Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (50 mg, 0.20 mmol), was dissolved in DMF (2 mL), 5-(pyrazin-2-yl)pyridin-2-amine (41 mg, 0.24 mmol) and DIEA (174 uL, 1.0 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 212. MS m/z 404.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.10 (s, 1H), 9.31 (d, 1H), 9.11 (dd, 1H), 8.73-8.71 (m, 1H), 8.63 (d, 1H), 8.52 (dd, 1H), 8.34 (d, 1H), 8.21 (d, 1H), 7.70-7.52 (m, 2H), 7.43-7.34 (m, 3H), 3.89 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([O:24][C:25]([N:27]([CH2:29][C:30](O)=[O:31])[CH3:28])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])[CH2:29][N:27]([C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH3:28])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)CN(C)C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (750 mg), (tert-butoxycarbonyl-methyl-amino)-acetic acid (589 mg) and HBTU (1.37 g) in dry DMF (40 ml) containing N-methylmorpholine (0.79 ml) was stirred at room temp for 18 h. The mixture was then evaporated and the residue was purified by chromatography. Elution with 4:1 petrol:ethyl acetate gave a pale brown oil (494 mg)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([CH:14]=[C:15](OCC)[NH:16][CH3:17])#[N:13]>>[C:12]([CH:14]=[C:15]([NH:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CCOC(=CC#N)NC
Reactant: Cc1nc[nH]c1CSCCN
Product: CNC(=CC#N)NCCSCc1[nH]cnc1C
Reaction time: 5 h

Procedure:
4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.5 g) was added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene (3.1 g) and the solution was stirred for 5 hours at 100°. The product was chromatographed on a column of neutral alumina with elution by chloroform/ethyl acetate (1:1) to give the title compound as a glass.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:44][C:37]1[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=1[CH2:35][O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 9.37 g (15.11 mmol) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 ml CH2Cl2 was treated at −20° C. with 34 ml TFA and warmed up to RT during 5.5 h. The reaction was evaporated and treated with aqueous sat NaHCO3 solution/EtOAc (3×) to give 7.77 g (quantitative) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, MS: 520 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>[Cu]>[CH:21]([NH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5])([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C#N)c(NC(C)C)cc1OC
Temperature: 90 °C
Reaction time: 120 h

Procedure:
A suspension of 4.52 g (25.4 mmol) 2-amino-4,5-dimethoxy-benzonitrile, 4.38 g (31.7 mmol) potassium carbonate and 100 mg copper powder in 15 ml 2-iodo-propane is stirred at 90° C. for 5 days. Extractive work-up with ethyl acetate/water and concentration i.V. affords a dark oil, which is purified by flash chromatography (ethyl acetate/hexane). yield: 4.15 g (74%) yellow oil.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.[C:10]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:17]([O:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:17]([O:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:2][CH3:1])=[O:26])=[CH:23][CH:22]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(C(=O)OCc2ccc(C(=O)Cl)cc2)cc1C(C)(C)C
Reactant: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 ml of methanol, 460 μl of triethylamine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 1.2 g (3.3 mmol) of 4-(3-tert-butyl-4-methoxybenzoyloxymethyl)benzoyl chloride dissolved in 30 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[NH:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[NH:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=1[C:7]([NH:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Yield: 103.6 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.85 g, 17.6 mmol) 2-(2,4,5-trifluoro-anilino)-4,5-difluorobenzoic acid (Example T, 4.54 g, 14.7 mmol), O-benzylhydroxylamine hydrochloride (2.34 g, 14.7 mmol), and triethylamine (2.45 mL, 17.6 mmol) provided 6.22 g of the crude title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]2[C:17](=[O:21])[O:18][CH2:19][CH2:20][C:11]3=2)[CH2:4][O:3]1.CS(O)(=O)=O.[CH3:27][OH:28]>>[CH3:27][O:28][C:17]([C:12]1[NH:13][C:14]2[C:10]([C:11]=1[CH2:20][CH2:19][OH:18])=[CH:9][C:8]([CH2:7][C@H:5]1[CH2:4][O:3][C:2](=[O:1])[NH:6]1)=[CH:16][CH:15]=2)=[O:21]
Reactant: CO
Reactant: O=C1N[C@@H](Cc2ccc3[nH]c4c(c3c2)CCOC4=O)CO1
Agent: CS(=O)(=O)O
Product: COC(=O)c1[nH]c2ccc(C[C@H]3COC(=O)N3)cc2c1CCO
Reaction time: 3 h
Yield: 93 %

Procedure:
To a suspension of 500 mg (1.74 mmoles) of the (S)-6-(2-oxo-1,3-oxazolidin-4-ylmethyl)-4,9-dihydro-3H-pyrano-[3,4-b]indol-1-one in 10 ml of methanol were added 0.12 ml (1.9 mmoles) of methanesulphonic acid. The mixture was left under stirring at the reflux temperature for 3 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 10 ml of a saturated bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried and evaporated to dryness and the evaporated solid recrystallised from ethanol to give 517 mg (93%) of the title ester as a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([NH:22][C:23]([N:13]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[C:9]([C:16]#[N:17])=[C:10]([CH3:15])[NH:11][C:12]1=[O:14])=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine (2.92 g, 10 mmol) in THF (30 mL) was added 95% sodium hydride (0.30 g, 12 mmol). After gas evolution ceased, ethyl isocyanate (0.44 mL, 12 mmol) was added via syringe. The reaction mixture was stirred for 0.5 h, quenched with water and extracted twice with EtOAc. The combined extracts were washed with 0.5 N aqueous NaOH, with water and with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (25% to 35% EtOAc/hexane) to give, after evaporation of solvent, 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl amide as a colorless solid (2.91 g; 80%): 1H NMR (CDCl3, 400 MHz) δ 8.65 (t, 3H, J=5.3 Hz), 7.91 (s, 1H), 7.39 (m, 1H), 7.35 (m, 1H), 7.21 (m, 1H), 7.15 (d, 1H, J=7.9 Hz), 6.24 (s, 1H), 3.25 (m, 2H), 2.10 (s, 3H), 1.10 (t, 3H, J=7.0 Hz); LC/MS (ES+) 363 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[Cl:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0322 g, 0.0698 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.0305 mL, 0.195 mmol) to obtain 4-(3,4-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0132 g, yield 28%).
Reaction SMILES: CO[CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>[Cl-].[Cl-].[Zn+2]>[C:5]1(=[O:6])[C:7]2[C:16]3=[C:16]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:14][CH:13]=[C:12]4[CH:14]=[CH:13][C:12]3=[CH:3][CH2:4]1
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1CC=c2ccc3cccc4ccc1c2c43

Procedure:
To the 7,24-bis-OSiMe3-protected 1″,2″-dihydro-3″-aldehyde (1″,2″-dihydro-Intermediate II, 30 mg) in THF (0.8 μL) at rt was added 1-methoxy-3-trimethylsilyloxy-butadiene (50 μL) followed by ZnCl2 (80 μL, 1M solution in Et2O) After 2 h at rt and 12 h at 0° C., bis-protected Diels-Alder adducts were obtained without workup by PTLC on silica gel (1×1000 μm plate) using 2/8 acetone/hexanes as eluant. The pure products (7 mg methoxy-substituted pyranone and 10 mg pyrenone) thus obtained were characterized by 1H NMR. Both products were deprotected separately as described previously (10 mg pyrenone yielded 9 mg deprotected product and 7 mg methoxypyranone yielded 6 mg deprotected product). The deprotected products were characterized by 1H NMR.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cncc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.5 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 3-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (95.0 mg, 49.5% yield) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#CC=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To a solution of 3-(4-(4-fluorophenoxyl)phenyl)acrylonitrile (5 g, 20.90 mmol) in ethanol (80 mL) was added NaBH4 (5.44 g, 144 mmol). The mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water (50 mL), and ethanol was removed under reduced pressure. The residue was partitioned between EA (100 mL) and water (50 mL). The organic phase was washed with saturated NaHCO3 solution (80 mL), brine (50 mL), dried over sodium sulfate, concentrated, and purified via flash chromatography to afford the title compound (4.7 g, 16.48 mmol, 79% yield) as a white solid. LCMS: rt=1.55 min, [M+H+]=242
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36]([O:40][C:41](=[O:44])[CH:42]=[CH2:43])([CH3:39])([CH3:38])[CH3:37]>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: c1ccc(Cc2ccc3oc(-c4ccc5c(c4)CCNC5)cc3c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Reaction time: 0.5 h

Procedure:
6-(5-benzylbenzofuran-2-yl)-1,2,3,4-tetrahydroisoquinoline (67 mg, 0.2 mmol) was dissolved in methanol (2 ml). DIEA (0.35 ml) and acrylic acid tert-butyl ester (51 mg, 0.4 mmol) were added. The mixture was headed to 90° C. for 30 minutes using microwave irradiation. All the solvents was evaporated and the crude product of tert-butyl 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate was used in the next step without further purification. MS (ESI) m/z: Calculated: 467.25; Observed: 468.30 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.S(=O)(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([I:18])=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (600 mg, 2.56 mmol, the product of 8th step for example 1-1) in chloroform (260 mL) was added N-iodosuccinimide (577 mg, 2.56 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The resulting mixture was diluted with 10% aqueous solution of sodium bisulfate (100 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (elution with 15% ethyl acetate in petroleum ether) to afford (6-fluoro-4-hydroxy-3-iodo-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 54%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:16][OH:17]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][OH:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde (3.0 g, 16.2 mmol) in ethanol (100 mL) and water (25 mL) was added sodium acetate (1.7 g, 21.0 mmol) and hydroxylamine hydrochloride (1.4 g, 19.5 mmol). The resulting mixture was heated to reflux for 2 hours. The solution was allowed to cool to room temperature, concentrated, and filtered to give 4-bromobenzaldehyde oxime (3.02 g, 93%). 4-Bromobenzaldehyde oxime (0.25 g, 1.25 mmol) was added to a stirred solution of 3-cyanophenyl boronic acid (0.28 g, 1.87 mmol) in glyme (13 mL). Sodium carbonate (0.39 g, 3.75 mmol) in water (2 mL) and tetrakis(triphenylphosphine) palladium (0) (0.07 g, 0.06 mmol) was added and the resulting solution was heated to reflux for 3 hours. The solution was cooled to room temperature and partitioned between a saturated ammonium chloride solution (100 mL) and ethyl acetate (150 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrile as a white solid (0.17 g, 61%). MS m/z 223; HRMS: calcd for C14H10N2O+H+, 223.08659; found (ESI, [M+H]+), 223.087; Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.49; H, 4.98; N, 12.51.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:50])([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=[N:27][N:26]=3)=[CH:17][C:16]=2[Cl:49])[CH3:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:50])([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:17][C:16]=2[Cl:49])[CH3:14])[C:9]([F:11])([F:10])[F:12])[CH:5]=[CH:4][N:3]=1
Reactant: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccc(OCCCc2nnn[nH]2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reaction time: 48 h
Yield: 86.8 %

Procedure:
2-(2-Chloro-pyridin-4-yl)-3-{2-chloro-4-[3-(1-trityl-(1H )-tetrazol-5-yl)-propoxy]-phenyl}-1,1,1-trifluoro-butan-2-ol (80 mg, from previous step) was dissolved in CH2Cl2 (2.5 mL). To the solution was added trifluoroacetic acid (1.25 mL) at RT and the mixture was allowed to stir for 48 hours; almost complete conversion was observed. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate and water. The layers were separated and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the desired compounds as a white solid (46 mg). MS (m/e)=476.1 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][CH2:22][CH2:23]CN2CCCC2=O)=[O:20])=[C:13]([Cl:31])[C:12]=1[Cl:32])([CH3:3])[CH3:2].[OH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]1CCN[CH2:41][CH2:40]1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:39]([CH2:38][CH2:37][O:36][CH2:35][CH2:34][OH:33])[CH2:40][CH2:41]2)=[O:20])=[C:13]([Cl:31])[C:12]=1[Cl:32])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)NCCCN2CCCC2=O)c(Cl)c1Cl
Reactant: OCCOCCN1CCNCC1
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)N2CCN(CCOCCO)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared from the cinnamide acid of Example 331, using the procedures described in Example 340 and substituting methyl isonipecotate with N-[2-(2-hydroxyethoxy)ethyl]piperazine. 1H NMR (300 MHz, DMSO-d6) δ 1.18 (d, 6H), 3.0 (m, 3H), 3.30 (m, 2H), 3.50 (m, 10H), 3.80 (m, 2H), 4.50 (t, 1H), 6.45 (d, 1H), 7.30 (d, 1H), 7.35 (dd, 1H), 7.55 (d, 1H), 7.60 (m, 2H), 7.75 (d, 1H), 7.80 (d, 1H). MS (ESI+) m/z 523 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([NH:34][C@@H:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:33])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: CC(C(=O)O)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)N[C@H](C)c1cccc2ccccc12)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100.0 mg (0.325 mmol) of 2-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionic acid from Example 105A are placed in 2 ml of DMF and treated with 61.2 mg (0.357 mmol) of (1R)-1-(1-naphthyl)ethanamine, 52.7 mg (0.390 mmol) of HOBt and 81.0 mg (0.422 mmol) of EDC hydrochloride. The mixture is stirred overnight at room temperature, then partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromato-graphy on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) and then further separated by preparative HPLC on chiral phase [Method 16]. 58 mg (39% of theory) of the diastereomerically pure target compound are thus obtained (see also Example 188).