Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:21]C(=O)C1C=CC=CC=1)[CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:11]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)=[O:7].O1CCCC1>C(N(CC)CC)C>[NH2:21][C@@H:4]([CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:11]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)=[O:7])[C:3]([O:2][CH3:1])=[O:30]
Reactant: COC(=O)[C@H](CC(=O)c1ccc2oc3ccccc3c2c1)NC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CC(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid methyl ester, prepared as described in Step (b) of Example 6, was dissolved in tetrahydrofuran containing one equivalent of triethylamine. The solution was stirred at room temperature for 1 hour, and then the solvent was removed by evaporation to give a solid. The solid was washed with water to give methyl (S)-2-amino-4-dibenzofuran-2-yl-4-oxo-butyrate as a mono-hydrate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31]CC)=[O:30].[OH-].[K+]>C1COCC1.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(C)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(C)c(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.495 g, 0.926 mmol) was hydrolyzed with potassium hydroxide (0.153 g, 2.73 mmol) in THF (7.5 mL) and water (7.5 mL) to afford 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid. Conversion to the sodium salt by treating with 1N sodium hydroxide (0.72 mL, 0.72 mmol) in methanol (12 mL) furnished the title compound as a cream-colored solid (0.228 g), mp 221-222° C. Mass spectrum (+ESI, [M+H]+) m/z 507. 1HNMR (500 MHz, DMSO-d6): δ8.25 (d, 1H, J=1.7 Hz), 8.0-8.05 (m, 2H), 7.75-7.8 (m, 2H), 7.7 (dd, 1H, J=7.3 Hz and 0.8 Hz), 7.35-7.45 (m, 4H), 7.15 (t, 1H, J=7.3 Hz), 4.45 (dd, 1H, J=9.8 Hz and 3.1 Hz), 3.25 (dd, 1H, J=13.9 Hz and 2.7 Hz), 3.05 (q, 1H, J=7.9 Hz), 2.7 (t, 2H, J=7.3 Hz), 2.4 (s, 3H), 1.5-1.55 (m, 2H), 1.1-1.15 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C33H30O5Na: Calculated: C, 74.99; H, 5.53; N, 0.00. Found: C, 74.63; H, 5.38; N, 0.08.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:13]([OH:15])=[O:14].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C1=C(F)c2ccc(O)cc2CC1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1=C(F)c2ccc(OCc3ccccc3)cc2CC1

Procedure:
That is, for example, 3,4-dihydro-1-fluoro-6-hydroxy-2-naphthalenecarboxylic acid (i) is reacted with benzyl bromide in the presence of a base such as potassium hydroxide, to obtain 3,4-dihydro-1-fluoro-6-benzyloxy-2-naphthalenecarboxylic acid (ii).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.[OH2:15]>C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:15])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 9 %

Procedure:
A solution of 0.25 g (1.0 mmol) of copper(II) sulfate pentahydrate in 5 mL of water is added to a solution of 0.16 g (1.0 mmol) of 2,2'-dipyridyl in 120 mL of tert-butyl alcohol. To this solution is added 8.6 g (50 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine. A solution of 13.6 g (200 mmol) of 50% aqueous hydrogen peroxide mixed with 13 mL of tert-butyl alcohol is added dropwise to the reaction mixture at 23-40° C. over three hours. The mixture is then stirred at ambient temperature for 72 hours. Gas chromatography shows 9% of the title compound is present in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (5.00 g, 29 mmol) in acetone (50 ml) were added ethyl iodide (4.95 g, 32 mmol) and potassium carbonate (4.37 g, 32 mmol), followed by stirring at room temperature for 20 hours. After filtration of the insoluble matter, the filtrate was subjected to evaporation under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 4-ethoxy-1-chloro-2-nitrobenzene (5.71 g).
Reaction SMILES: C([Li])CCC.[Cl-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][C:9]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH:41]1([C:44]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:45][CH:46]=O)[CH2:43][CH2:42]1>O1CCCC1>[CH:41]1([C:44]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)=[CH:45][CH:46]=[CH:14][C:11]2[CH:12]=[CH:13][C:8]([F:7])=[C:9]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:10]=2)[CH2:43][CH2:42]1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Reactant: O=CC=C(c1ccc(Cl)cc1)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(C=CC=C(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A stirred solution of 0.71 gram (4.4 mL-0.011 mole) of n-butyllithium (2.5M in hexane) in 50 mL of dry tetrahydrofuran was cooled to -78° C., and 4.98 grams (0.01 mole) of 4-fluoro-3-phenoxyphenylmethyltriphenylphosphonium chloride (prepared in Steps C-E) was quickly added. Upon completion of addition the reaction mixture was stirred at -78° C. for one hour, and then a solution of 2.03 grams (0.01 mole) of 3-cyclopropyl-3-(4-chlorophenyl)-2-propenal (prepared in Steps A and B) in 10 mL of dry tetrahydrofuran was added dropwise during a 10 minute period. Upon completion of addition the reaction mixture was stirred at -78° C. for one hour and then was allowed to warm to ambient temperature where it was stirred for two hours. The reaction was quenched with 10 mL of aqueous dilute hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The ether extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 1.4 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[Cl:33][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:35]3[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=3)[C:19](=[O:34])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28]([CH:30]1[CH2:31][CH2:32]1)=[O:29]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)C4CC4)c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(NC(=O)C4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-{2-[7-chloro-6-(cyclopropanecarbonylamino)-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (80 mg in a mixture of 8 mL trifluoroacetic acid and 0.03 mL anisole) was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, resolvated in methylene chloride and washed with saturated sodium bicarbonate. The concentrated organics were purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 94:3:1) to give the title compound (52 mg). MASS: 494 (M+H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1.NN.O>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1
Reactant: Cc1nn(C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c2ccc(N)cc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To a solution of 307a (crude, 2.5 mmol) in ethanol (95%, 30 mL) was added NH2NH2.water (1.25 g, 25.0 mmol), Pd/C (100 mg) under nitrogen protection. The mixture was stirred at 50° C. for 1.5 h. It was then cooled to room temperature and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure and the residue was recrystallized from anhydrous ethanol (5 mL) to afford 307b as white solid (340 mg, 84% over two steps). MS-ESI: [M+H]+ 162.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[F:12].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22])[CH:17]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH:10]=[CH:17][C:16]2[CH:19]=[C:20]([CH3:23])[C:21]([OH:22])=[C:14]([CH3:13])[CH:15]=2)=[CH:5][C:4]=1[F:12]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1ccc(C(C)=O)cc1F
Product: COc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1F

Procedure:
This compound was synthesized from 4′-methoxy-3′-fluoroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC(C)=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of 3-methyl-2-buten-1-ol (780 mg, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 0.3 h. Water was added and the mixture was extracted with ether. The etherphase was dried and evaporated to give the title compound.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:6])[CH2:3][NH2:4].C(NCC)C>C(Cl)Cl>[NH2:1][C@H:2]([C:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:6])[CH2:3][NH2:4]
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCNCC
Product: NC[C@H](N)C(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 1-L round bottom flask is charged with Fmoc-Dap-Z, CH2Cl2 (122 mL) and diethylamine (61 mL, Acros). The solution is stirred at room temperature and the completion monitored by HPLC. After 7 hours, the mixture is concentrated (bath temp. <30° C.). The residue is suspended in CH2Cl2 (300 mL) and concentrated. This is repeated twice. To the residue is added MeOH (20 mL) and CH2Cl2 (300 mL), and the solution is concentrated. The residue is suspended in CH2Cl2 (100 mL) and toluene (400 mL), concentrated, and the residue left under vacuum overnight to give product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].BrC[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: BrCCc1ccccn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCn2cccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.1 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.45 mmol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powdered potassium hydroxide (0.224 g, 4 mmol) was added and heated at 100 deg C. for 3 h. 2-(2-Bromo-ethyl)pyridine (0.09 g, 0.51 mol) was added at the same temperature and stir for 3 h at RT Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.01 g, 7% yield). 8-Chloro-2-methyl-5-(2-pyrrol-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.010 g, 0.0319 mmol) was dissolved in THF (0.5 mL), A solution of oxalic acid dihydrate (0.004 g, 0.0319 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as white solid (0.01 g, 78% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=1>O.CC(C)=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12]([N:1]=[N+:2]=[N-:3])=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)C=Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Sodium azide (67 g, 1 mol) was suspended in a mixture of water and acetone (300 mL, 1:1). The mixture was cooled to 0° C., a solution of compound 3 (126.9 g, 0.52 mol) in dry acetone (400 mL) was added at 5° C. The resulting mixture was stirred at 0-5° C. for 4 h and then poured into water (1.5 L). The precipitate was filtered off, washed with water, dried. Additional drying in vacuo over P2O5 gave 4 (130.3 g, 100%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: O=C(NC1CC1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and cyclopropylamine (64 mg, 1.1 mmol). Yield: 50 mg (57%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]OC(OC)(C)C.O>CO>[CH3:22][O:15][C:14]([C@H:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9]1)=[O:16]
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Yield: 86 %

Procedure:
A mixture of 26 g (117.5 mmol) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid, 0.66 ml of sulfuric acid, and 100 ml of dimethoxypropane in 700 ml of methanol are heated to reflux for 3 hours. For the working-up, the reaction mixture is reduced to ⅘ of its volume, then the residue is added under stirring to a mixture of ice and water. The precipitated product is collected on a filter funnel, washed with cold water and finally dried under high vacuum to yield 23.7 g (86% of theory) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M−H)+; optical integrity: 97.4% e.e. .
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([S:34][CH2:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[S:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:23]=[CH:24][CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([S:34][CH2:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[S:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO)c1

Procedure:
To a solution of (-)-methyl 5-(3-(t-butyldiphenylsilyloxymethyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 5) (1.377 g, 2.26 mmol.) in THF (25 mL ) a t room temperature was slowly added tetra-n-butyl ammonium fluoride (1M) in THF (2.34 mL). The solution was stirred 2 hrs at room temperature Ethyl acetate was added to the reaction mixture, and the organic layer it was washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography using 40% acetone in hexane afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([OH:11])=O.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic acid (0.051 g, 0.10 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.033 g, 0.17 mmol), methanesulfonamide (0.016 g, 0.17 mmol) and triethylamine (0.040 mL, 0.29 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel followed by trituration with methylene chloride/hydrogen chloride in diethyl ether gave the title compound as the hydrochloride salt (0.015 g, LRMS: 542.1, 544.1).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>C(O)C>[OH:2][N:1]=[C:8]([NH2:9])[C:7]1[CH:10]=[CH:11][C:4]([CH3:3])=[N:5][CH:6]=1
Reactant: NO
Reactant: Cc1ccc(C#N)cn1
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cn1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 0.765 g, 10 mmol) in ethanol (10 mL) was treated with a solution 6-methylnicotinonitrile (Aldrich, 12.8 g, 100 mmol) in ethanol (10 mL). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3 H), 6.02 (bs, 2 H), 7.59 (m, 1 H), 8.06-8.0 (m, 2 H), 10.2 (s, 1 H) ppm; MS (DCI/NH3) m/z 152 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@H:7]1[CH2:30][O:29][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)=[N+]=[N-].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C(=O)(O)[O-].[Na+]>CO.[Pd]>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][C@H:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:29][CH2:30][C@H:7]([O:6][CH2:5][CH2:4][NH:1][C:38](=[O:40])[CH3:39])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCN=[N+]=[N-])CO3)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@@H](C)O[Si](C)(C)C(C)(C)C)c3c2C1
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A mixture of the product from step B (0.73 g, 1.69 mmol) and palladium-on-carbon (10%, 0.07 g) in methanol (50 mL) was placed under an atmosphere of hydrogen and stirred overnight. The mixture was filtered, evaporated to an oil (0.61 g, 88%) which was dissolved in dichloromethane (30 mL). To this solution was added triethylamine (0.304 g, 3.01 mmol) and acetyl chloride (0.142 g, 0.129 mL, 1.81 mmol), and the mixture was stirred for 1 h, mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate. The dried extracts were evaporated to a residue which was purified by chromatography (silica, gradient, 30% to 90% ethyl acetate in hexane) to give an oil (0.41 g, 61%): LCMS (+ESI) m/z 448 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12]C(Cl)Cl>Cl[Ti](Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a N2 purged flask is added TiCl4 (0.44 mL) followed by 2-Bromo-4-fluoro-1-methoxy-benzene (400 mg, 1.95 mmol). The stirred mixture is cooled in an ice water bath and treated dropwise with 1,1-dichloromethyl methyl ether (0.35 mL, 1.95 mmol). After stirring for 90 minutes, the resulting slurry is treated with CH2Cl2 (200 mL) and reaction is allowed to warm up to room temperature. After passing through a column, the title compound is isolated (220 mg, 48%). MS (ESI): 232.9 (M+1)+1.