Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].Cl.[CH3:35][O:36][NH2:37]>>[OH:1][CH:2]([C:3]([NH:37][O:36][CH3:35])=[O:4])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 472.2
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=S.C(O)C>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:21]([NH:22][CH3:23])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 70 %

Procedure:
A solution of 1-benzyl-6-hydrazino-3-propyluracil (2.0 g, 7.3 mM) and methyl isothiocyanate (1.5 ml, 22 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. Ethanol (20 ml) was added to the solution, which was cooled to give crystals. Recrystallization from DMF/ethanol gave colorless needles (1.6 g, 70%), m.p. 307°-310° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (505 mg, 3.1 mmol), 3,5-dimethyl-1H-1,2,4-triazole (300 mg, 3.1 mmol) and Cs2CO3 (1.54 g, 4.7 mmol) in THF (20 mL) was heated at reflux overnight. The mixture was filtered and the filtrate was concentrated to give 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine that was used without further purification. MS: m/z=224.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:15]COCCOC)=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:12][C:10](=[O:11])[C:9]1[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[CH:7][C:8]=1[CH3:14]
Reactant: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(C)(C)C)c(O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl benzoic acid from Example AAA (20.9 g, 70.5 mmol), MeOH (150 mL), and H2SO4 (10 mL) was refluxed for 5 hours and stirred overnight at room temperature. The mixture was concentrated by half, diluted with H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.48 (s, 3 H), 3.82 (s, 3 H), 6.48 (s, 1 H), 7.87 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([CH2:21]O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:16]1([CH2:21][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCC1CCCC1)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
Trifluoromethanesulfonic anhydride (6.72 mL, 39.94 mmol) is dissolved in DCM (40 mL) and cooled to −40° C. To this is added dropwise cyclopentanemethanol (4.00 g, 39.94 mmol) dissolved in DCM (10 mL) and anhydrous pyridine (3.23 mL, 39.94 mmol). The reaction is stirred at −40° C. for 45 min. The reaction is diluted with hexanes (30 mL) and run through a plug of silica using hexanes (300 mL) as the eluent. Concentration without heating gives trifluoromethanesulfonic acid cyclopentylmethyl ester as a clear, colorless oil that is used immediately.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[C:10]([CH3:24])([CH3:23])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1Br)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1Br)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To a mixture of 2-(2-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (30 g, 74 mmol) and triethylsilane (50 mL) at 25° C. was added trifluoroacetic acid (15 mL) dropwise. The resulting mixture was stirred at 25° C. for 4 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (15 g, 78%) as a white solid: LC/MS m/e calcd for C20H22BrNO2 (M+H)+: 389.31, observed: 388.0 & 390.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[C:32]([OH:42])(=O)[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:32](=[O:42])[CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and hydrocinnamic acid (10.3 mg, 0.068 mmol) in 0.68 ml of CH2Cl2 and 0.08 ml of DMF, 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) was added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (18 mg, 46%) as a white solid, m.p. 110°-117° C. (amorphous).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>CN(C=O)C>[CH2:20]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1onc(-c2ccccc2)c1-c1cn(Cc2ccccc2)cn1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A solution of 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) in DMF (2 mL) was added over 10 min to a suspension of NaH (20 mg, 0.47 mmol) in DMF (1 mL) at room temperature and after 30 min benzyl bromide (83.5 mg, 0.49 mmol) was added. After 2 h at room temperature, the mixture was poured into aqueous acetic acid (10%) and extracted with ethyl acetate. The organic extracts were then washed with water and brine, and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1) afforded the title compound (88 mg, 63%) which was obtained as a colourless gum. MS: m/e=316.1 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:20]([N:22](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.CS(C)=O>[C:20]([CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:22]
Reactant: COC(=O)CCCC(CCO)CCc1cccnc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CCCC(CCC#N)CCc1cccnc1
Reaction time: 0.5 h

Procedure:
A solution of 0.8 g (3.0 mmol) methyl 7-hydroxy-5-[2-(3-pyridyl)ethyl]-heptanoate in 3 ml methylene chloride is cooled to 0° and 0.52 ml (3.7 mmol) triethylamine is added followed by 0.26 ml (3.3 ml) methylsulfonyl chloride. The reaction mixture is stirred at 0° for 30 min and then 1.65 g (25 mmol) finely powdered potassium cyanide is added followed by 15 ml dimethyl sulfoxide. After stirring for 30 min the cold bath is removed and the mixture is stirred at room temperature for 18 h. The reaction mixture is poured on to saturated aqueous ammonium chloride solution and is then extracted with ethyl acetate (3×70 ml). Combined organic phase is washed with water (4×60 ml), brine (60 ml) and dried (MgSO4), filtered and evaporated to give an oil which is purified by flash chromatography to give both the desired methyl 7-cyano-5-[2-(3 -pyridyl)ethyl]-heptanoate and the mesylate of the starting alcohol. The mesylate is subjected to the cyanide displacement conditions described above to yield additional methyl 7-cyano-5-[2-(3-pyridyl)ethyl]-heptanoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][C:26]([N:29](S(C)(=O)=O)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CS(=O)(=O)N(c1ccc(Br)cc1)S(C)(=O)=O
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(NS(C)(=O)=O)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methyl ethyl)phenyl]-2-({4-[(methylsulfonyl)amino]phenyl}amino)thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (85 mg, 0.272 mmol) and N-(4-bromophenyl)-N-(methylsulfonyl)methanesulfonamide (89 mg, 0.272 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][C:13]=2[CH2:24][CH3:25])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:10]2)=[C:13]([CH2:24][CH3:25])[CH:14]=1)#[CH:19]
Reactant: CCc1cc(C#C[Si](C)(C)C)ccc1C1(OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane (Intermediate 89, 240 mg, 0.69 mmol) in methanol (6 mL) was treated with potassium carbonate (10.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (190 mg, 99%) was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15]>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:14](=[O:16])[CH3:15])[CH:6]=1
Reactant: CC(=O)Cl
Reactant: Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)n1cnc(C)c1

Procedure:
To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL of acetonitrile at 0° C. was added triethylamine (NEt3) (4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to attain RT then filtered to remove the ppt and the filtrate was concentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was used without further purification in the next step. To a solution of 1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mL acetonitrile was added SEM-C1 (5.80 g, 35.0 mmol) and the solution was stirred at 25° C. for 10 h. The solvents were removed by evaporation and to the residue was added 100 mL of 2.5 M NaOH and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then extracted with ether (3×100 mL), dried over Na2SO4 and concentrated. The title compound was purified by chromatography on silica gel eluting with 75% EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C10H20N2O4Si, 213.1 (M+H). found 213.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[C@H:20]([OH:23])[CH2:21][OH:22].Cl[C:25]1C=CC(C2C(C=C)=C(C)C=C3C=2C=CC=N3)=CC=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[C:3]([C@H:20]([OH:23])[CH2:21][OH:22])=[C:2]([CH3:25])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(Cl)cc2n1
Reactant: C=Cc1c(C)cc2ncccc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO

Procedure:
Compound 3H was prepared following the procedure used to prepare compound 1H of Example 1, except that 5-(4-chlorophenyl)-7-methyl-6-vinyl-quinoline (3G) was used instead of compound 1G. LCMS-ESI+ (m/z): 314.2, 316.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C:7](=[CH2:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC>CO>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
175 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in the presence of 12 mg of [Ru2Cl4 (S-Binap)2 ].(NEt3) in 30 ml of methanol for 20 hours at room temperature and under 30 bar. The reaction mixture is filtered, concentrated by evaporation and purified by means of FC (hexane/ethyl acetate=1:1). The title compound so obtained (Rf in hexane/ethyl acetate=1:1)=0.15 is deprotected by hydrogenation with 90 mg of 10% Pd/C in 10 ml of methanol at room temperature and under normal pressure to form N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide.
Reaction SMILES: [Br-].[CH2:2]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)#[N:34].O>COC(C)(C)C>[CH2:2]([C:7]1[CH:32]=[CH:31][C:10]([CH:11]=[CH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#CC1CCC(C=O)CC1
Agent: [Br-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A mixture of 2.51 g of p-pentylbenzyl-triphenylphosphonium bromide and 615 mg of a cis/trans mixture (about 1:1) of 4-cyanocyclohexanecarboxaldehyde in 30 ml of t-butyl methyl ether was placed at 0° C. under argon gasification in a sulphonation flask fitted with a thermometer and solid substance addition tube, treated within 2 minutes with 673 mg of solid potassium t-butylate and subsequently stirred for a further 1.5 hours. The red-brown heterogeneous mixture was then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was suspended in 150 ml of hexane, freed from precipitated triphenylphosphine oxide by filtration (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.4 bar) of the resulting oil (1.36 g) on silica gel using 3% ethyl acetate/petroleum ether as the eluting agent gave 1.02 g (81%) of 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile as a colourless oil; Rf values (10% ethyl acetate/petroleum ether): 0.27 and 0.37 (stereoisomer mixture).
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OO)(=[O:21])C.O>C(Cl)Cl>[CH2:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]2[CH:15]([O:21]2)[CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOCC1C=CCCC1
Reactant: CC(=O)OO
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCOCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 16.4g (0.065 mol) 3-decyloxymethylcyclohexene, and 100 mL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 250 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:14][CH3:15]>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:14][CH3:15])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(O)c1cnccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1cnccc1Cl
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 4-chloronicotinic acid (7.03 g, 44.6 mmol) in 100 mL of hexamethylphosphoric triamide (HMPA) was added a solution of 5.5 N sodium hydroxide (13 mL) at 0° C. Then iodoethane (27.8 g, 179 mmol) was added into the reaction mixture at 0° C. over 1 h, and stirring was continued for a further 1 h at room temperature. The mixture was diluted with 250 mL of water, and then extracted three times with ether. The ethereal extracts were combined, washed three times with water, then dried (MgSO4), filtered, and the solvent was evaporated to give ethyl 4-chloronicotinate (6.21 g) as a brown oily residue, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(CCCCCCN(CCc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)cc1N
Reaction time: 4 h
Yield: 55.2 %

Procedure:
N-[2-(3-Amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (2.62 g., 0.01 moles) in dry dimethylformamide (50 ml) was added dropwise with stirring to sodium hydride (0.3 g., 80% oil dispersion, 0.01 moles) in dry dimethylformamide (50 ml) under nitrogen. The solution was warmed at 60° for 30 min then cooled and N-(6-bromohexyl)-2,2,2-trifluoro-N-(2-phenylethyl)acetamide (3.80 g., 0.01 mole) was added. The solution was stirred for 4 hours then quenched with water and extracted with ethyl acetate. The extracts were washed with water dried and evaporated to give crude N-[2-(3-amino-4-methoxyphenyl)ethyl]-N'-(2-phenylethyl)-1,6-hexanediylbis (2,2,2-trifluoroacetamide) (3.1 g) as a pale brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[C:13]1(N)[C:18]([F:19])=[C:17](F)[C:16](F)=[C:15]([NH2:22])[C:14]=1F.Cl.Cl>>[F:19][C:18]1[CH:13]=[CH:14][C:15]2[NH:22][C:11]3[CH2:10][CH2:5][N:4]([CH2:2][CH2:1][C:3]4[CH:12]=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH2:3][C:12]=3[C:16]=2[CH:17]=1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: Fc1ccc2[nH]c3c(c2c1)CN(CCc1ccc2ccccc2n1)CC3

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception that 2-vinylquinoline was used instead of 2-vinylpyridine. The product was converted to the dihydrochloride salt; mp 192°-194° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1.C1CCNCC1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>ClCCl>[C:46]([NH:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1)(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (27 mg, 0.049 mmol), (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) was added acetic anhydride (0.12 mmol) in dichloromethane (0.12 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to give 1-(3-acetylamino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (30 mg, quant.): ESI/MS m/e 590.4 (M++H, C29H37F2N5O6).