Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[O:10]1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]>O>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[C:26]([C:27]([O:29][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[O:28])=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC(OC(=O)c2cccnc2Nc2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 50 °C
Yield: 49.5 %

Procedure:
Triethylamine (20 ml) and 3-bromophthalide (21.3 g) were added to a suspension of 2(3'-trifluormethylanilino)-nicotinic acid (28,2 g in 500 ml of acetone). The mixture was refluxed during 4 hours. The obtained greenish yellow suspension was poured into 6000 ml of water, which was previously heated at 50° C. The stirred reaction mixture was cooled to 5° C., and the formed precipitate was filtered and washed with cool water. Yield: 52% (20.5 g) of phthalidyl 2-(3'-trifluormethylanilino)-pyridin-3-carboxylate, m.p: 162°-164° C.
Reaction SMILES: [OH:1]O.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[O:15][C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2>CO>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]1[C:16]2[O:15][C:14]([C:12]([NH:11][C@@H:5]3[CH:6]4[CH2:7][CH2:8][N+:3]([O-:1])([CH2:10][CH2:9]4)[CH2:4]3)=[O:13])=[CH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: OO
Reactant: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Solvent: CO
Product: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3C[N+]4([O-])CCC3CC4)oc12
Reaction time: 18 h

Procedure:
35.8 μl (0.35 mmol) of 30% strength hydrogen peroxide are added to a solution, cooled to 0° C., of 110 mg (0.29 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide (Example 130) in 2 ml of methanol. After 18 h at room temperature, a further 35.8 μl (0.35 mmol) of 30% strength hydrogen peroxide are added. After a further 18 h at room temperature, the reaction solution is concentrated, and the residue is dried under high vacuum. 111.5 mg (97.2% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[CH:21]=[N+:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:17][O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[CH:21]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13](=[O:36])[N:14]([CH2:33][CH2:34][CH3:35])[C:15](=[O:32])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:17]=1[NH2:18]>>[CH2:7]([C:8]1[NH:11][C:12]2[C:13](=[O:36])[N:14]([CH2:33][CH2:34][CH3:35])[C:15](=[O:32])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[C:17]=2[N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCn1c(=O)c(N)c(N)n(CCCCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCCCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, phenylacetic acid is reacted with 5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil to yield 8-benzyl-1-propyl-3-[4-(4-nitrophenyl)butyl]xanthine. In turn, 5,6-diamino-3-propyl-1-[4-(4-nitroyphenyl)butyl]-3-uracil is made by the synthetic methods of Example 1, starting with n-propyl isocyanate and 4-(4-nitrophenyl)butylamine. By the methods of Example 3 and Example 4,8-benzyl-3-[4-(4-nitrophenyl)butyl]-1-propylxanthine is alkylated with a mixture of 1,2-dichloroethane and 2-(ethylamino)ethanol, to afford 8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[4-(4-nitrophenyl)butyl]-1-propylxanthine, which, in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[4-(4-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:39](OC)(OC)[O:40][CH3:41]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][CH:39]1[O:40][CH3:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 40 %

Procedure:
A solution of 10.0 g of methyl (2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 0.334 g of pyridinium p-toluenesulphonate and 3.75 cm3 of trimethyl orthoformate in 70 cm3 of toluene is heated to reflux. 4 cm3 of solvent are distilled off. After cooling to a temperature in the region of 20° C. and filtration, the filtrate is concentrated to dryness under reduced pressure. The residue is taken up with 50 cm3 of hexane. The slurry obtained is filtered, rinsed and drained. 4.6 g of (4S,5R)-3-t-butoxycarbonyl-2-methoxy-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine are thereby obtained in a 40% yield in the form of a mixture of diastereoisomers, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][O:14][CH3:15])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:12][CH2:13][O:14][CH3:15])[C:5]=1[O:10][CH3:11])[CH:21]=[O:22]
Reactant: COCCc1cc(Br)cc(OC)c1OC
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCc1cc(C=O)cc(OC)c1OC
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g of 5-bromo-1,2-dimethoxy-3-(2-methoxy -ethyl)benzene in 20 ml of THF there was added dropwise 2 ml of n-butyllithium (2.66 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 30 minutes, 0.7 ml of N-formylmorpholine was added and the temperature was raised from −70° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (806 mg) as an oil.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:12]=1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)nc1NC1CCCCC1

Procedure:
By allowing ethyl 2,6-dichloronicotinate and cyclohexanamine to undergo the reaction at 50° C. for 1 hour in DMF in the presence of potassium carbonate, ethyl 6-chloro-2-(cyclohexylamino)nicotinate was obtained. By carrying out hydrolysis of an ethanol solution of this at 70° C. for 18 hours in the presence of 1 M sodium hydroxide, 6-chloro-2-(cyclohexylamino)nicotinic acid was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][C:22]=2[O:31][CH3:32])=[C:9]([CH3:33])[N:8]=1.[C:34]([O-])(O)=O.[Na+]>CO>[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:34])=[O:29])=[CH:23][C:22]=2[O:31][CH3:32])=[C:9]([CH3:33])[N:8]=1
Reactant: O=C([O-])O
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a solution of the product from step (v) (0.09 g) in MeOH (1 mL). The solution was heated at 70° C. for 3 h and then poured into saturated aqueous NaHCO3 solution (10 mL). The aqueous was extracted with EtOAC and the combined organic phases were dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.007 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[N:22]=[C:23](N)[NH:24][C:25]=1[Cl:26]>>[Cl:26][C:25]1[N:24]=[CH:23][N:22]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]5[O:15][CH2:16][CH2:17][O:18][C:11]=5[CH:10]=4)[C:5]([F:19])=[CH:4][N:3]=3)=[CH:10][CH:11]=2)[C:21]=1[Cl:20]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1nc(Cl)c(Cl)[nH]1
Product: Fc1cnc(Nc2ccc(-n3cnc(Cl)c3Cl)cc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 4,5-dichloro-1H-imidazoleamine gave N2-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.10 (s, 1H), 9.85 (s, 1H), 8.20 (d, 1H, J=4.2 Hz), 8.01 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.36 (d, 1H, J=9 Hz), 7.25 (d, 1H, J=3 Hz), 7.14 (dd, 1H, J=2.1 and 9 Hz), 6.85 (d, 1H, J=8.7 Hz); LCMS: ret. time: 23.59 min.; purity: 95%; MS (m/e): 474 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([CH2:18]P(=O)(OCC)OCC)#[N:17].[H-].[Na+].O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:18]/[C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#C/C=C/C1CCN(Cc2ccccc2)CC1
Yield: 109.8 %

Procedure:
A solution of 1-benzyl-4-formylpiperidine (4.5 g) in tetrahydrofuran (20 ml) was added dropwise to a suspension of diethyl cyanomethylphosphonate (4.31 g) and sodium hydride (0.97 g, 60% suspension in oil) in tetrahydrofuran (30 ml) at 0° C. under stirring. After stirring for 1 hour at ambient temperature, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo to give (E)-3-(1-benzylpiperidin-4-yl)-2-propenenitrile (5.5 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C@H:19]([NH:23]C(OC(C)(C)C)=O)[C:20](O)=O.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:52]>C(Cl)Cl.O>[ClH:52].[ClH:52].[Br:1][C:2]1[C:3]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:18]([C@@H:19]([NH2:23])[CH3:20])=[N:10][C:4]=2[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N)c(Nc2ccccc2)c1Br
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 181.8 %

Procedure:
To a solution of 3-bromo-4-methoxy-N2-phenylbenzene-1,2-diamine (421 mg, 1.8 mmol), Boc-ala-OH (343 mg, 1.8 mmol) and HOAT (247 mg, 1.8 mmol) in DCM (10 mL) at 0° C. was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (383 mg, 1.99 mmol) and the reaction mixture stirred at 0° C. for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (10 mL, 4 M) and the reaction mixture heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (758 mg, 100%). LCMS (Method C): RT=2.15 min, [M+H]+=346 & 348.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([C@H:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([C@H:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:18]([O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Benzyl bromide (4.40 g, 25.7 mmol) was added dropwise to a mixture of (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (4.00 g, 12.9 mmol) and Cs2CO3 (4.20 g, 12.9 mmol) in DMF (80 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (80 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1 to 4:1) to afford (2S,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (3.7 g, 66% yield) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.CN(C=O)C.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[CH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccccc1-c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
2-(2-bromophenyl)-1H-imidazole (WO 9407486; 1.0 g, 4.48 mmol) was dissolved in THF (11 mL) and DMF (11 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 197 mg, 4.93 mol) was added and the reaction stirred for 20 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (0.79 mL, 4.93 mmol) was added and the reaction stirred overnight at room temperature. The reaction was quenched with MeOH then partitioned between water and Et2O. The organic layer was dried (MgSO4) and concentrated in vacuo and the residue was purified by flash column chromatography to afford 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole as an off-white solid (1.5 g).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=[CH2:3].I[CH2:30][CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35]>>[CH2:1]([C:4]1([CH2:30][CH2:31][O:32][Si:33]([CH:37]([CH3:38])[CH3:39])([CH:34]([CH3:36])[CH3:35])[CH:40]([CH3:41])[CH3:42])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Product: C=CCC1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3.70 g (8.9 mmol) of a mixture of C-3 diastereomers of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-oneoxopentanoate (Example 35, Step B) and 20.7 g (63 mmol) of (2-iodoethoxy)triisopropylsilane in dry, degassed THF (60 mL) was added 54.5 mL (54.5 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly via syringe over 6 min. After 10 min, the orange solution was warmed to 40° C. and stirred for an additional 2.25 h. The reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2-25% EtOAc/hexanes, gradient elution) provided the title compound (mixture of C-3 epimers) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][OH:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1

Procedure:
15.1 g (100 mmol) of N-benzylethanolamine is dissolved in 50 ml of tetrahydrofuran and mixed with 15 ml of water and 13.8 g (100 mmol) of potassium carbonate. After instillation of 20.5 g (105 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for 6 hours at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C@@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si](C(C)(C)C)(C)C)[CH:26]=2)[C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C@H:7]([CH3:39])[CH2:6]1)[CH:3]=[CH2:4].O>C1COCC1>[CH2:2]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C@@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[C@H:7]([CH3:39])[CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Aqueous hydrochloric acid (3 M, 7 mL) was added to a solution of 4-{(R)-((2R,5S)-4-allyl-2,5-dimethyl-piperazin-1-yl)-[3-(tert-butyl-dimethylsilanyloxy)-phenyl]-methyl}-N,N-dimethyl-benzenesulfonamide (1.3 g) in THF (15 mL). The mixture was stirred at room temperature overnight. Water (15 mL) was added to the reaction. The reaction mixture was extracted with diethyl ether (25 mL×3). The remaining H2O layer was neutralized by 10% aqueous NaOH to pH=8-9 and then extracted by EtOAc (30 mL×3). The combined EtOAc layers were washed by water (20 mL×3) and brine (20 mL×1), dried over Na2SO4 and concentrated to give 0.83 g of crude product. The crude product was purified by silica gel chromatography conducted on CombiFlash™ Sq 16x (gradient: 100% CH2Cl2 to 7% MeOH in CH2Cl2) to give 4-[(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)-(3-hydroxy-phenyl)methyl]-N,N-dimethylbenzenesulfonamide (720 mg; 70%). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H, J=8.5 Hz), 7.35 (d, 2H, J=8.5 Hz), 7.14 (dd, 1H, J=8.0, 8.0 Hz), 6.89 (bs, 1H), 6.85 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0, 2.5 Hz), 5.83 (1H, m), 5.24-5.12 (m, 3H), 3.32 (dd, 1H, J=13.5, 5.0 Hz), 2.86 (dd, 1H, J=13.5, 8.0 Hz), 2.78 (dd, 1H, J=11.5, 3.0 Hz), 2.72 (s, 6H), 2.65 (dd, 1H, J=11.0, 2.5 Hz), 2.51 (m, 2H), 2.14 (dd, 1H, J=11.5, 9.0 Hz), 1.81 (dd, 1H, J=11.0, 9.5 Hz), 1.16 (d, 3H, J=6.0 Hz), 0.98 (d, 3H, J=6.0 Hz); MS (FAB, glycerol) m/z: 444 (M++H), 290, 153; Found: C, 58.32; H, 6.66; N, 8.18. Calc. (C24H33N3O3S 0.8 CH2Cl2): C, 58.23; H, 6.82; N, 8.21.
Reaction SMILES: O.[OH-].[Li+:3].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:54]OC)[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15]C)=[O:14])([CH3:7])[CH3:6].[C:57](=O)=[O:58]>O1CCOCC1>[OH:4][C:5]([C:8]1[NH:9][C:10]([CH3:54])([O:58][CH3:57])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([O-:15])=[O:14])([CH3:6])[CH3:7].[Li+:3]
Reactant: O=C=O
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC1(C)NC(C(C)(C)O)=C(C(=O)[O-])N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
15 ml of an aqueous solution containing 243 mg of lithium hydroxide monohydrate were added, whilst ice-cooling, to a solution of 2.72 g of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 82 (a)] in 33 ml of dioxane, and the resulting mixture was stirred at 5°-10° C. for 16 hours. At the end of this time, a small piece of dry ice was added to the reaction solution, and the reaction solution was concentrated by distillation under reduced pressure to a volume of about 15 ml. The concentrate was mixed with ethyl acetate and a saturated aqueous solution of sodium chloride and stirred. The resulting reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give a glassy salt of lithium 4-(1-hydroxy-1-methylethyl)-2-methoxy-methyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate. The whole of this product was dissolved in 25 ml of N,N-dimethylacetamide, and 533 mg of potassium carbonate were added to the resulting solution, after which a solution of 1.13 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity degree:74%) in 5.6 ml of N,N-dimethylacetamide was added dropwise to the mixture, whilst ice-cooling. The mixture was then stirred at 50° C. for 3 hours, after which it was diluted with ethyl acetate and water. The mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure. The resulting crystalline residue was washed with diethyl ether, to give 2.70 g of the title compound, melting at 144°-146° C. (with decomposition).