Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:17]2[CH:18]=[C:19]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C(=O)OC)=[CH:28][CH:27]=3)=[O:25])[CH:20]=[CH:21][CH:22]=2)[NH:3]1.O.[OH-].[K+]>O1CCOCC1>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]/[C:12]1[NH:13][CH:14]=[CH:15][CH:16]=1)=[C:8]([C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:25])[C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[CH:20]=[CH:21][CH:22]=1)[CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)Oc1ccc(C(=O)Nc2cccc(-c3cccc4c3C(=Cc3ccc[nH]3)C(=O)N4)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(O)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 90 °C

Procedure:
A solution of the crude carbonic acid methyl ester 4-[3-[2-oxo-3-[(1H-pyrrol-2-yl)methylene]-2,3-dihydro-1H-indol-4-yl]-phenylcarbamoyl]-phenyl ester (90 mg, 0.194 mmol) in 2 mL of 1,4-dioxane (Aldrich) was treated with 1.5 mL of distilled water and then powdered potassium hydroxide (25 mg, 0.445 mmol) . The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was then allowed to cool to room temperature and directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 45% ethyl acetate-hexanes elution) to provide a crude yellow solid containing the desired product and a 1,3-dicyclohexylcarbodiimide derivative. Most of the 1,3-dicyclohexylcarbodiimide derivative was removed by precipitation from an ethanolic solution through the slow addition of distilled water. The precipitated solid was collected by suction filtration. The filtrate was concentrated in vacuo and then directly purified by column chromatography. Two additional rounds of flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution each) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-hydroxybenzamide (yield: 49 mg, 60%) as a yellow solid (mp 236-238° C.).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+:5].[Na+].[C:7](=O)([OH:9])[O-:8].[Na+]>>[C:1](=[O:2])([O-:4])[O-:3].[Na+:5].[Na+:5].[C:7](=[O:9])=[O:8]
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C=O

Procedure:
The method of claim 1, wherein a portion of the stripped product from step five containing sodium carbonate and sodium bicarbonate is heated under pressure to above 125° C. to decompose the sodium bicarbonate contained and form sodium carbonate and carbon dioxide, and release carbon dioxide and water vapor for use in step five.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:18]1[CH2:24][CH:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[O:21][CH2:20][C:19]1=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(OCC)C.C1COCC1>[CH2:11]([N:18]1[CH2:24][CH:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[O:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of lithium aluminum hydride (347 mg) in diethyl ether (30 mL) was added, under a nitrogen stream, aluminum(III) chloride (406 mg) at room temperature, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to −78° C., a solution of (6RS,7RS)-4-benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-3-one (2.51 g) in THF (20 mL) was added dropwise, and the mixture was stirred at 0° C. for 3 hr. To the reaction mixture was added 1 N aqueous sodium hydroxide solution (5 mL) at −78° C., and the mixture was stirred at room temperature for 2 hr, and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (2.42 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: BrBr.Br[C:4]12[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]3[CH:18](Br)[C:8]1([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=13)[CH2:7][N:6]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]2=[O:31].C([SnH](CCCC)CCCC)CCC.C1C=CC=CC=1>C(Cl)Cl>[CH:25]1([CH2:24][N:6]2[CH2:7][C:8]34[CH2:18][CH:11]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH:4]3[C:5]2=[O:31])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]4=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C1N(CC2CCCCC2)CC23c4ccccc4C(c4ccccc4C12Br)C3Br
Agent: BrBr
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C1C2c3ccccc3C3CC2(CN1CC1CCCCC1)c1ccccc13

Procedure:
The above product (2.94 g) is treated with 1.41 g of bromine in methylene chloride at room temperature. The resulting crude 12b,13-dibromo-2-cyclohexylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrol-1-one is heated under reflux with 9 g of tributyltin hydride and 25 ml of anhydrous benzene for 3 days. The benzene is removed and the residue is concentrated further using short-path distillation (1 micron, 125° bath temperature). Crystallization of the residue from isopropyl alcohol gives 2.39 g of 2-cyclohexylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrol-1-one; nmr spectrum: τ 2.2-3.3 (m, 8); 5.9-6.2 (m, 2); 6.6-7.0 (m, 4); 8.1 (m, 2) and 8.1-9.7 (m, 11).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:12][N:11]=[N:10][N:2]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
Into the same device as used in Example 1 were placed 1.19 g (0.010 mole) of paracyanophenol, 1.95 g (0.030 mole) of sodium azide, 4.13 g (0.030 mole) of triethylamine hydrochloride and 12 ml of toluene. The mixture wasreacted for 8 hours in the same manner as in Example 1, giving 1.34 g (0.0083 mole) of 5-(4-hydroxyphenyl)-1H-tetrazole (yield 82.7% based on paracyanophenol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].I[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C=O)C.C1COCC1.C(OCC)(=O)C.O>[CH2:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCCCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNc1cc(-c2ccncc2)sc1C(=O)OC
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
To a stirred solution of methyl 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylate (1.21 g, 5.00 mmol) in DMF (25 mL) was added sodium hydride (60%, 0.220 g, 5.50 mmol). After 10 min, 1-iodobutane (0.626 mL, 5.50 mmol) was added and stirring was continued for 5 h. The mixture was poured into water (60 mL) and sat. aqueous sodium hydrogen carbonate (60 mL). Ethyl acetate (100 mL) and THF (33 mL) were added to the mixture for extraction, and the insoluble precipitate was filtered off. The organic layer was washed with brine, dried over magnesium sulfate, filtrated and concentrated at reduced pressure. The obtained residue was purified by column chromatography (Combiflash, 40 g silica gel, hexanes to 30:70 hexanes/ethyl acetate) to afford the title compound (0.460 g, 32%) as a yellow oil:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]2[CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([CH:30]=[C:21]([CH3:20])[N:22]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: Cc1cn2cc(O)ccc2n1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2nc(C)cn2c1
Yield: 13 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2-methyl-6-hydroxyimidazo[1,2-α]pyridine obtained according to preparation 5, the desired product is obtained in the form of a white solid with a yield of 13%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(O)(C)C>C1COCC1.O>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[OH:25])=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C(O)c2ccc3c(c2)OCO3)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 1-bromo-3-methoxy-benzene (1.49 g, 8.0 mmol) and dry THF (20 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.6 mmol) and stirred for 20 min. Then a mixture of benzo[1,3]dioxole-5-carbaldehyde (1.03 g, 6.8 mmol) in dry THF (15 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.5 mL, 46 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×40 mL). The combined organic phases were washed with water (2×40 mL), dried over MgSO4 and concentrated to give benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl)-methanol as an oil (2.23 g, 113% crude yield). The product was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][C:8]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)([OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=1)(C)(C)C.[OH-].[Li+]>CO.O>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)([OH:25])[CH2:7][C:6]([OH:31])=[O:5])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(O)(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(O)(CCc1cccc(OCc2ccccc2)c1)C1CCCC1

Procedure:
The title compound was prepared by dissolving (S) 5-(3-benzyloxy-phenyl)-3-cyclopentyl-3-hydroxy-pentanoic acid tert-butyl ester (1.6 g, 3.8 mmol) from Example CCCCC in methanol (20 mL). Lithium hydroxide (0.32 g, 7.6 mmol) in H2O (5 mL) was added and the reaction heated to reflux overnight, cooled and pumped to dryness under vacuum. The product was partitioned between H2O and Et2O. The aqueous layer was decanted, acidified with 1N HCl and extracted with EtOAc. The organic phase was dried (MgSO4), and concentrated to give the title compound. 1H-NMR (CDCl3) δ 1.3-1.7 (m, 8 H), 1.85-1.95 (m, 2 H), 2.3 (t, 1 H), 2.45-2.7 (m, 4 H), 5.1 (s, 2 H), 6.75-6.85 (m, 3 H), 7.15 (t, 1 H), 7.3-7.45 (m, 5 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][C@@H:6]([OH:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.N1C=CN=C1.[CH3:35][C:36]([Si:39](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:38])[CH3:37]>CN(C=O)C>[Si:39]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][C@@H:6]([OH:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)([C:36]([CH3:38])([CH3:37])[CH3:35])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A mixture of 25 (950 mg, 2.34 mmol) and imidazole (396 mg, 5.81 mmol) was dissolved in 5 mL of DMF. TBDPSCl (0.74 mL, 2.79 mmol) was added to the solution dropwise over a 30 min-period using a syringe. The reaction was stirred at room temperature for 16 h. The crude product was chromatographed (SiO2, gradient, hexane/EtOAc 10:1 to 5:1) to give 1.37 g (2.12 mmol, 91%) of 56 which was slightly contaminated with TBDPSCl. Rf 0.46 (hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 4H, H-2 of phenyl), 7.43-7.32 (m, 6H, H-3 and H-4 of phenyl), 3.82 (m, 1H, H-3/H-7), 3.67 (s, 3H, CO2CH3), 3.46 (m, 1H, H-3/H-7), 2.40-0.69 (m, 28H), 1.04 (s, 9H, C(CH3)3), 0.93 (d, 3H, J=6.4 Hz, CH3), 0.79 (s, 3H, CH3), 0.64 (s, 3H, CH3); MS (ESI) Calcd for C41H60O4SiNa (M+Na+): 667.4. Found: 667.4.
Reaction SMILES: [NH2:1][C:2]([C:16]([O:18]CC)=[O:17])([CH2:8][CH2:9][CH:10]([F:15])[CH:11]([NH2:14])[CH:12]=[CH2:13])[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl.C1OC1C>C(O)C.C(O)(C)C>[NH2:1][C:2]([C:16]([OH:18])=[O:17])([CH2:8][CH2:9][CH:10]([F:15])[CH:11]([NH2:14])[CH:12]=[CH2:13])[C:3]([OH:5])=[O:4]
Reactant: C=CC(N)C(F)CCC(N)(C(=O)OCC)C(=O)OCC
Agent: CC1CO1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: C=CC(N)C(F)CCC(N)(C(=O)O)C(=O)O

Procedure:
The crude material 23 (11.5 g, about 31 mmoles since some solvent left) is dissolved in ethanol (150 mL) and 2N NaOH (150 mL) and stirred at room temperature for 3 hours. The mixture is neutralized with conc. HCl (about 25 mL) with cooling, then acidified (HCl). After evaporation and drying, the residue is dissolved in ethanol, filtered through millipore, and evaporated again. Dissolving in water, filtration, and evaporation yields a solid (11 g, 2 g more than theory). This is dissolved in isopropanol (130 mL) and treated with propylene oxide (6.5 mL, 3 equivalents). Crude 24 (7.2 g, somewhat more than theory) is collected. Thin layer chromatography (ethanol/NH4OH 80/20 revelation ninhydrin) indicates the presence of some decarboxylated product. The compound 24 is used without further purification. Recrystallization from water/ethanol is possible. Caution: no heating!
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[C:24]([Cl:30])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:12])=[C:24]([Cl:30])[CH:23]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=C1CCCN1C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Yield: 66.2 %

Procedure:
Using the procedure to synthesize Example 1 and using reagents N-cyclohexylpyrrolidinone (15 g, 89.7 mmol), LDA (2.0 M, 53.8 mL, 107.6 mmol) and 4-bromo-1-bromomethyl-2-chloro-benzene (preparation 5) (30.6 mg, 107.6 mmol) affords 22 g (66%) of 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:58]([N:62]=[C:63]=[O:64])[CH2:59][CH2:60][CH3:61]>C(O)C>[CH2:58]([NH:62][C:63](=[O:64])[NH:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:59][CH2:60][CH3:61]
Reactant: CC(C)[C@@H](CCN)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCCCN=C=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)NCC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
0.100 g (0.145 mmol) of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-amino-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride in 1 ml of ethanol is treated with 0.05 ml (0.25 mmol) of Hunig base, cooled to 0° and treated with 0.018 ml (0.16 mmol) of butyl isocyanate in 1 ml of ethanol. Then, the reaction mixture is stirred at room temperature for 2 hours and subsequently evaporated under reduced pressure. Chromatography of the residue on 5 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.063 g of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-(3-butylureido)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 754 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1.[OH-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].COCCOCCOC.C(=O)=O>C(COC)OC.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=[O:17])=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCOCC
Solvent: COCCOC
Solvent: COCCOCCOC
Product: O=CCCc1ccc(-c2ccccc2Cl)cc1

Procedure:
β-(2'-chloro-4-biphenylyl)propionyl chloride (28 g.) in 500 ml glyme is treated dropwise with a solution of lithium tri-t-butoxyaluminum hydroxide (25.5 g.) in 500 ml. diglyme while maintaining the reaction temperature at -70°C with dry ice. When addition is complete, the mixture is allowed to come to room temperature, is diluted with ether, and washed with water, dilute HCl and brine. The solvent is dried over sodium sulfate, evaporated under vacuo and the residue distilled to give β-(2'-chloro-4-biphenylyl)propionaldehyde
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1
Reactant: C1=COCCC1
Reactant: CC(=O)c1cc(CO)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(COC2CCCCO2)on1

Procedure:
A solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (252 mg, 1.79 mmol), 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol) in DCM (10 mL) was stirred at RT for 16 hr and then for a further 0.5 hr at 40° C. after the addition of more 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol). The reaction mixture was diluted with water (5 ml) and the solution extracted with DCM (2×20 ml). The combined organic layers were washed with brine (5 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography (Isolute, 9:1 heptane:EtOAc) to give the title intermediate: 1H NMR (500 MHz, CDCl3) delta 1.56-1.53 (2H, m), 1.68-1.60 (2H, m), 1.89-1.69 (2H, m), 2.65 (3H, s), 3.62-3.51 (1H, m), 3.93-3.78 (1H, m), 4.68 (1H, d, J=13.9 Hz), 4.75 (1H, t, J=3.3 Hz), 4.86-4.80 (1 H, m), 6.63 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].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]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1

Procedure:
1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.2 g, 0.2 mmol) was added to a stirred and degassed solution of 4-bromonitrobenzene (5 g, 24.8 mmol) and pyridine-3-boronic acid (3.4 g, 27.2 mmol) in dimethyl formamide (50 mL) and 2N sodium carbonate solution in water (20 mL). The reaction mixture was stirred at 100° C. for 18 hours, then allowed to cool. The solution was filtered through celite (Diatomaceous Earth), then ethyl acetate (200 mL) was added and the organic phase was washed three time with brine (200 mL). The organic was dried (anhydrous magnesium sulfate), concentrated and purified by chromatography on silica gel (30% v/v ethyl acetate in petroleum ether) to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:18])[CH3:17]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)(Cl)Cl>[C:11]([C:7]1[CH:8]=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
A mixture of 2,6-di-t-butylphenol (1 g) in trifluoroacetic anhydride (5 ml) is carefully treated with 0.28 ml of glacial acetic acid and the reaction mixture is stirred at 20°-25° for 1 hr. The reaction mixture is diluted with chloroform and is separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (1.39 g) is chromatographed on 180 g of silica gel. The column is packed and eluted with chloroform/acetone (99/1). An initial fraction of 200 ml is collected, followed by 7 ml fractions. Based on their TLC homogeniety, fractions 20-55 are combined and concentrated. Recrystallized from hexane gives the tire compound, mp 148°-150°; IR (mineral oil) 3581, 3007, 2956, 2925, 2871, 2856, 1663, 1596, 1581, 1465, 1463, 1442, 1423, 1370, 1364, 1356, 1320, 1305, 1274, 1239, 1232, 1138, 1124, 1108 an 886 cm-1 ; NMR (CDCl3, TMS) 7.84, 5.73, 2.56, and 1.47δ; CMR (CDCl3, TMS) 197.6, 158, 4, 135.8, 129.1, 126.1, 34.4, 30.2 and 26.3δ; MS (m/z) M+ (found)=248; other ions at m/z 233, 217, 205, 189, 178, 115, 57 and 43.