Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][CH2:15][C:16]1[N:21]=[C:20]([O:22][C:23]2[C:24]([F:33])=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH3:32])=[CH:26]3)[CH:19]=[CH:18][N:17]=1)(=[O:13])[CH3:12].[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=[O:36].[NH4+].[Cl-]>C1COCC1.O>[F:33][C:24]1[C:23]([O:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:15][O:14][C:11](=[O:13])[CH3:12])[N:21]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:32])[N:28]2[C:35](=[O:36])[NH:34][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:46])[F:45])[CH:38]=1
Reactant: CC(=O)OCc1nccc(Oc2ccc3[nH]c(C)cc3c2F)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1nccc(Oc2ccc3c(cc(C)n3C(=O)Nc3cccc(C(F)(F)F)c3)c2F)n1

Procedure:
LHMDS (1.0 M in THF, 7.68 mL, 7.68 mmol) is added over 1 min to a solution of (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate (1.21 g, 3.84 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (0.70 mL, 5.08 mmol) in THF (40 mL) at −78° C. for 40 min. Saturated aqueous NH4Cl (100 mL) and water (20 mL) are added and the mixture is extracted with EtOAc (3×60 mL). The combined organic layers are washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give acetic acid 4-[4-fluoro-2-methyl-1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-2-ylmethyl ester. MS (ESI) m/z 503.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1H) 8.68 (d, J=5.81 Hz, 1H) 8.12 (s, 1H) 7.92 (d, J=7.83 Hz, 1H) 7.66 (t, J=8.08 Hz, 1H) 7.51-7.55 (m, 2H) 7.11-7.18 (in, 2H) 6.64 (s, 1H) 5.02 (s, 2H) 2.59 (s, 3H) 1.88 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])([CH3:4])([CH3:3])[CH3:2].N1(CCN)C[CH2:45][O:44][CH2:43]C1>>[C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][CH2:35][CH2:36][N:37]1[CH2:39][CH2:45][O:44][CH2:43][CH2:38]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)OC(C)(C)C)c2c1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN3CCOCC3)n(CC(=O)OC(C)(C)C)c2c1
Yield: 92 %

Procedure:
The title compound was obtained following the same procedure described in Example 1, Step 3 for the synthesis of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1H-indole-6-carboxylate, using 2-morpholin-4-ylethyl amine instead of N,N-dimethylethane-1,2-diamine. The title compound was obtained in a 92% yield; MS (ES+) m/z 590 (M+H)+
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8](=[O:28])[NH:9][N:10]=[CH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O.C(O)(=O)C>[C:29]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:28])[NH:9][NH:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)COc1cccc2c1CCC(C=NNC(=O)N(c1ccccc1)c1ccccc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)COc1cccc2c1CCC(CNNC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of the compound prepared in example 13 (291 mg) in methanol (6.5 ml) was added sodium cyanoborohydride (42 mg) and added dropwise followed by acetic acid (1.45 ml). The mixture was stirred overnight at room temperature. After acidified by adding 2N hydrochloric acid until pH 1, the mixture was stirred for 30 min. The mixture was diluted with water. After neutralized by adding sodium bicarbonate until pH 7~8, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (235 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH2:9][CH2:10][CH2:11][Si:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[C:6](O)[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([CH2:9][CH2:10][CH2:11][Si:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[C:6]([SH:22])[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C[Si](C)(CCCc1nnc(N)nc1O)c1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(CCCc1nnc(N)nc1S)c1ccccc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
In a flask were placed 2.90 g (0.0105 mole) of 3-amino-5-hydroxy-6-(4-methyl-4-phenyl-4-silapentyl)-1,2,4-triazine, 8.94 g (0.0201 mole) of phosphorus pentasulfide, and 40 mL of pyridine. This mixture was heated at reflux under a nitrogen atmosphere for one hour. The reaction mixture was concentrated under reduced pressure to a volume of approximately 25 mL and then mixed with 150 mL of ice water. The resulting mixture was warmed on a steam bath for 4 hours after which it was cooled to ambient temperature. An orange solid was collected from this mixture by filtration and was stirred with 60 mL of methanol. Filtration of this mixture yielded 2.70 g of 3-amino-5-mercapto-6-(4-methyl-4-phenyl-4-silapentyl)-1,2,4-triazine, m.p. 255°-257° C. (decomposition). The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[F:17][C:18]1([F:33])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3([C:30](Cl)=[O:31])[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:30]([C:27]2([C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:33])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:28]2)=[O:31])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1ccc(N)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-5-methylpyridin-2-amine (11 g, 78 mmol) and triethylamine (22.0 mL, 156 mmol) in dichloromethane (100 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (20.3 g, 78 mmol) in dichloromethane (50 mL). The resulting reaction mixture was allowed to stir at room temperature for eighteen hours. The reaction mixture was then washed with 1N aqueous NaOH (2×200 mL), 1 N aqueous HCl (1×200 mL) and saturated aqueous NaHCO3 (1×200 mL). The organics were dried over sodium sulfate and evaporated to yield the product (26.9 g, 73.3 mmol, 94% 2-step). ESI-MS m/z calc. 366.06, found 367.3 (M+1)+. Retention time 2.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.89-7.87 (m, 1H), 7.78-7.76 (m, 1H), 7.54-7.53 (m, 1H), 7.41-7.39 (m, 1H), 7.33-7.30 (m, 1H), 2.26 (s, 3H), 1.52-1.49 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Reactant: NCCc1ccc(O)cc1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 141 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+ of 436. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.72 (s, 1H) 8.34 (d, 2H) 7.95 (d, 1H) 7.68 (m, 2H) 7.17 (d, 2H) 6.72 (d, 2H) 4.54 (s, 2H) 3.96 (t, 2H) 3.71 (s, 2H) 3.35 (m, 4H) 2.96 (t, 2H) 1.76 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH2:9][C:8]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7](=[O:23])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1CCC(C(C)C(OCC)=O)C(=O)C=1)C(C)C.[OH-].[Na+].C(C1CCC(C(C)C(O)=O)(C(O)=O)C(=O)C=1)C(C)C.C(C1CCC(C(C)C(O)=O)C(=O)C=1)C(C)C>C(O)C>[C:11]([C:8]1([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[CH2:9][CH2:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]1=[O:23])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)C1(C(=O)OCC)CCC(CC(C)C)=CC1=O
Agent: CC(C)CC1=CC(=O)C(C(=O)O)(C(C)C(=O)O)CC1
Agent: CC(C)CC1=CC(=O)C(C(C)C(=O)O)CC1
Agent: CCOC(=O)C(C)C1CCC(CC(C)C)=CC1=O
Solvent: CCO
Product: CCOC(=O)C1(C(C)C(=O)O)CCC(CC(C)C)=CC1=O
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A chromatographed 1 gm. mixture of ethyl 2-(4-isobutyl-1-carboethoxy-2-oxocyclohex-3-enyl)propionate and ethyl 2-(4-isobutyl-2-oxocyclohex-3-enyl)propionate was dissolved in ethanol (4.0 ml.) and then 5.5 ml. of 1 N sodium hydroxide solution was added. The resulting mixture was stirred at 40° C. for 20 hours and then concentrated to about 7 ml. volume. The aqueous residue was extracted with 5 ml. of Skellysolve B and the extract was backwashed with 3 ml. of 1 N sodium hydroxide. The aqueous phases were combined and acidified, extracted as before, dried and concentrated to give an oil, 0.672 g. This oil product consisted of 2-(4-isobutyl-1-carboxy-2-oxocyclohex-3-enyl)propionic acid and 2-(4-isobutyl-2-oxo-cyclohex-3-enyl)propionic acid. This was shown by taking gas liquid chromatographs (glc.) and mass spectra of portions of the product oil which had been converted to silyl esters and methyl esters.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH:3]([NH:6][C:7](=[O:9])[CH3:8])[CH2:4][OH:5]>CO>[OH:1][CH:2]([C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH:3]([NH:6][C:7](=[O:9])[CH3:8])[CH2:4][OH:5]
Reactant: CC(=O)NC(CO)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CC(=O)NC(CO)C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a clean, round bottom flask N-[2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl] acetamide (1.27 g 5 mmoles) was dissolved in methanol (50 ml). The flask was then fitted with a suitable adaptor and coupled to an hydrogenation apparatus. The atmosphere in the flask was then replaced with nitrogen. The adaptor was then removed and 10% palladium on carbon catalyst (466 mg) was added to the flask. The adaptor was replaced and the hydrogenation apparatus manipulated to replace the atmosphere in the flask with hydrogen. The flask contents were then stirred at room temperature under an atmosphere of hydrogen overnight. The hydrogenation apparatus was manipulated to replace the atmosphere in the flask with nitrogen. The flask was then disconnected from the hydrogenation apparatus.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (2 g, 8.02 mmol) in dichloromethane (30 mL) and pyridine (1.3 mL, 16.04 mmol, d=0.978), was added benzyl chloroformate (1.17 mL, 8.18 mmol, d=1.195). After stirring at room temperature for 24 hours, the reaction mixture was diluted with dichloromethane (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to obtain benzyl 1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][CH2:19][CH2:20][NH:21][C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].S1C=CC=C1>CO.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[CH2:4][NH:18][CH2:19][CH2:20][NH:21][C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]
Reactant: NCCNC(=O)C1CCCCC1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1C=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(C(=O)c2ccccc2)cc1CNCCNC(=O)C1CCCCC1

Procedure:
A mixture of 2-amino-5-benzoylbenzaldehyde (0.007 mol) and cyclohexanecarboxylic acid (2-amino-ethyl)-amide (0.007 mol) in methanol was hydrogenated at 50° C. with 10% Pd/C (0.5 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 gas (1 equiv.) the catalyst was filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (Biotage column) (eluent:CH2Cl2:methanol gradient). The desired fractions were collected and the solvent evaporated to yield the title compound as a residue.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)=[O:24].Cl.O>C1COCC1.C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:14]2[C:13]([C:23](=[O:24])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:29][CH:30]=3)=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:2]=[O:1])[S:16][C:15]=2[CH:17]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C3OCCO3)sc2c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C=O)sc2c1

Procedure:
To a solution of [2-(2-[1,3]dioxolan-2-yl-phenyl)-6-methoxy-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (crude) in THF (15 mL), add HCl (2 mL, 5M) and water (2 mL). Heat the mixture to reflux for 30 min. Dilute with CH2Cl2 and quench with aq. NaHCO3. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% (2M NH3 in MeOH)/CH2Cl2) to afford 2-{6-methoxy-3-[4(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzaldehyde (410 mg) which is contaminated with unidentified byproducts and is used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C([Li])CCC.[C:21]([N:40]1[CH:44]=[C:43]([CH:45]=[O:46])[N:42]=[CH:41]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[OH:46][CH:45]([C:43]1[N:42]=[CH:41][N:40]([C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:44]=1)[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Under nitrogen atmosphere, 5.8 liters of THF was added to 105.6 g (0.40 mol, 1.2 eq) of 6-bromo-N-methyl-2-naphtamide, the mixture was warmed to 50° C. to dissolve it. 500 mL (0.50 mol, 2.4 eq) of a 1.6 M solution of n-butyllithium in hexane was added dropwise at −65° C. or lower over 35 minutes. The mixture was stirred at −65° C. for 1 hour. A solution of 112.7 g (0.33 mol) of 1-trityl-4-formyl-1H-imidazole in 810 mL of THF was added dropwise at −65° C. or lower over 40 minutes. The mixture was stirred at −65° C. for 2 hours. 1.5 Liters of an aqueous saturated ammonium chloride solution was added dropwise at −20° C. or lower, and the mixture was warmed to 30° C. After separation of the layers, the organic layer was washed with 1.5 liters of an aqueous saturated sodium chloride solution two times. After concentration under reduced pressure, 1 liter of ethyl acetate was added to the residue, and the mixture was stirred at 25° C. for 3 hours. Crystals were filtered, and washed with ethyl acetate. Vacuum drying (50° C.) to a constant weight afforded 87.9 g of 6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (yield 50%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13](C)C=C[C:6]=1S([O-])(=O)=O)(=[O:3])[CH3:2].C(O)(=[O:18])C>>[OH:18][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:14]=[CH2:13]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1cc(C)ccc1S(=O)(=O)[O-]
Product: C=CC(CO)OC(C)=O

Procedure:
Alternatively, the acetoxy-tosylate could be prepared by initial reaction of EpB with acetic acid under palladium(0) catalysis to afford 1-hydroxy-2-acetoxy-3-butene. Tosylation under normal conditions (p-TsCl, Et3N, CH2C12, 88%) afforded the desired product. However, the isomeric inconsistency of the monoacetate material (acetyl migration during distillative purification) and the inseparability of the positional isomers of two intermediates posed significant problems, since the unwanted isomers complicated the enzymatic hydrolysis. Therefore, the former (diol) preparation is preferred.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1cc(S(=O)(=O)NCCCCO)ccc1Br
Reactant: OB(O)c1ccc(F)cc1F
Product: Cc1cc(S(=O)(=O)NCCCCO)ccc1-c1ccc(F)cc1F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-3-methylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a thick oil. δC (DMSO, 62.9 MHz): 20.0, 26.4, 29.5, 43.1, 62.2, 104.2 (t, 25.4), 111.6 (d, J 21.5), 123.8 (d J 11.7), 124.4, 128.4, 131.7, 131.8 (m), 138.4, 139.4 (d, J 3.9), 159.4 (d J 250.0, 11.7) and 162.8 (dd 250.0, J 11.7).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:30])[CH2:10][CH2:11][C:12]1[S:13][C:14]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)=[CH:15][C:16]=1[OH:17].Br[CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:30])[CH2:10][CH2:11][C:12]1[S:13][C:14]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)=[CH:15][C:16]=1[O:17][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1sc(C(=O)c2cccc(C(=O)OC)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(C(=O)c2cccc(C(=O)OC)c2)cc1OCCCC/C=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 81.9 %

Procedure:
804 mg of cesium carbonate is added to a solution of 430 mg of 3-[5-(3-Methoxycarbonylbenzoyl)-3-hydroxy-2-thienyl]-propionic acid methyl ester and 332 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene in 2.9 ml of dimethylformamide and the suspension is stirred for 21 hours at room temperature. The reaction mixture is filtered, the filtrate residue is washed with dichloromethane, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel with hexane. 542 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[N:15][OH:16])=[N:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl.O>CN(C=O)C>[CH3:1][NH:2][C:3](=[O:17])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[N:15][O:16][CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=1)=[N:5][O:6][CH3:7]
Reactant: ClCc1cccc(Cl)c1
Reactant: CNC(=O)C(=NOC)c1ccccc1C=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(=NOC)c1ccccc1C=NOCc1cccc(Cl)c1
Temperature: 110 °C
Yield: 58.7 %

Procedure:
To a solution of 1 g (4.26 mmol) of N-methyl-2-{2-(hydroxyiminomethyl)phenyl}-2-methoxyiminoacetamide and 0.62 g (4.5 mmol) of potassium carbonate in 10 ml of DMF, was added 0.69 g (4.29 mmol) of 3-chlorobenzyl chloride and the mixture was stirred under heating at 110° C. for 3 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, successively washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed over SiO2 to give 0.9 g of the title compound (yield: 58.8%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH3:30])[CH:22]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([OH:20])[CH:28]=[CH:27][C:24]=1[CH2:25][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(O)ccc1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(O)ccc1CN1CCCC1

Procedure:
NaB(OAc)3H (8.7 g, 0.041 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.4 mL, 0.0.41 mol) and 4-hydroxy-2-methoxybenzaldehyde (5 g, 0.033 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 2 h and cooled. Then 10 N NaOH (4.1 mL) and water (30 mL) were added. The organic layer was separated, the aqueous one was extracted with chloroform (2×50 mL). The organic fractions were evaporated. The residue was distributed between water and CH2Cl2. Concentrated HCl (2.98 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (3.37 g, 07%) as yellow crystals. 1H-NMR (400 MHz)-data (dmso-d6, j, Hz): 9.25 (s, 1H ArOH), 7.02 (d, 1H, J=8.3, Ar—H), 6.36 (d, 1H, J=2.2, Ar—H) 6.30 (dd, 1H, J1=8.3, J2=2.2, Ar—H), 3.70 (s, 3H, ArOCH3), 3.44 (s, 2H, ArCH2), 2.38-2.44 (m, 4H, pyrrolidine (CH2)2N), 1.62-1.68 (m, 4H, CH2CH2CH2CH2).