Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.[CH3:30][C:31]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:39]2[C:31]([CH3:30])=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=[O:34])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
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: C1COCCO1
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 109.2 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (176 mg, 0.418 mmol) in dioxane (4.5 mL) and water (1.5 mL) was added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (173 mg, 0.626 mol), potassium carbonate (289 mg, 2.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.2 mg, 0.0259 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was filtered. Separation by HPLC with TFA afforded the title compound (238 mg, 99%). LC-MS m/z 522 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[O:30][N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][C:31]5[O:30][N:29]=[C:28]([CH3:27])[CH:32]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, off-white solid (107 mg, 95%), MS (ISP) m/z=452.4 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-(3-methylisoxazol-5-yl)-acetic acid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cccc(C(C)=O)c1
Agent: N
Product: CC(=O)c1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-(3-ethynylphenyl)ethanone (GFS Chemicals, 72 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.70 (s, 3H), 7.67-7.85 (m, 2H), 7.94 (s, 1H), 8.13 (dt, J=5.1, 1.5 Hz, 1H), 8.18 (dt, J=7.6, 1.5 Hz, 1H), 8.40-8.54 (m, 2H), 8.80 (dd, J=5.2, 1.6 Hz, 1H), 9.20 (d, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O1CCC[CH2:14]1.C[Mg]Br.[Cl-].[NH4+]>S(Cl)(Cl)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH3:12][O:11][C:10]1[C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COc1cccc(C(=O)O)c1C
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: C[Mg]Br
Solvent: O=S(Cl)Cl
Product: COc1cccc(C(C)=O)c1C
Reaction time: 0.25 h

Procedure:
A solution of 2-methyl-3-methoxybenzoic acid (10.0 g, 60.2 mmol) in thionyl chloride (50 ml) was heated at reflux for 1 h and then cooled and concentrated in vacuo. To the residue was added tetrahydrofuran (100 ml) and iron (III) acetylacetonate (638 mg, 1.8 mmol) and the solution was cooled to −20° C., before addition of methyl magnesium bromide (3M in diethyl ether, 22.1 ml, 66.2 mmol). After stirring for 15 min, the mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7](=[O:10])[CH2:8]Br)[CH3:2].C(N(CC)CC)C.[C:40]1([C:46]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH2:48][CH2:49][NH2:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4](=[O:32])[C@H:5]([CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7](=[O:10])[CH2:8][NH:50][CH2:49][CH2:48][S:47][C:46]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:2]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CNCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 22 %

Procedure:
To a solution of N-bromoacetyl-S-Triphenylmethyl-L-cysteine ethyl ester (1.0 g, 1.98 mmol.) and triethylamine (0.4 mL, 2.9 mmol.) in methylene chloride (10 mL) was added S-triphenylmethyl-2-aminoethanethiol (0.64 g, 2.0 mmol.). The reaction mixture allowed to stir at room temperature for seven days. Water (10 mL) was added. The organic layer was washed with NaHCO3 (2×10 mL), water (2×10 mL), and brine (10 mL), dried (magnesium sulfate), and concentrated in vacuo to give a foamy product. Flash chromatography using ethyl acetate:hexane (3:1) gave the product in 22% yield. MS (M+H)=751, calculated 751.3.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C#C>N1C=CC=CC=1>[C:10]([O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C#CCC(O)CCCC
Agent: C#C
Solvent: c1ccncc1
Solvent: O
Product: C#CCC(CCCC)OC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λ max. 3240 (terminal acetylene) and 1730 cm-1 (benzyloxy group).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+].C(OCC)C>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[O:42])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:23][N:24]([CH3:26])[CH2:25]3)[CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (40.0 mg) in tetrahydrofuran (15 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 1.60 ml), followed by stirring at room temperature for 1 hr. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 15 min. The organic layer was separated, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing a target compound were concentrated to give a solid, to which diethyl ether (1 ml) and hexane (1 ml) were added to suspend. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (18.5 mg, 31.9%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:44])=[C:14]([C:37]([NH:39][CH2:40][CH2:41][O:42][CH3:43])=[O:38])[C:15](=[O:36])[N:16]3[CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:44])=[C:14]([C:37]([NH:39][CH2:40][CH2:41][O:42][CH3:43])=[O:38])[C:15](=[O:36])[N:16]3[CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC2CCN(C(=O)OCc3ccccc3)CC2)c1=O
Agent: [Pd]
Solvent: CO
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC2CCNCC2)c1=O
Yield: 71.1 %

Procedure:
To a solution of Phenylmethyl 4-{[7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridin-1(2H)-yl]methyl}-1-piperidinecarboxylate (18 mg, 0.03 mmol) in methanol (3 mL) was added palladium on carbon (10 wt %, 18 mg). Hydrogen was bubbled through the reaction mixture for several minutes and then the atmosphere was maintained with a balloon of hydrogen until the reaction was judged complete by LC/MS. The resultant suspension was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound (10 mg, 71%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.23 (m, 1 H), 8.48 (s, 1 H), 7.36 (s, 1 H), 7.14 (dd, J=8.4, 5.4 Hz, 2 H), 6.99 (t, J=8.6 Hz, 2 H), 4.09 (s, 2 H), 4.02 (m, 2 H), 3.57 (m, 2 H), 3.53 (m, 2 H), 3.35 (s, 3 H), 3.14 (m, 2 H), 2.52 (m, 2 H), 1.78 (m, 1 H), 1.56-1.39 (m, 4 H); HRMS m/z calcd for C25H30N4O4F (M+H)+ 469.2251, found 469.2252.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:10]([CH2:29][CH2:30][CH3:31])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:38]1([N:44]=[C:45]=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH:38]1([NH:44][C:45]([NH:26][S:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:11]3[CH:27]=[CH:28][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][C:10]=3[CH2:29][CH2:30][CH3:31])=[CH:18][CH:19]=2)(=[O:24])=[O:25])=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(S(N)(=O)=O)cc1
Reactant: O=C=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(S(=O)(=O)NC(=O)NC2CCCCC2)cc1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(4-phenoxy-2-propyl phenoxy)propoxy]benzenesulfonamide (0.045 g, 0.102 mmol) and acetone (3 mL) was added potassium carbonate (0.028 g, 0.204 mmol). To the resulting suspension was added cyclohexyl isocyanate (0.026 mL, 0.204 mmol) dropwise. The reaction suspension was then stirred in a 65° C. oil bath for 6 h. After cooling to room temperature, the reaction was concentrated to a residue. The residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was chromatographed over silica gel with hexanes/ethyl acetate (4:1) and hexanes/ethyl acetate (3:1) to obtain the title compound.
Reaction SMILES: ClCC[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.BrBr.C(N)(C)(C)C.[CH3:19][CH:20]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:29])[CH:28]=1)=[O:22]>C(Cl)Cl>[CH3:19][CH:20]([NH:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:29])[CH:28]=1)=[O:22].[C:6]1([CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCCl)c1ccccc1
Agent: BrBr
Agent: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: Cc1ccccc1

Procedure:
3-Chloro-propiophenone starting material was brominated in methylene chloride by dropping bromine under controlled conditions. On reaction completion the mother liquor was worked up and then the second reaction was executed by transferring the bromoderivative solution onto the tert-butylamine. The second substitution reaction (the tert-butylamine amino-group substitutes the bromine atom) forms the final bupropion molecule. After work up of the mother liquor, a bupropion toluene solution was obtained. The solvent was evaporated and bupropion was dissolved in isopropanol. From the isopropanol solution, the hydrobromide was precipitated with hydrogen bromide gas. On precipitation completion, the product was centrifuged, washed with isopropanol and dried under vacuum. On dryer discharge approval it was discharged in Kraft drums within double polyethylene bags.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].ON1C(=O)N(O)C(=O)N(O)[C:14]1=[O:23].N(C(C)(C)C#N)=NC(C)(C)C#N.[O:36]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:14]([OH:23])=[O:36])(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=O
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Agent: [Co+2]
Agent: CC(=O)Oc1cccc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)Oc1cccc(C(=O)O)c1

Procedure:
A mixture of 0.300 g of m-tolyl acetate, 0.018 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (5% by mole relative to m-tolyl acetate), 5 g of acetic acid, 0.003 g of cobalt(II) acetate.4H2O and 0.003 g of 2,2′-azobisisobutyronitrile was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 3-acetoxybenzoic acid in 75% yield at 78% conversion of m-tolyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:10]2)[CH:5]=[N:6][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:13](=[O:14])[N:9]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:41])([F:40])[F:29])[CH:3]=3)[N:10]=2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1n(Cc2cncc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.15 mmol) of the compound from Example 28A and 43 mg (0.23 mmol) of 2-(trifluoro-methyl)phenylboronic acid were dissolved in 2 ml of dioxane. For 10 min, a stream of argon was passed through this solution, and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were then added under argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol) of a 2 N aqueous sodium carbonate solution was added under argon. The mixture was stirred under reflux for 20 h. After cooling to RT, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 36 mg (44% of theory) of the target compound.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:47][C@H:48]([C:56]([OH:58])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[C:1]([O:20][CH:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:47][C@H:48]([C:56]([OH:58])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:29])=[O:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 73.3 %

Procedure:
Starting from N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycine (2.0 g) prepared by the method described in Example 40 and L-phenylalanine (2.64 g), N-[N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycyl]-L-phenylalanine (1.8 g) was obtained as powders according to a similar manner to that of Example 29.
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:26]1([CH3:40])[CH:31]=[CH:30][C:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:36]1([CH3:39])[CH:35]=[CH:34][C:33]([N:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:40])=[CH:27][CH:28]=2)[C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:38][CH:37]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Clc1c2ccccc2c(-c2cccc3ccccc23)c2ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(C)cc2)c2c3ccccc3c(-c3cccc4ccccc34)c3ccccc23)cc1

Procedure:
In a flask were 9-α-naphthylanthracene and an equivalent amount of N-bromosuccinimide, and the reaction mixture was stirred overnight and then filtered. The filtrate was passed through a column filled with alumina. Chloroform was evaporated from the solution under a reduced pressure, and then the residue was recrystallized from petroleum ether, to give 10-chloro-9-α-naphthylanthracene. Then, in a three-necked flask were placed 10-chloro-9-α-naphthylanthracene, an equivalent amount of di-p-tolylamine, an equivalent amount of potassium carbonate, copper powder and nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 10-di-p-tolylamino-9-α-naphthylanthracene.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[O:30])[CH:4]=1)[C:11]([OH:13])=[O:12])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)OCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)[CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]1[S:13][C:14]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[C:15]([C:17]([O:19]C)=O)[N:16]=1)=O)(C)(C)C.[NH2:49][CH2:50][CH2:51][OH:52].C(O)(C(F)(F)F)=O>>[NH2:8][C@@H:9]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=1)[CH2:10][NH:11][C:12]1[S:13][C:14]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[C:15]([C:17]([NH:49][CH2:50][CH2:51][OH:52])=[O:19])[N:16]=1
Reactant: NCCO
Reactant: COC(=O)c1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nc(C(=O)NCCO)c(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesized by treating the intermediate methyl 2-(((S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propyl)(tert-butoxycarbonyl)amino)-5-(isoquinolin-6-yl)thiazole-4-carboxylate with 2-aminoethanol followed with a TFA treatment to remove the tert-butoxycarbonyl protecting groups. LCMS (M+H) calc. for C25H25F3N5O2S 516.2. 1H NMR (400 MHz, CD3OD) δ ppm 9.70 (s, 1H) 8.53-8.60 (m, 1H) 8.38-8.46 (m, 2H) 8.36 (s, 1H) 8.10-8.19 (m, 1H) 7.73 (d, J=6.85 Hz, 2H) 7.58 (d, J=6.85 Hz, 2H) 4.52-4.61 (m, 1H) 3.93 (s, 1H) 3.78-3.87 (m, 1H) 3.71 (t, J=5.48 Hz, 2H) 3.63 (dd, J=14.67, 6.46 Hz, 1H) 3.44-3.51 (m, 2H) 3.06-3.23 (m, 2H).