Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.FC1C(O)=C(F)C(F)=C(F)C=1F.[ClH:25].CN(C)CCCN=C=NCC.[Br:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[ClH:25].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:42][C:41]1[CH:43]=[CH:44][C:38]([Br:37])=[CH:39][CH:40]=1)=[O:12])[CH2:2]2
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)CC1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CC1CN2CCC1CC2)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
500 mg (2.43 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid are dissolved in 10 ml of dichloromethane. At 0° C., 1.79 g (9.72 mmol) of pentafluorophenol and 699 mg (3.65 mmol) of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added. Stirring at room temperature for 14 h is followed by concentration in vacuo, dissolving of the residue in 8 ml of dimethylformamide, addition of 627 mg (3.65 mmol) of p-bromoaniline and stirring further at room temperature for 14 h. 10 ml of 10% strength sodium bicarbonate solution and 10 ml of ethyl acetate are slowly added. The resulting precipitate is filtered off with suction, and the filtrate is extracted three times with ethyl acetate. After drying over sodium sulfate, concentration results in a precipitate, which is filtered off. The solid is suspended in dioxane, mixed with 4M HCl in dioxane and stirred at room temperature for 30 minutes. Renewed filtration of the solid with suction results in 621 mg (71% of theory) of the title compound in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.C[Sn](C)(C)[C:39]1[CH:43]=[C:42]([S:44]([CH3:47])(=[O:46])=[O:45])[S:41][CH:40]=1.[F-].[Cs+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:39]1[CH:43]=[C:42]([S:44]([CH3:47])(=[O:46])=[O:45])[S:41][CH:40]=1)[CH:7]=[CH:6]2
Reactant: CS(=O)(=O)c1cc([Sn](C)(C)C)cs1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3csc(S(C)(=O)=O)c3)ccc2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
Combine palladium(II)acetate (0.043 g 0.19 mmol) and trycyclohexylphosphine (0.081 g, 0.29 mmol) in acetonitrile (15 mL) and sonicate for 10 minutes. Add [6-methoxy-1-[4-[2-(1-piperidyl)ethoxy]phenoxy]-2-naphthyl]trifluoromethanesulfonate (0.5 g, 0.95 mmol), trimethyl-(5-methylsulfonyl-3-thienyl)stannane (0.94 g, 2.9 mmol) and palladium mixture to a suspension of cesium fluoride (0.5 g, 3.3 mmol) in acetonitrile (40 mL). Warm the resulting mixture to 90° C. and stir for 18 hours. Cool the mixture to room temperature and concentrate. Partition the resulting residue between ethylacetate and saturated aqueous sodium bicarbonate. Separate the layers and wash the organic layer with saturated aqueous ammonium chloride and brine, then dry with sodium sulfate. Concentrate the resulting solution and purify by flash chromatography (0-5% methanol in dichloromethane) to obtain the title compound (0.3 g, 0.55 mmol).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)=[CH:9][C:8]=1[C:34]([F:37])([F:36])[F:35])[CH3:5]>C(O)(C)C.C1COCC1.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)=[CH:9][C:8]=1[C:34]([F:36])([F:37])[F:35])[CH3:3]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Sodium hydroxide (50 mg) was added to a solution of ethyl 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D37) (83 mg) in isopropanol (5 mL), THF (3 mL), water (1.5 mL). The reaction mixture was stirred at room temperature overnight. The organic solvents were removed. 2 M HCl was used to adjust the pH value to around 6.0. The crude product was purified by Mass Directed Auto Prep to afford 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E15) (40 mg). δH (DMSO-d6, 400 MHz): 1.41 (6H, d), 2.64 (2H, t), 3.01 (2H, t), 5.56 (1H, m), 7.22 (1H, t), 7.29 (1H, d), 7.84 (1H, d), 7.96 (1H, dd), 8.79 (1H, d), 9.36 (1H, d), 10.86 (1H, s), 12.07 (1H, br s); MS (ES): C22H19F3N4O4 requires 460; found 461.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([C:43]2([OH:47])[CH2:46][O:45][CH2:44]2)=[N:32][C:31]=1[CH3:48]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:47][C:43]1([C:33]2[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:30]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])=[C:31]([CH3:48])[N:32]=2)[CH2:44][O:45][CH2:46]1
Reactant: Cc1nc(C2(O)COC2)n(COCC[Si](C)(C)C)c1I
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C)c(-c2c(C)nc(C3(O)COC3)n2COCC[Si](C)(C)C)c1
Reaction time: 7 h
Yield: 59.8 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 282.7 mg, 1.02 mmol) in dioxane (12 mL) A solution of K3PO4 (904.9 mg, 4.26 mmol) in water (1.2 mL), 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.3, 350 mg, 0.85 mmol) and Pd(dppf)2Cl2 (62.4 mg, 0.09 mmol) were added to the reaction. The mixture was stirred for 7 h. The reaction mixture was cooled, then diluted with 60 mL of EtOAc. The solids were removed by filtration, the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (2:3) eluent to furnish 220 mg (60%) of the title compound as an orange oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl.Cl[CH2:30][C:31]1[N:32]=[CH:33][S:34][CH:35]=1>CN(C=O)C.C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:30][C:31]2[N:32]=[CH:33][S:34][CH:35]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1cscn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 74B (0.75 g, 2.31 mmol) in DMF/THF (1:4, 20 mL) were added potassium tert-butoxide (0.77 g, 6.93 mmol), tetrabutylammonium iodide (0.09, 0.23 mmol) and the commercially available HCl salt of 4-(chloromethyl)thiazole (TCI-US, 0.59 g, 3.46 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled, diluted with ethyl acetate (20 mL) and quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (1×25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.32 (s, 9H), 3.76 (s, 3H), 5.49 (s, 2H), 7.09 (d, J=9.2 Hz, 1H), 7.36 (s, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.61 (d, J=3.1 Hz, 1H), 9.10 (d, J=2.0 Hz, 1H); MS (ESI+) m/z 422 (M+H)+; Anal. Calculated for C19H20ClN3O2S2: C, 54.08; H, 4.78; N, 9.96. Found: C, 54.10; H, 4.62; N, 9.81.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1>[C:24]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2cccc(OC(=O)c3ccccc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.0 g), triethylamine (1.90 mL) and N,N-dimethylaminopyridine (56 mg) in THF (10 mL) was added benzoyl chloride (1.16 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.74 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:13]2[N:17]([CH2:18][OH:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[N:14]=2)=[O:12])[C:4]=1[CH3:24].Cl.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][C:30](O)=[O:31])[CH3:27].[OH-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][C:30]([O:19][CH2:18][N:17]1[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[N:14]=[C:13]1[S:11]([CH2:10][C:5]1[C:4]([CH3:24])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=1)=[O:12])=[O:31])[CH3:27]
Reactant: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2CO)c1C
Reactant: CCN(CC)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CC(=O)OCn1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccccc21
Temperature: 25 °C
Reaction time: 39 h

Procedure:
A mixture of [2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]methanol (3.5 g 0.010 mol), N,N-dicyclohexylcarbodiimide (2.1 g 0.010 mol), N,N-diethylglycine hydrochloride (1.7 g 0.010 mol) and 4-dimethylaminopyridine (1.3 g 0.011 mol) in pyridine (75 ml) was stirred at room temperature for 39 h. N,N-dicyclohexyl urea which had precipitated was removed by filtration. The filtrate was evaporated, the residue was dissolved in dichloromethane. The dichloromethanesolution was washed with NaOH 0.080 g (0.0020 mol), dissolved in water (25 ml) and then once with water (25 ml). The organic phase was dried (Na2SO4), filtered and the solvent was evaporated off, giving the desired product. The identity of the product was confirmed with NMR.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: Ic1cnccn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(-c2cnccn2)cc1
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of 0.40 g (1.53 mmol) of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid in 4.0 ml of dioxane was added 0.18 mL (1.73 mmol) of 2-iodopyrazine, 10.3 mg (0.037 mmol) of tricyclohexylphosphine, 13.9 mg (0.015 mmol) of Pd2(dba)3, and 2.0 ml (1.27 M, 2.59 mmol) of aqueous potassium phosphate solution. The resulting suspension was degassed for 10 mins. After 30 min in the microwave at 150° C., the reaction mixture was cooled, acidified with 1N HCl, extracted with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.10 g (32%) of (4-pyrazin-2-ylphenyl)acetic acid. 1H NMR (CD3OD, 400 MHz) 9.1 (s, 1H); 8.66 (t, J=1.74 Hz, 1H); 8.51 (d, J=2.57 Hz, 1H); 8.04 (d, J=8.15 Hz, 2H); 7.46 (d, J=8.15 Hz, 2H); 3.70 (s, 2H). ES-MS M+1=215.1.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][C:19](=O)[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>C(O)C>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][CH:19]([NH2:28])[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: NC1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A reaction mixture was prepared from 2.7 g. of 1-benzoyl-4-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 7.7 g. of ammonium acetate and 125 ml. of ethanol. 590 mg. of sodium cyanoborohydride were added and the resulting suspension stirred at ambient temperature for 22 hours. The reaction mixture was then poured over an ice-1N hydrochloric acid mixture and the acidic aqueous layer extracted with chloroform. The aqueous layer was then made basic with 14N aqueous ammonium hydroxide and the alkaline layer extracted several times with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform yielded a residue which was shown to be essentially one spot material by TLC. The residue was recrystallized from a mixture of methylene dichloride and ether to yield crystals of 1-benzoyl-4-amino-1,2,2a,3,4,5-hexahydrobenz-[cd]indole melting at 118°-120° C.; yield 825 mg.
Reaction SMILES: C([NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:10]2=[CH:9][CH:8]=1)(=O)CCC.Cl>CO>[NH2:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:10]2=[CH:9][CH:8]=1
Reactant: CCCC(=O)Nc1ccc2[nH]c(CCC)nc2n1
Agent: Cl
Solvent: CO
Product: CCCc1nc2nc(N)ccc2[nH]1
Temperature: 45 °C
Yield: 79.6 %

Procedure:
A mixture of 5-butyramido-2-propylimidazo[4,5-b]pyridine (250 mg, 1.07 mmol), MeOH (20 mL), and concentrated aqueous HCl (2 mL) was heated to 45° C. for 16 hours. Concentration and neutralization with NaHCO3 gave 150 mg of the title compound as a glass.
Reaction SMILES: N[C@H](C[OH:5])C.N[C@H](CO)CCC(=O)N.N[C@H](CO)CC(=O)O.N1CCC[C@H]1CO.N[C@@H](CO)CC(=O)O.N[C@@H](CO)CCCCN.[NH2:47][C@@H:48]([CH2:54][OH:55])[CH2:49][CH2:50][C:51](=[O:53])[OH:52]>>[NH2:47][C@H:48]([C:54]([OH:5])=[O:55])[CH2:49][CH2:50][C:51](=[O:52])[OH:53]
Reactant: C[C@H](N)CO
Reactant: N[C@@H](CO)CCC(=O)O
Agent: NC(=O)CC[C@H](N)CO
Agent: NCCCC[C@@H](N)CO
Agent: N[C@@H](CO)CC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A10 -ol, Ala-ol, Gln-ol, Asp-ol, Pro-ol, D-Asp-ol, D-Lys-ol, D-Glu-ol or -Asp-Glu-ol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[NH:16][C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([Br:35])[C:33]=1[Br:34])[CH2:29]Br>CN(C)C=O.O>[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]([CH2:29][C:28]2[CH:27]=[C:26]([Br:25])[C:33]([Br:34])=[C:32]([Br:35])[CH:31]=2)[C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2[nH]1
Reactant: BrCc1cc(Br)c(Br)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.675 g. of 80% w/w suspension; freed of mineral oil as in Example 1) in dimethylformamide (100 ml.) under a nitrogen atmosphere was added 4-(2-benzyloxyethyl)-6-fluoro-1,2-dihydro-2-oxoquinoline (6.0 g.). The mixture was stirred at 40° C. for one hour and then treated at this temperature with 3,4,5-tribromobenzylbromide (9.1 g.). The mixture was stirred overnight at ambient temperature and then diluted with water (200 ml.) and the product extracted with ethyl acetate (3×150 ml.). The combined organic extracts were washed with water (2×100 ml.), dried (MgSO4), and evaporated. The residue was a mixture of O- and N-substituted products. Chromatography of this residue on silica gel using a 50:50 v/v mixture of ether and petroleum ether (b.p. 40°-60° C.) as eluant gave 4-(2-benzyloxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline, as an oil, Infra-Red Spectral Absorption ν max. 1665 cm.-1.
Reaction SMILES: C(NC1C=[C:12]([CH:51]=C(C)C=1)[C:13]([NH:15][C@@H:16]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=[C:80]([C:82]2[O:83][CH:84]=[CH:85][N:86]=2)[CH:79]=[C:78]([C:87]([N:89]2[CH2:93][CH2:92][CH2:91][C@@H:90]2[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.COC[C@H]1CCCN1C(C1C=C(C=C(C2OC=CN=2)C=1)C(O)=O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:49][C:47]1[CH:48]=[C:43]([CH2:42][C@H:16]([NH:15][C:13](=[O:14])[C:12]2[CH:51]=[C:80]([C:82]3[O:83][CH:84]=[CH:85][N:86]=3)[CH:79]=[C:78]([C:87]([N:89]3[CH2:93][CH2:92][CH2:91][C@@H:90]3[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=2)[C@H:17]([OH:18])[C@H:26]2[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][NH:27]2)[CH:44]=[C:45]([F:50])[CH:46]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)C1
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Step 11 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoic acid (Preparation H, 40 mg, 0.12 mmol) in dichloromethane (3 mL) was added Hunig's base (46 mg, 0.36 mmol) to make a clear solution and HATU (60 mg, 0.156 mmol) was then added. After stirring for 20 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 1 (A), 64 mg, 0.12 mmol) and the reaction mixture was stirred at rt for 16 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 70 mg of the title compound (70% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.84 (9H, s), 0.87 (3H, m), 1.46-1.50 (1H, m), 1.74 (1H, m), 1.92-2.06 (3H, m), 2.17-2.23 (2H, m), 2.66 (1H, m), 2.77-2.81 (2H, m), 2.92 (1H, m), 3.05 (1H, m), 3.29-3.38 (4H, m), 3.48 (1H, m), 3.58 (1H, m), 3.66 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.07-4.09 (1H, m), 4.12-4.14 (1H, m), 4.43 (1H, brd s), 4.61 (1H, m), 6.58 (1H, m), 6.77 (2H, d, J=10 Hz), 7.22 (1H, s), 7.69 (1H, s), 8.10 (1H, s), 8.28 (1H, s), 8.53 (1H, brd s), 8.64 (1H, s). MS (ESI) (M+H)+ 841.61.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[N:4]([CH3:25])[C:3]1=[O:26].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH3:25][N:4]1[C:5]2[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=2[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[N:8][CH:2]([NH:1][C:35]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[O:36])[C:3]1=[O:26]
Reactant: COc1cc(OC)c(C2=NC(N)C(=O)N(C)c3ccccc32)c(OC)c1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cc(OC)c(C2=NC(NC(=O)Nc3cccc(C)c3)C(=O)N(C)c3ccccc32)c(OC)c1

Procedure:
By condensing 3-amino-1,3-dihydro-1-methyl-5-(2,4,6-trimethoxyphenyl)-1,4-benzodiazepin-2-one with 3-methylphenyl isocyanate, 1,3-dihydro-1-methyl-3-(3-methylphenylureido)-5-(2,4,6-trimethoxyphenyl)-1,4-benzodiazepin-2-one is obtained; m.p.=240° C, Yield =94%.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([B-](F)(F)F)=[CH:35][CH:34]=1)#[N:32].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=1
Reactant: N#Cc1ccc([B-](F)(F)F)cc1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(C#N)cc2)c1
Temperature: 120 °C
Yield: 84 %

Procedure:
In a 50 mL 4-necked flask, methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1 g, 3.18 mmol, Eq: 1.00, CAN 1211589-51-3) and cesium carbonate (3.11 g, 9.55 mmol, Eq: 3) were combined with toluene (25 ml) and water (2.8 ml) to give a colorless solution. The reaction mixture was 3× degassed and purged with argon; then palladium(II) acetate (14.3 mg, 63.7 μmol, Eq: 0.02), potassium (4-cyanophenyl)trifluoroborate (732 mg, 3.5 mmol, Eq: 1.1, CAN 850623-36-8) and butyldi-1-adamantylphosphine (68.5 mg, 191 μmol, Eq: 0.06) were successively added. The degassing-purging cycle was repeated after each addition. The reaction mixture was then heated to 120° C. for 5 hours. After cooling, the reaction mixture was poured into 50 mL H2O and extracted with AcOEt (2×50 mL). The organic layers were washed with H2O/NaCl solution, combined, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 50 g, 50% to 100% CH2Cl2 in heptane) yielded finally 898 mg of the title compound as white foam; MS (EI) 337.2 (M+H)+.