Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[C:2]=1[CH:13]=[O:14].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:15]1([CH:13]([C:2]2[C:3]([CH:11]([OH:12])[C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[OH:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cc2ccccc2cc1C=O
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2ccccc2cc1C(O)c1ccccc1
Yield: 86.6 %

Procedure:
2,3-Naphthalenedicarboxaldehyde (10.0 g) in dry tetrahydrofuran (100ml) was added to phenylmagnesium bromide [derived from bromobenzene (53 g) and magnesium (8 g)] in dry tetrahydrofuran (500 ml) over 1 hr. and the solution was refluxed for a further 3 hr. On cooling, water (500 ml) was added and the ethereal layer was decanted. The aqueous slurry was washed with ether (4 × 500 ml) and the combined ethereal extracts were dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography on silica gel and recrystallised from dichloromethane/petroleum ether (b.p. 40°-60°) to yield two isomers of 2,3-bis(1-phenyl-1-hydroxymethyl)naphthalene (III) (8.0 g. m.p. 145° and 3.0 g, m.p. 164°).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].C(Cl)Cl.N([O-])=[O:19].[Na+]>O.C(Cl)Cl.O>[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([OH:19])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
The title compound was prepared by a slightly modified literature procedure.*3-aminophenyl methyl sulfone hydrochloride (1.18 g, 5.70 mmol) was suspended in water/CH2Cl2. The mixture was neutralized with 25% aqueous NaOH. The CH2Cl2 layer was isolated and evaporated to dryness. Aqueous H2SO4 (60%; 10 mL) was added to the residue and the solution was cooled to 0° C. A solution of NaNO2 (0.345 g, 5.00 mmol) in water (5 mL) was added dropwise. The solution was stirred at 0° C. for 30 min. and at 90° C. for 30 min. The reaction mixture was allowed to come to room temperature. Extraction with CH2Cl2, drying (MgSO4), and concentration gave 0.39 g (40%) of the title compound as a solid. MS m/z 172 (M)+. HRMS m/z calcd for C7H8O3S (M)+172.0194, found 172.0198.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2[OH:21])([CH3:5])[CH3:4].[OH2:22]>COCCOC>[CH:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:4][C:3]([O:6][CH2:7][CH3:15])=[O:22])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]2=[O:21])([CH3:5])[CH3:4]
Reactant: O
Reactant: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccc(OC(C)C)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 0.149 g of 60% sodium hydride in 20 cm3 of 1,2-dimethoxyethane, 1.23 cm3 of triethyl phosphonoacetate and 1.08 g of 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydro-isoindol-1-one. The mixture is refluxed for 5 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and the mixture is then extracted with 3 times 100 cm3 of diethyl ether. The organic extracts are combined, washed with 100 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (80 kPa) on a cartridge of silica gel (particle size 32-63 μm), eluting with a mixture of cyclohexane/ethyl acetate (90/10 by volume) and then with a mixture of cyclohexane/ethyl acetate (80/20 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1yl)acetate is thus obtained in the form of a colorless oil. (Rf=0.57, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[C:7]([F:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c(F)ccc(S(=O)(=O)Cl)c1F
Temperature: 150 °C
Reaction time: 2 h

Procedure:
77 mmol of 2,6-difluorobenzoic acid were dissolved in 15.5 ml of chlorosulfonic acid and stirred for 2 h at 150° C. The reaction mixture was cooled to room temperature and poured into 100 ml of ice/water. The solid was filtered and dried to yield the title compound as a colorless solid. MS (m/e): 255.1 (M−H, 44%)
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[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].[H-].[Na+].[CH3:41][S:42][CH2:43]Cl>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24][CH2:41][S:42][CH3:43])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CSCCl
Reactant: CCCCNC(=O)C(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
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCSC)c1)C(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg of N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (Example 5a) in 5 ml of dimethylformamide is added dropwise to a suspension, stirred at room temperature, of 7.6 mg of a 65% NaH dispersion in 3 ml of dimethylformamide. The reaction mixture is stirred for a further 30 minutes at more temperature and then a solution of 0.017 ml of chlorodimethyl sulfide in 2 ml of dimethylformamide is added thereto. The reaction mixture is stirred for a further 24 hours and then concentrated by evaporation. The residue is partitioned between ether and water. The organic phases are concentrated by evaporation and the title compound is obtained from the residue by FC (12 g of silica gel, dichloromethane/diethyl ether=2:1): Rf (dichloromethane/diethyl ether=2:1)=0.33.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([CH3:17])[CH2:15]O.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)([CH3:17])[CH3:15]
Reactant: CC(CO)c1ccc2c(c1)Cc1ccccc1-2
Reactant: c1c[nH]cn1
Product: CC(C)(c1ccc2c(c1)Cc1ccccc1-2)n1ccnc1

Procedure:
Using 2-(9H-fluoren-2-yl)propanol and imidazole as starting compounds, the process of Example 1 was repeated to obtain 1-[1-(9H-fluoren-2-yl)-1-methylethyl]-1H-imidazole.
Reaction SMILES: [NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31](OC)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O.[NH2:43][NH2:44]>CO>[NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:43][NH2:44])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 24 h

Procedure:
43 g of Boc-Tyr-(D)-Ala-Gly-Phe-OCH3 are dissolved in 300 ml of methanol and 35 ml of hydrazine hydrate are added. After one day at room temperature, the mixture is evaporated and the residue is triturated with water which has been acidified to pH 3 with HCl. The precipitated product is filtered and dried to yield the title compound. M.P. 195° (decomp.). [α]D20 =-20.9 (C=1 in DMF).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[O:36]([CH2:38][C:39](Cl)=[O:40])[CH3:37]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available methoxyl-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:22]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>N1C=CC=CC=1>[N:22]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:21][C:18]3[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:20][CH:19]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)N1CCC(N2CCCCC2)CC1
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc(OC(=O)N3CCC(N4CCCCC4)CC3)cc2)cc1OC
Yield: 80.3 %

Procedure:
(Z)-2-(3,4-dimethoxyphenyl)-3-(4-hydroxyphenyl)acrylonitrile (compound 1) (0.28 g) and 4-piperidinopiperidinocarbonyl chloride (0.23 g) were dissolved in pyridine (5 ml), and the resultant solution was stirred for a whole day and night. After completion of reaction, the resultant reaction mixture was added to water (200 ml), and the thus-precipitated product was purified by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (0.38 g, yield: 79%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16].Cl>C(Cl)Cl>[CH3:18][CH:14]1[CH2:19][C:9]2[C:10](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:15]1=[O:16]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Yield: 93 %

Procedure:
107 g (810 mmol) of AlCl3 are slowly added to a solution of 34.4 g (324 mmol) of m-xylene (99% pure) and 74 g (324 mmol) of 2-bromoisobutyryl bromide (98% pure) in 600 ml of analytical grade methylene chloride via a solids metering funnel at room temperature, while stirring vigorously, whereupon vigorous evolution of gas started. The mixture was stirred at room temperature for 15 hours, poured onto ice-water, which was acidified with 25 ml of concentrated HCl and extracted several times with ether. The combined organic phases were washed first with a saturated NaHCO3 solution and then with a saturated NaCl solution and dried with magnesium sulfate. The oil which remained after the solvent had been stripped off under reduced pressure was distilled over a short distillation bridge. 52.4 g of the indanone 1 passed over at 81-90° C./0.1-0.2 mbar in the form of a colorless oil which crystallized at room temperature. The yield was 93%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=1[OH:21])([O-:3])=[O:2].C(N(C)C)C1C=CC=CC=1.[C:32](Cl)(=[O:36])/[CH:33]=[CH:34]/[CH3:35]>CCCCCCC>[C:32]([O:21][C:5]1[C:6]([CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:36])/[CH:33]=[CH:34]/[CH3:35]
Reactant: C/C=C/C(=O)Cl
Reactant: CCCCCCC(C)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Agent: CN(C)Cc1ccccc1
Solvent: CCCCCCC
Product: C/C=C/C(=O)Oc1c(C(C)CCCCCC)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
2,4-Dinitro-6-(1-methylheptyl)phenol (98.5 percent pure) (252 gm) is dissolved in heptane (225 gm). Benzyldimethylamine (140.8 gm) is added dropwise over 40 minutes, keeping the temperature of the mixture below 40° C., and the mixture is stirred for 15 minutes. Crotonyl chloride (139 gm) is then added dropwise over 30 minutes, keeping the temperature below 60° C., and the mixture is stirred at 60° C. for 30 minutes and cooled to less than 50° C. The mixture is washed twice with water and then cooled to 20° C. The mixture is washed with a mixture of methanol and aqueous sodium hydroxide, with water and methanol, and finally with dilute hydrochloric acid. The organic layer is stripped at 70° C. under vacuum to remove heptane and leave 2,4-dinitro-6-(1-methylheptyl)phenyl crotonate (282.6 gm) as an orange/brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(O)(=O)C>CO.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(N)n2)cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(N)c(N)n2)cc1
Yield: 90.9 %

Procedure:
To a suspension of 6-({[4-(methyloxy)phenyl]methyl}oxy)-3-nitro-2-pyridineamine (4.8 g, 17.5 mmol) and zinc (11 g, 175 mmol) in methanol (200 mL) was added dropwise acetic acid (5 mL) at rt. After 0.5 h the reaction was filtered through celite and then the solvent was evaporated. The residue was partitioned between water (500 mL) and ethyl acetate (500 mL), the phases were separated and the water extracted with ethyl acetate (5×500 mL). The combined organic phases were dried, filtered and evaporated to afford 3.9 g of the title compound as a black solid (91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1ccc(I)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 3-fluoro-4-iodobenzoic acid (1.3 g, 4.9 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. was added oxalyl chloride (1.2 mL, 15.0 mmol) followed by catalytic DMF (7 drops). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, and then concentrated in vacuo to provide 1.2 g of 3-fluoro-4-iodobenzoyl chloride as a yellow solid. The acid chloride (600 mg, 2.1 mmol) was dissolved in anhydrous CH2Cl2, and dimethylamine (2.1 mL, 4.2 mmol, 2M in THF) was added followed by triethylamine (0.6 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with CH2Cl2. The organic layer was washed with water, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting solid was stirred with diethyl ether and filtered to afford 353 mg of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (dd, 1H), 7.32 (dd, 1H), 7.04 (dd, 1H), 2.97 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1.CCOCC>[C:16]([O:15][C:13]([NH:12][CH:4]([CH:3]([OH:20])[CH:2]([NH:1][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
The resultant compound of Example 11 (0.05 mmol) in 2 ml of pyridine was cooled to 0° C. and treated with 0.05 mmol of p-toluenesulfonyl chloride. After 2 h, the solution was diluted with ether, washed sequentially with 1N HCl, aqueous NaHCO3, and saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography gave the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:22]([O:26][C:27]([C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])[C:30](O)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:22]([O:26][C:27]([C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])[C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:31])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2cc(N)cc(C(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccc(Cl)cc1Cl)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(Cl)cc3Cl)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c2)ccn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
A mixture of tert-butyl 3-amino-5-(2-methylpyridin-4-yl)benzoate (100 mg, 0.35 mmol), (S)-2-(tert-butoxycarbonyl)-3-(2,4-dichlorophenyl)-propanoic acid (152 mg, 0.45 mmol), HBTU (174 mg, 0.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (92 μl, 0.53 mmol) in N,N-dimethylformamide (0.70 mL) was allowed to stir at 80° C. for 4 hours. Upon completion, the mixture was directly purified by HPLC to give 206 mg of tert-butyl 3-((S)-2-(tert-butoxycarbonyl)-3-(2,4-dichlorophenyl)propanamido)-5-(2-methylpyridin-4-yl)benzoate 49.1C. LCMS (ES+) m/z 601.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:15]1([O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[B:21]([OH:24])[OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccccc1COC1CCCCC1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccccc1COC1CCCCC1
Reaction time: 2 h

Procedure:
31.2 ml of n-butyllithium (1.6 M) in solution in n-hexane are added dropwise at −70° C. to 13.45 g of 1-bromo-2-[(cyclohexyloxy)methyl]benzene, obtained in step 1.1, in solution in 150 ml of tetrahydrofuran. After 2 hours at −70° C., 10.2 ml of trimethyl borate are introduced dropwise and the temperature of the reaction medium is allowed to rise to −30° C. The medium is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulfate. After evaporation, 11.7 g of a yellow oil are obtained.
Reaction SMILES: [C:1]([Mg]Br)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]=[O:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]([OH:37])[C:1]([CH3:4])([CH3:3])[CH3:2])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCc1nc(C=O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
2.77 ml of a 2M solution of t-butylmagnesium bromide in tetrabydrofuran were added at -55° C. and under an atmosphere of nitrogen to a solution of 1.32 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-formylimidazole-5-carboxylate [prepared as described in step (a))above] in 26 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature of -55° C. to -50° C. for 30 minutes. At the end of this time, the reaction mixture was diluted with 50 ml of ethyl acetate and with a saturated aqueous solution of ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.87 g of the title compound as an amorphous solid.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]1([CH2:11][CH2:12][CH2:13][C:14]([Cl:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1cccc2ccccc12
Temperature: 70 °C

Procedure:
0.37 g of 4-Naphthalen-1-yl-butyric acid was dissolved in 5.0 ml of toluene, and 0.35 ml of thionyl chloride and 1 drop of dimethylformamide were added, followed by heating at 70° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a crude 4-naphthalen-1-yl-butyryl chloride. To the resulting crude 4-naphthalen-1-yl-butyryl chloride was added 2.3 ml of a toluene solution of 0.40 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine, followed by stirring at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Wako-gel C-200, chloroform:methanol=10:1) to give 0.58 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyryl)piperazine as an oil.