Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:12][CH2:11]1)=[O:8].O1CCOCC1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]3[CH:48]=[CH:47][C:46](B4OC(C)(C)C(C)(C)O4)=[CH:45][C:39]=3[C:40]=2[C:41]([NH:43][CH3:44])=[O:42])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]3[CH:48]=[CH:47][C:46]([C:2]4[CH:19]=[C:6]([C:7](=[O:8])[NH:9][C:10]5([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=6)[CH2:12][CH2:11]5)[C:5]([O:20][CH3:21])=[CH:4][C:3]=4[CH3:22])=[CH:45][C:39]=3[C:40]=2[C:41]([NH:43][CH3:44])=[O:42])=[CH:32][CH:31]=1
Reactant: COc1cc(C)c(Br)cc1C(=O)NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)c(OC)cc3C)cc12
Temperature: 85 °C
Yield: 57 %

Procedure:
Alternative synthesis. To a sealed tube was added 5-bromo-2-methoxy-4-methyl-N-(1-(pyridin-2-yl)cyclopropyl) benzamide (1.9024 g, 5.27 mmol), dioxane (70 mL), 2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (2.529 g, 6.40 mmol), cesium carbonate (2.57 g, 7.90 mmol), water (14.00 mL) and finally tetrakis(triphenylphosphine)palladium(0) (0.304 g, 0.263 mmol). The vessel was sealed and heated for 16 hours at 85° C. in an oil bath. The mixture was cooled to room temperature, diluted with 20 ml of DCM and pushed through a plug of celite. The resulting dark solution was concentrated to a grey oil. To this residue was added 20 ml of 0.5N HCl, followed by 20 ml of water. The flask was cooled in an ice bath for 30 minutes and the resulting solids were collected by filtration and washed with 10 ml of water and dried under vacuum. The crude product was taken up in 1:1 ethyl acetate/hexane and pushed through a plug of silica gel. Solvent was removed giving 1.65 grams of the product as a light tan solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:10].[CH3:11][C:12]1[CH:23]=[C:22]2[C:15]([NH:16][CH:17]=[C:18]2[CH2:19][CH2:20][NH2:21])=[CH:14][CH:13]=1>C(O)C>[ClH:10].[CH3:11][C:12]1[CH:23]=[C:22]2[C:15](=[CH:14][CH:13]=1)[NH:16][C:17]1[CH:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:21][CH2:20][CH2:19][C:18]2=1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=CCC1CCCCC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2[nH]c3c(c2c1)CCNC3CC1CCCCC1
Temperature: 25 °C

Procedure:
A suspension of cyclohexylacetaldehyde (631 mg, 5.0 mmol.) and 5-methyltryptamine hydrochloride (1.0 g, 4.3 mmol.) in ethanol (20 mL) was heated to reflux for 36 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was triturated with ethanol and washed with diethyl ether. The product was isolated by filtration (731 mg). m/e=282, mp 230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=1
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (200 mg, 0.58 mmol) was dissolved in pyridine (3.0 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (132 μL, 0.88 mmol) was added, and the mixture was stirred at 70° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed successively with water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (145 mg, 45%) as a colorless powder.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](/[CH:42]=[CH:43]/B(O)O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]=[CH:43][C:10]2[CH:11]=[C:12]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]4)=[O:23])[C:17]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)=[CH:38][CH:37]=1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(C=Cc4ccc(Cl)cc4)c3)c2C)C1
Yield: 67 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and trans-2-(4-chlorophenyl)vinylboronic acid gave (5-{3-[2-(4-chloro-phenyl)-vinyl]-phenyl}-1,4-dimethyl-1H-pyrazol-3-yl)-(3-diethylamino-pyrrolidin-1-yl)-methanone in 67% yield as light brown oil. MS: 477.0 (MH+, 1 Cl).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:19][C:20]1[CH:51]=[CH:50][C:23]([CH2:24][N:25]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[N+](C1C=CC=CC=1S(N(CC1C=CC(CN2C3C(=CC=CC=3)C=C2C2C=CC=CC=2)=CC=1)C1C=CC(CCC(OC)=O)=CC=1)(=O)=O)([O-])=O>CN(C)C=O.O>[N+:47]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[S:38]([N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:51][CH:50]=1)[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=1)(=[O:40])=[O:39])([O-:49])=[O:48]
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COC(=O)CCc1ccc(N(Cc2ccc(CCl)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: COC(=O)CCc1ccc(N(Cc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(N(Cc2ccc(Cc3c(-c4ccccc4)[nH]c4ccccc34)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 0.436 g, 10.9 mmol) was added to a solution of 2-phenylindole (2.11 g, 10.9 mmol) in N,N-dimethylformamide (5 mL) by small portions, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 1 hr. To the reaction mixture was added dropwise a solution of methyl 3-(4-{[4-(chloromethyl)benzyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (3.65 g, 7.26 mmol) in N,N-dimethylformamide (5 mL), and the mixture was allowed to warm to room temperature and stirred for 3 hr. Water and 10% aqueous citric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give a mixture (1.53 g, yield 32%) of the title compound and methyl 3-[4-([(2-nitrophenyl)sulfonyl]{4-[(2-phenyl-1H-indol-1-yl)methyl]benzyl}amino)phenyl]propanoate as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[O:23].[Li+].[BH4-]>C1COCC1>[OH:23][CH2:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[C:6]2[C:10]([CH2:9][O:8][C:7]2=[O:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCO)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde (97 mg, 0.29 mmol) in THF (5 mL) was added an aliquot of a 2 M LiBH4 in THF (150 μL, 0.300 mmol). The reaction mixture was stirred at room temperature for 1 hour when complete consumption of the starting materials was observed by TLC. The reaction mixture was worked up by addition of an aqueous 1N HCl solution and extraction with EtOAc. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography to provide the product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H), 2.97 (t, 2H, J=6 Hz), 3.76 (t, 2H, J=6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H) ppm.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O-:20])=[O:19])[CH2:14]2)(=O)=O)=CC=1.[C-:21]#[N:22].[Na+]>CS(C)=O.S([O-])([O-])(=O)=O.[Fe+2]>[C:21]([CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:13]([CH3:17])([CH3:14])[CH3:12])=[O:19])[CH2:14]1)#[N:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN(C(=O)[O-])C2)cc1
Reactant: [C-]#N
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CC#N)C1
Temperature: 100 °C
Yield: 156.5 %

Procedure:
A mixture of tert-butyl ((R)-3-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 207, 22.3 g) and sodium cyanide (6.13 g) in DMSO (100 mL) was stirred and heated at 100° C. for 4 hours. After cooling, a saturated aqueous solution of iron (II) sulphate was added and the mixture was stirred at room temperature for 8 hours. The resultant mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with an mixture of ethyl acetate and petroleum ether (20%) to give tert-butyl (S)-3-cyanomethylpyrrolidine-1-carboxylate (12.3 g) as a white solid which was used without further characterisation.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (386 mg, 2 mmol), aniline (182 μL, 2 mmol) and DIEA (419 μL, 2.4 mmol) in 3 mL dioxane was stirred in microwave at 180° C. for 10 min. After removal of the solvent, the residue was dissolved in 3 mL DCM, subjected to silica gel column purification to give 308 mg (yield 61.7%) (6-chloro-3-nitro-pyridin-2-yl)-phenyl-amine. Calculated mass=249. Observed mass=250.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:20]I>CN(C=O)C.O>[CH3:20][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 2.1 g, 41.8 mmol) in DMF (80 mL) at 0° C. was added a solution of tert-butyl 3-nitrophenylcarbamate (18) (8.3 g, 34.9 mmol) in DMF (50 mL). The mixture was stirred at 0° C. for 0.5 hour before CH3I (4.9 mL, 52.35 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (200 mL), and extracted with DCM (60 mL×3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl methyl(3-nitrophenyl)carbamate (19) 8.8 g as yellow solid (yield 100%). LC-MS (ESI): m/z (M+1) 253.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate T4.1 (39.00 g, 114 mmol) in DMF (228 mL, 114 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (29 g, 171 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), and potassium carbonate (47 g, 342 mmol), followed by tetrakis(triphenylphosphine)palladium (9.2 g, 8.0 mmol). The mixture was heated to 90° C. and stirred for 18 hours. The reaction was cooled to room temperature. Water was then added to the reaction, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford dimethyl 2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-2,4-dicarboxylate T4.2 as a clear oil (32.00 g, 88% yield). MS ESI (pos.) m/e: 319.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH:17]=[C:16]([CH3:39])[CH:15]=2)=[CH:9][C:8]=1[CH2:40][CH3:41])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH:17]=[C:16]([CH3:39])[CH:15]=2)=[CH:9][C:8]=1[CH2:40][CH3:41])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3C)c2)cc1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3C)c2)cc1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
A mixture of 3-{2-ethyl-4-[3-methyl-5-(2-o-tolyloxy-4-trifluoromethyl-phenoxy)phenoxy]-phenyl}-acrylic acid ethyl ester (1.83 g, 3.17 mmol) and 10% Pd/C (1.80 g) in ethyl acetate (100 mL) is purged with N2 then H2 and then stirred under a H2 balloon at rt for 5 hours. The mixture is filtered through hyflo, and the solvent is removed in vacuo to afford 1.77 g (97%) of the title compound. Rf=0.22 (9/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C34H33F3O5 578, found 579 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>ClCCl.CN(C)C=O>[N:24]([CH2:9][C@@H:6]1[CH2:5][CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:11])[CH3:1])=[N+:25]=[N-:26]
Reactant: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@@H](CN=[N+]=[N-])[C@@H]1C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol (500 mg,) was dissolved in dichloromethane (15 mL). The solution was chilled in an ice bath and triethylamine (0.633 mL) was added, followed by methanesulfonyl chloride (0.278 mL). The reaction was stirred for 2 hours at 0° C., and was transferred to a separatory funnel and washed with 1N aqueous HCl (15 mL), saturated aqueous NaHCO3 (20 mL) and brine (15 mL), then dried (Na2SO4), filtered and concentrated to give a crude oil, which was dissolved in N,N-dimethylformamide (7.5 mL). Sodium azide (1054 mg) was added and the mixture was heated to 110° C. for 1.5 hours, and was cooled and partitioned between water (30 mL) and ethyl acetate (3×25 mL). The organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated to give a crude oil, which was purified by flash chromatography on silica gel eluting with 50 to 100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: [NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([N:47]1[CH2:61][CH2:60][CH2:59][C@H:48]1[C:49]([O:51]CC1C=CC=CC=1)=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])=[O:35])[CH3:33])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C>>[NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([N:47]1[CH2:61][CH2:60][CH2:59][C@H:48]1[C:49]([OH:51])=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])=[O:35])[CH3:33])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C

Procedure:
The above peptide XV was hydrogenated as described for the preparation VIII to obtain the product in quantitative yield. Rf3 0.22. Anal. calcd. for C40H61N9O12 : C 55.66, H 7.12, N 14.60%. Found: C 55.86, H 7.23, N 14.14%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH2:19][S:20][CH3:21])(=[O:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[C:13]([NH:16][C@H:17]([C:22]([NH:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1)=[O:23])[CH2:18][CH2:19][S:20][CH3:21])(=[O:15])[CH3:14]
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(C)=O)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
2.85 g of dopamine hydrochloride, 4.32 g of N-hydroxysuccinimide ester of N-acetyl-L-methionine, 3.04 g of triethylamine and 15 ml of dimethylformamide are treated in the same manner as described in Example 5. After the reaction, the mixture is condensed under reduced pressure to remove solvent. The residue is dissolve in ethyl acetate, washed with water and dried. The solution is condensed to remove solvent. 3.1 g of N-(N-acetyl-L-methionyl)-dopamine are obtained as caramel.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=2[CH2:15][CH2:16][CH3:17])=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCCc1c(OCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A mixture of 1.5 g of 1-[4-(2-bromoethoxy)-2-hydroxy-3- propylphenyl]ethanone 0.83 g of 4-hydroxybenzoic acid ethyl ester and 0.95 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone and 10 ml of anhydrous DMF was stirred at reflux for 20 hours. The mixture was filtered and solvent was removed in vacuo. The residue was dissolved in ethyl acetic and washed with water. The extract was dried over magnesium sulfate) and concentrated in vacuo to an oil which was purified by HPLC using 25% ethyl acetate-hexane to give 1.3 g, m.p. 99-100 (75%) of 4-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-benzoic acid ethyl ester, the title compound. Analysis Calculated for C22H26O6 : C, 68.36; H, 6.78. Found: C, 68.39; H, 6.79.
Reaction SMILES: C(=N[C@H](C1C=CC=CC=1)CC1C=CC(C)=CC=1)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C1CCCCC=1.C(#N)C.[C:34](OOC(C)(C)C)(=[O:41])[C:35]1C=CC=CC=1>[Cu].C1C=CC=CC=1.C(O)(=O)C>[C:34]([O:4][CH:3]1[CH2:2][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:41])[CH3:35]
Reactant: Cc1ccc(C[C@H](N=Cc2ccccc2O)c2ccccc2)cc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Cu]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)OC1C=CCCC1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 0.50 g of the copper complex of (S)-(-)-N-salicylidene-1-phenyl-2-(p-tolyl)ethylamine, 0.045 g of copper powder, 25 ml of cyclohexene, 25 ml of acetonitrile, 5 ml of acetic acid and 5 ml of t-butyl peroxybenzoate was heated with stirring at 70° C for 7 hours in a nitrogen atmosphere. After cooling, the reaction mixture was admixed with 50 ml of benzene, washed successively with a 2N aqueous hydrochloric acid solution, water, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was distilled under reduced pressure to obtain 1.88 g of 2-cyclohexenyl acetate. B.P. 75°-76° C/21 mmHg.