Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:19][C:18]([CH2:20][OH:21])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:19][C:18]([CH:20]=[O:21])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(OC3CCCC3)c2)[nH]c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(OC)c(OC3CCCC3)c2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 97.9 %

Procedure:
To 30 ml of dichloromethane solution containing 1.08 g (3.0 mmol) of ethyl 5-(3-cyclopentoxy-4-methoxyphenyl)-2-hydroxymethyl-1H-pyrrol-3-carboxylate obtained in Reference example 47-(d) was added 3.13 g (36 mmol) of manganese dioxide, and the mixture was stirred at room temperature for 1.2 hours. After completion of the reaction, the reaction suspension was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure to obtain 1.05 g of the title compound as a yellowish solid. (Yield: 97%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[O:25][CH2:24][CH2:23][O:22]2)=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1

Procedure:
A mixture of 94 parts of 2-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione, 21 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of 1-butanol and 450 parts of methylbenzene is stirred and refluxed for 15 hours using a water-separator. The reaction mixture is cooled and washed with a diluted sodium hydroxide solution. The organic phase is dried, filtered and evaporated. The solid residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 102 parts of 2-[2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1H-isoindole-1,3(2H)-dione
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N=Cc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](N[S@](=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of (R)—N-((5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (6.5 g, 15.53 mmol) in anhydrous THF (78 mL) was slowly added tBuLi (1.7 M solution in pentane, 27.4 mL, 46.6 mmol) at −78° C. After the reaction mixture was stirred at −78° C. for 3 h, the reaction was quenched with MeOH (10 mL) followed by addition of saturated NH4Cl solution (30 mL). Upon warming up to room temperature, the reaction mixture was stirred for 30 min and then extracted with EtOAc (250 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield enantiomerically enriched (R)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (3.93 g, 53.1%) as a pale yellow solid. Only single diastereomer was formed and isolated. 1H NMR (CDCl3, 400 MHz): δ 7.87 (1H, m), 7.37-7.29 (3H, m), 7.27-7.21 (2H, m), 7.11-6.96 (2H, m), 4.43-4.28 (2H, m), 4.24-4.09 (2H, m), 1.28 (9H, s), 1.00 (9H, s). LC/MS (uplc): MH+ 477.2, 1.44 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:36](Cl)(=[O:38])[CH3:37]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:36](=[O:38])[CH3:37])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[((1R,2S)-2-hydroxy-indan-1-ylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH:15]([O:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][N:25]=2)C2C=CC=CC=2F)(C)[CH2:9]1)=O)(C)(C)C.[ClH:34]>CCOC(C)=O.O1CCOCC1>[ClH:34].[F:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:29]1[CH:28]=[CH:27][CH:32]=[CH:31][C:30]=1[F:33])[N:25]=[C:24]2[O:23][CH2:15][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(Oc2n[nH]c3ccc(F)cc23)c2ccccc2F)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCCC(COc2nn(-c3ccccc3F)c3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a room temperature stirred solution of Intermediate 57 (0.127 g, 0.278 mmol) in EtOAc (0.925 ml) was added 0.902 ml of a 4.0 M HCl solution in dioxane. The reaction was allowed to stir overnight at room temperature. Upon completion as indicated by HPLC, the reaction was concentrated under reduced pressure. EtOAc was added to the solid and then concentrated down under reduced pressure. This process was repeated five times. The solid was triturated with EtOAc/Et2O (2:1), the solid was filtered and then washed with Et2O (2×15 ml). The solid was placed in a drying oven under reduced pressure to yield 0.089 g (81.7%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: ClCCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
A 10-liter jacketed reactor equipped with an overhead stirrer, a thermocouple, an addition funnel, and a dry ice/acetone condenser was charged with 2-(4-chlorophenyl)ethanol (2005 g, 12.8 mol) and swept with nitrogen. DMF (49.6 mL, 640 mmol) was charged to the reactor and the reactor contents were heated to 60° C. Thionyl chloride (1607.3 g) was added at a rate sufficient to maintain the temperature at >49° C. and <70° C. On completion of the addition, the reaction was held at 52.6° C. (jacket temperature). It was then cooled to 20° C. and allowed to stir at room temperature overnight. The reaction mixture was concentrated at 22 torr and 60° C. (water bath) for 1.5 h, to leave 1-chloro-4-(2-chloroethyl)benzene (2256 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[C:23]([CH3:25])=O>C(Cl)Cl>[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:4][CH2:5][N:9]([CH2:23][CH3:25])[CH2:10][CH3:11])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Reactant: CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCN(CC)CCn1c2ccccc2c2c(Cl)ncnc21
Yield: 82 %

Procedure:
A suspension of 4-chloroindolo[2,3-d]pyrimidine hydrochloride (407 mg, 2 mmol), 2-N,N-diethylaminoethyl chloride hydrochloride (413 mg, 2.4 mmol), anhydrous cesium carbonate (1.95 g, 6 mmol) and 4 molecular sieves (1.5 g) in acetone (6 mL) are heated at reflux under a nitrogen atmosphere for 1.5 h. The mixture is filtered through celite, washing the filter cake with acetone (4×10 ml), followed by concentration of the filtrate under reduced pressure affording a viscous amber oil, which is dissolved in CH2Cl2, (20 ml), and washed with water (2×25 mL), dried (MgSO4), and the solvent is removed in vacuo. The crude product is chromatographed on silica, eluting with 4% methanol/chloroform to give 4-chloro-9N-(2-(N,N-diethylamino)ethyl)indolo[2,3-d]pyrimidine (495 mg, 82%), as a pale yellow oil. 1H NMR (DMSO) δ8.79 (1H, s), 8.41 (1H, d, J=8.0 Hz), 7.66-7.58 (2H, m), 7.46-7.42 (1H, m), 4.57 (2H, t, J=6.8 Hz), 2.90 (2H, t, J=7.1 Hz), 2.63 (4H, d, J=7.0 Hz), 0.99 (6H, t, J=7.0 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([O:33]CC)=[O:32])=[N:22]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([OH:33])=[O:32])=[N:22]2)=[CH:16][CH:15]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)nc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)nc2)c2ccccc12
Yield: 47.9 %

Procedure:
Ethyl 2-[1-[[6-(2-naphthamido)pyridin-3-yl]methyl]-1H-indazol-3-yl]acetate (154 mg, 0.33 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (70 mg, 1.67 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 69 mg, at a yield of 47.7%.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14]([NH2:16])=[O:15])[C:11](=[O:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1COCC1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:16][C:14](=[O:15])[CH2:13][N:12]2[CH:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]2=[O:17])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CCCCCc1ccccc1
Reactant: NC(=O)CN1C(=O)CC1SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(CCCCCc1ccccc1)NC(=O)CN1C(=O)CC1SCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
A solution of (4-benzylthio-2-oxoazetidin-1-yl)acetamide (0.63 g, 2.52 mmol) in dry THF (15 ml) was added to a suspension of sodium hyride (60% in oil, 0.10 g, 2.5 mmol) in dry THF at -10° C. under a nitrogen atmosphere. The reaction was stirred at -10° C. for 10 minutes and was then treated with a solution of 6-phenylhexanoyl chloride (0.58 g, 2.75 mmol) in dry THF (5 ml) dropwise over 2 minutes maintaining the temperature at -10° C. The cooling bath was removed an after stirring for 60 minutes the reaction was treated with sodium hydride (50 mg, 1.25 mmol) and 6-phenylhexanoyl chloride (0.29 g, 1.38 mmol) in dry THF (2 ml). The reaction was stirred for 60 minutes, poured into ice/brine (100 ml), extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with aq. sat. NaHCO3 solution, brine, dried (MgSO4) and evaporated under reduced pressure to an orange oil. Purification by repeated column chromatography eluted with hexane:ethyl acetate (3:1 to 1:1) gave the product as a colourless oil (0.22 g, 21% yield, contains 10% 6-phenylhexanoic acid) 1H nmr δ (CDCl3) 1.3-1.7 (6H, m, 3×CH2), 2.44 (2H, t, J=7.4 Hz, NHCOCH2), 2.62 (2H, t, J=7.6 Hz, PhCH2), 2.96, 3.02 (1H, dd, J=2.4, 15.3 Hz, H3), 3.39, 3.45 (1H, dd, J=5.1, 15.3 Hz, H3), 3.61, 4.32 (each 1H, d, J=18.8 Hz, NCH2CO), 3.76 (2H, m, SCH2), 4.9 (1H, m, H4), 7.1-7.3 (10H, m, 2×Ph--H), 8.17 (1H, m, NH)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxyphenylacetic acid (Acros, 3.04 g, 20 mmol) in 20 mL of DMF were added K2CO3 (6.90 g, 50 mmol) and benzyl bromide (4.75 mL, 40 mmol) at room temperature. The reaction mixture was stirred for 24 h. The suspension was filtered and washed with diethyl ether. The filtrate was then washed with brine and dried over MgSO4. Filtration, followed by concentration, provided the crude benzyl 2-(3-(benzyloxy)phenyl)acetate which was used in the next step. MS (ESI+) m/z 355 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1>C(O)C.[Pd]>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(/C=C\CCCCCN(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCCCCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
0.88 g of methyl 4-[(Z)-7-(dimethylamino)-1-heptenyl]benzoate was dissolved in 20 ml of ethanol, 20 mg of 5 percent palladium on carbon were added thereto and the suspension was stirred under hydrogen at normal pressure and room temperature for 2 hours. The reaction mixture was filtered through siliceous earth and the filtrate was evaporated. There was obtained 0.85 g (95%) of methyl 4-[7-(dimethylamino)heptyl]benzoate as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[K+]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)nc(-c2ccncc2)c1C(=O)O
Yield: 89.9 %

Procedure:
A solution of ethyl 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylate (15 g) and aqueous potassium hydroxide (3.48 g, in 30 ml H2O) in ethanol (150 ml) was refluxed for 4.5 hours. After evaporating the solvent, the residue was dissolved in a suspension of water (150 ml) and chloroform (150 ml) under stirring. The separated aqueous layer was adjusted to pH 5.5 with 10% aqueous hydrochloride. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylic acid (12.3 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]=1B(O)O.[CH2:18]([O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](OS(C(F)(F)F)(=O)=O)=[CH:37][CH:36]=1)[NH:23][C:24](=[O:33])[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=2[O:11][CH2:12][O:13][CH3:14])=[CH:37][CH:36]=1)[NH:23][C:24](=[O:33])[C:25]1[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31])[CH3:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COCOc1cccc(OCOC)c1B(O)O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OCOC)cccc2OCOC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-Di(methoxymethoxy)benzeneboronic acid (0.25 g) was coupled with N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine ethyl ester in a similar procedure as described in Example 5-3) to afford N-(2,6-dichlorobenzoyl)-4-[2,6-di(methoxymethoxy)phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 562 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([C:14]#[C:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:15]([CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)=[CH:14]2)=[O:25]
Reactant: COC(=O)c1ccc(NC(C)=O)c(C#CCCOC2CCCCO2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A solution of crude 4-acetylamino-3-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-benzoic acid methyl ester (33.4 g, approximately 65 mmol) in anhydrous THF (300 mL) was mixed with a 1.0 M solution of tetrabutylammonium fluoride in THF (110 mL, 110 mmol); the reaction mixture was stirred at 90° C. for 4 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated and the residue was taken in ethyl acetate (300 mL). The organic phase was washed with water (300 mL), brine (200 mL), and dried over anhydrous Na2SO4. The solvent was evaporated and the crude compound was purified by column chromatography on silica gel, eluting with hexanes and ethyl acetate (3:1), to give 2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carboxylic acid methyl ester. Yield: 14.9 g (76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[N+:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:40]2[CH:41]=[CH:42][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 50 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as generally described in Example 37 was reacted with 4-nitro-phenyl boronic acid (50.1 mg, 0.3 mmol) by adapting the procedure as described in Example 43 to give title compound (28.2 mg, 50%). LC/MS (m/z): 565 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:24])[CH3:2].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH3:2]
Reactant: CCOC(=O)CCc1c(O)ccc2ccc(OCC(=O)OCC)cc12
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCc1c(OCCCCCBr)ccc2ccc(OCC(=O)OCC)cc12
Temperature: 65 °C
Reaction time: 17.5 h
Yield: 74.4 %

Procedure:
A mixture of 1.08 g (3.12 mmol) of 7-(2-ethoxy-2-oxoethoxy)-2-hydroxy-1-naphthalenepropanoic acid ethyl ester from the preceding example, 4.31 g (18.7 mmol) of 1,5-dibromopentane, 2.59 g (18.7 mmol) of anhydrous granular potassium carbonate, and 70 mL of 2-butanone was heated at 65° C. for 24 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate. The solids were washed thoroughly with ethyl acetate and the filtrate and the washes were combined and concentrated in vacuo. To the residue was added 60 mL of ethanol and 1 mL of concentrated sulfuric acid and the resulting solution was stirred at room temperature for 17.5 hr. Most of the ethanol was removed under reduced pressure and the residue was flash chromatographed on 110 g of silica gel, eluting with hexane-ethyl acetate (6:1) to give 1.15 g (74.4%) of the title compound as an off-white, waxy solid, mp 29.5°-32° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25](=[O:28])[CH2:26][CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:26][CH3:27]
Reactant: CCC(=O)c1cc(C)ccc1C
Reactant: Br[Mg]c1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1cc(C)ccc1C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 100 ml. of a 1.5 molar solution of 2-benzyloxyphenyl magnesium bromide in tetrahydrofurane a solution of 24.3 g. of 2',5'-dimethyl-propiophenone in 50 ml. of dry tetrahydrofurane is added under moderate reflux. The reaction mixture is stirred under slight boiling for 30 minutes, cooled and poured onto a saturated solution of ammonium chloride in ice water. Tetrahydrofurane is distilled off under reduced pressure, and the residue is extracted with benzene. The benzene phase is washed to neutral with water, and dried over anhydrous sodium sulfate. The benzene is evaporated in vacuo and the residue is fractionated to yield 43.9 g. of the named compound, boiling at 160°-162° C./1.33 Pa.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH:3]([N:7]1[CH2:10][CH:9]([CH2:11][C:12]2[N:13]([CH3:37])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:27]2[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]2[CH3:36])[N:15]=3)[CH2:8]1)[C:4]([OH:6])=O.[OH-].[NH4+:40]>>[CH3:1][CH:2]([CH3:38])[CH:3]([N:7]1[CH2:10][CH:9]([CH2:11][C:12]2[N:13]([CH3:37])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:17]=[C:16]([N:27]2[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]2[CH3:36])[N:15]=3)[CH2:8]1)[C:4]([NH2:40])=[O:6]
Reactant: [NH4+]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C(=O)O)C(C)C)C3)n(C)c2n1
Agent: [OH-]
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C(N)=O)C(C)C)C3)n(C)c2n1

Procedure:
Following General Procedure K, 3-methyl-2-(3-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)butanoic acid and ammonium hydroxide were coupled to give 579. LCMS m/z: 259.7 (2M+H+)