mmol) of 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid methyl ester and 50 mL of anhydrous THF. The solution was cooled to approximately −10° C. in an ice-methanol bath and 1.0 M DIBAL-H in THF was added (50 mL). The reaction was allowed to warm to room temperature over 30 minutes and remained at room temperature for another 1 h. The reaction was concentrated in vacuo to remove THF then was washed into a separatory funnel with ethyl acetate and saturated sodium potassium tartrate. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude [2-(2-chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-methanol was recovered as a colorless oil, yield: 3.54 g; 1H NMR (400 MHz, CDCl3): δ 7.33-7.50 (m, 4H), 6.64 (s, 1H), 4.45 (s, 2H); MS (ES): 277 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cccc(N)c2)cc1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
In 100 ml of tetrahydrofuran was dissolved 2.70 g of methyl 3'-nitro-biphenyl-4-carboxylate obtained in Reference Example 8. To the solution was added 1.0 g of 10% palladium-on-carbon and the mixture was subjected to catalytic reduction for 2 hours. After removing the catalyst by filtration, the solvent was removed under reduced pressure to obtain 2.34 g of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:35])=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:35])=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Br)cc(Br)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Br)cc(Br)c3)cc2)cc1)C(=O)O
Yield: 87.1 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 123) (110 mg, 0.18 mmol) and sodium hydroxide (1M, 1.0 ml, 1.0 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (90 mg, 86%) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[N:11]([OH:18])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[N:11]([O:18][CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)[C@@H]1COC(N)=O
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1COC(N)=O

Procedure:
In 40 ml of acetonitrile is dissolved 650 mg of (3S,4S)3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-1-hydroxy-2-azetidinone, and 0.39 ml of triethylamine and 712 mg of p-nitrobenzyl bromoacetate are added to the solution under ice-cooling with stirring. The reaction solution is stirred at room temperature (15°-25° C.) for 3.5 hours. The solvent is distilled off under reduced pressure, and 50 ml of a mixed solution (1:1) of ethyl acetate and tetrahydrofuran and 50 ml of water are added to the residue. The organic layer is separated, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The remaining crystals are treated with 15 ml of a mixed solution (1:2) of ether and hexane and filtered to give 98 mg (88.6%) of the above-identified comoound as crystals, m.p. 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=[O:24]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[O:24])[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(O)c1ccccn1
Product: NC(=O)c1c(NC(=O)c2ccccn2)ncn1Cc1ccccc1
Yield: 87 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.0 g (4.6 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and picolinic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.29 g of 1-benzyl-4-(2-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:41])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:33][O:34]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:41])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:33][OH:34])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1ccc(C#N)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1ccc(C#N)s1
Yield: 101.3 %

Procedure:
A solution of 170 mg of N-(4-chlorobenzyl)-2-{[[2-(5-cyanothien-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 4 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 5% MeOH in CH2Cl2 provides 146 mg of the title compound as a white solid. Recrystallization from acetonitrile affords white needles.