Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][N:24]([CH3:25])[CH3:23])[CH:28]=3)=[CH:16][CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)Cc1cccc(-c2ccc(N3CC(NC(=O)OC(C)(C)C)CC3=O)cc2)c1

Procedure:
525 mg (1.48 mmol) tert-butyl[1-(4-bromo-phenyl)-5-oxo-pyrrolidin-3-yl]-carbamate are dissolved in 30 ml of toluene and 5 ml of water and combined with 318 mg (1.77 mmol) 2-(N,N-dimethylaminomethyl)phenylboronic acid, 48 mg (0.15 mmol) tetrabutylammonium bromide and 314 mg (2.96 mmol) potassium carbonate, and lastly 173 mg (0.15 mmol) tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is refluxed for 90 minutes at 400 Watt in the microwave. Then another 330 mg (1.84 mmol) 2-(N,N-dimethylaminomethyl)phenylboronic acid are added and the mixture is heated for one hour at 400 Watt in the microwave. The reaction solution is evaporated to dryness i. vac. The residue is purified by reversed phase chromatography.
Reaction SMILES: [OH:1][CH:2]([CH3:34])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11](NCCNCC(O)C)=[CH:10][CH:9]=1.[C:35]([OH:38])(=[O:37])[CH3:36].C(O)C>CC(C)=O>[C:35]([OH:38])(=[O:37])[CH3:36].[C:35]([OH:38])(=[O:37])[CH3:36].[OH:1][CH:2]([CH3:34])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CNCCNc1ccc(NCCNCC(C)O)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(O)CNCCNc1cccc2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A mixture of 228 mg. of 1,4-bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone, 60 mg. of glacial acetic acid, and 10 ml. of ethanol is heated on a steam bath for 10 minutes, cooled, treated with 50 ml. of acetone and cooled to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([SH:20])=[N:9]2)=[CH:4][CH:3]=1.[CH3:21]I>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([S:20][CH3:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: SC1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: CI
Solvent: CCO
Product: CSC1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Yield: 105.4 %

Procedure:
A mixture of 8.0 g of 4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-2-thiol, 4.0 g of methyl iodide and 100 ml of ethanol was heated at reflux for 4 hours. The solvent was removed in vacuo and the residue distributed between methylene chloride and 10% aqueous NaHCO3 solution. The organic layer was dried and evaporated to give 8.8 g of 4,5-bis(4-chlorophenyl)-4,5-dihydro-2-(methylthio)-1H-imidazole as a colorless oil. The NMR spectrum was consistent with this structure. The hydrochloride salt was prepared with dry hydrogen chloride gas in ether to give the title compound as colorless crystals (5.3 g), m.p. 236° dec.
Reaction SMILES: [C:1]1([NH:11][C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: c1ccc(COc2cccc(CCNc3cccc4ccccc34)c2)cc1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of N-naphthyl-2-[3-(phenylmethoxy)phenyl]acetamide (3.00 g, 8.16 mmol) in tetrahydrofuran (25 mL) under nitrogen was added a solution of 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran (12.3 mL, 12.3 mmol) and heated to reflux for 5 hours. The reaction was quenched with a 5% hydrochloride solution. After stirring 30 minutes, the reaction was basified with a 10% sodium carbonate solution and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (2.724 g, 94% yield): 1H NMR (CDCl3) 7.78 (d, 1H), 7.67 (d, 1H), 7.18-7.46 (m, 10H), 6.89 (m, 3H), 6.66 (d, 1H), 5.01 (s, 2H), 4.40 (br, 1H), 3.55 (t, 2H), 3.05 (t, 2H); ES-MS (m/z) 354 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[N:3]=[N:2]1.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[Si:17]([O:10][C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]nnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]nnc12
Reaction time: 0.17 h

Procedure:
1H-benzo[d][1,2,3]triazol-4-ol (2.0 g) in tetrahydrofuran (30 mL) was treated with 60% sodium hydride (0.622 g). After 10 minutes, tert-butylchlorodimethylsilane (2.454 g) was added. The solution was stirred for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel using 10-50% ethyl acetate in hexanes as eluent to give the title compound.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.[Cu]I>[Br:1][C:2]1[O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Oc1ccccc1C=C(Br)Br
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc2ccccc2o1
Temperature: 80 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a solution of 2-(2,2-dibromovinyl)phenol (2.8 g, 10 mmol) in tetrahydrofuran (30 mL) was added copper (I) iodide (0.1 g, 0.5 mmol) and potassium phosphate (4.2 g, 20 mmol). The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 12 hours. After the reaction, the mixture was poured into water (200 mL) and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give the pure product 2-bromobenzofuran (1.8 g, 92%).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH2:34][CH3:35])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.C(Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SiH](CC)CC)C.C(N(CC)CC)C.[C]=O.CN([CH:87]=[O:88])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:32]([O:31][C:29]([C:26]1([CH2:34][CH3:35])[CH2:27][CH2:28][N:23]([C:20]2[N:19]=[CH:18][C:17]([C:4]3[CH:3]=[C:2]([CH:87]=[O:88])[C:10]4[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=4[CH:5]=3)=[CH:22][N:21]=2)[CH2:24][CH2:25]1)=[O:30])[CH3:33]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C=O)c2s1
Temperature: 75 °C
Yield: 80 %

Procedure:
A medium pressure reaction vessel was charged with the following reagents and solvent(s): Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (2.54 g, 4.52 mmol), palladium acetate (102 mg, 0.452 mmol), Pd(dppf)Cl2.CH2Cl2 (200 mg, 0.2 mmol), 3-diphenylphosphanylpropyl(diphenyl)phosphane (200 mg, 0.5 mmol), triethylsilane (2.3 mL, 14 mmol), triethylamine (1.3 mL, 9.05 mmol) in DMF (35 mL). The mixture was pressurised to 100 psi of carbon monoxide and heated at 75° C. overnight. The reaction was filtered through a 0.4 micron filter, and the majority of the DMF was removed in vacuo. Partitioning the crude mixture between DCM (100 mL) and washing with water (100 mL) followed by sat. aq. brine (100 mL) afforded a dark red syrup upon drying over MgSO4 and removal of the volatiles. Subjecting the residue to flash chromatography (Grace 80 g, 0-10% DCM/MeOH) yielded 1.85 g (80% yield) of the product as a yellow solid. 1HNMR (CDCl3) δ 10.20 (d, J=12.8 Hz, 1H), 8.65 (d, J=9.9 Hz, 2H), 8.11 (d, J=1.6 Hz, 1H), 7.86 (d, J=1.7 Hz, 1H), 4.58 (dt, J=13.7, 3.4 Hz, 2H), 4.23 (qd, J=7.1, 3.4 Hz, 2H), 3.57-3.41 (m, 2H), 3.28-3.10 (m, 2H), 2.26 (d, J=13.2 Hz, 2H), 1.61 (dt, J=7.5, 5.7 Hz, 4H), 1.52-1.39 (m, 2H), 1.31 (td, J=7.2, 3.6 Hz, 6H), 0.91-0.84 (m, 3H). MS: 511.0 [M+H]+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:33][CH2:34][C@@H:35]([OH:44])[CH2:36][CH:37](O)[CH2:38][C:39]([O:41]C)=O)[C:12]([CH:30]([CH3:32])[CH3:31])=[C:13]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.CCN(CC)CC.CC(OC(C)=O)=O.Cl>CO.CN(C1C=CN=CC=1)C.O>[C:23]1([NH:22][C:21]([C:13]2[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[N:11]([CH2:33][CH2:34][C@@H:35]3[CH2:36][CH:37]=[CH:38][C:39](=[O:41])[O:44]3)[C:12]=2[CH:30]([CH3:32])[CH3:31])=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CC(O)C[C@H](O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1CC=CC(=O)O1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
A suitable nitrogen inerted reactor is charged with KOH (110.0 mmol) and water (300 mL). To this rapidly stirring solution is added the crude Step 6 solution of (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, methyl ester (ca. 100 mmol/>98% ee) in MeOH (250 mL). The mixture is heated under a nitrogen atmosphere to an internal temperature of ca. 85° C. During this time, MeOH is removed via distillation. The resulting reaction mixture is allowed to cool to 45° C., where it is washed with MtBE (2×150 mL). The MtBE phases are separated and discarded. To the 45° C. aqueous phase is added toluene (125 mL), followed by a slow addition of 6N HCl (20 mL). The two-phase mixture is stirred for 10 minutes, and the layers are separated. The aqueous phase is extracted with a second portion of toluene (125 mL) and discarded. The combined organics are heated to reflux under a nitrogen atmosphere. During this time, 130 mL of distillate is collected and discarded. The resulting solution is cooled to ca. 60° C., where NEt3 (140 mmol), DMAP (2.0 mmol) and Ac2O (70.0 mmol) are added successively at such a rate as to maintain an internal reaction temperature of 55° C. to 65° C. This solution is stirred for ca. 1.5 hrs at 60° C. The mixture is cooled to 50° C., where 1N HCl (100 mL) is added slowly. The two-phase mixture is stirred for 10 minutes, the phases are separated, and the aqueous phase discarded. The organic phase is washed with second portions of 1N HCl (100 mL) and water (100 mL) while maintaining a temperature of 45° C. to 55° C. The toluene solution is diluted with Bu2O (200 mL) and the resulting solution is slowly cooled to 0° C. with continuous agitation. The resulting solid is collected on a filter funnel and dried under vacuum to provide 5-(4-fluorophenyl)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white to off-white solid (34.4 g). This material is carried on to subsequent steps without further purification, or optionally, it can be re-precipitated from IPA/H2O.
Reaction SMILES: C(N)(=O)CCC.[OH:7][NH:8][C:9](=[O:40])[C@:10]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29][CH2:28]3)=[CH:21][CH:20]=2)=[CH:15][C:14]1=[O:34]>>[OH:7][NH:8][C:9](=[O:40])[C@:10]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([OH:33])[CH2:31][CH2:32]3)=[CH:21][CH:20]=2)=[CH:15][C:14]1=[O:34]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Agent: CCCC(N)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
The title compound (300 mg, 83%) was prepared from (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-Netrahydro-2H-pyran-2-yloxy)butanamide (480 mg, 0.726 mmol) by a procedure analogous to that described for (2R)—N-hydroxy-4-[4-{4-[(cis-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide Example 8, Step F. LCMS m/z 493.7 (M+1)1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.23 (m, 4H) 1.54 (s, 3H) 1.58-1.72 (m, 1H) 1.81 (br. s., 4H) 2.06-2.21 (m, 1H) 2.41 (s, 1H) 3.08 (s, 3H) 3.25-3.41 (m, 1H) 3.74 (br. s., 1H) 3.80 (d, J=6.44 Hz, 2H) 3.98-4.17 (m, 1H) 6.48-6.71 (m, 2H) 6.85-7.06 (m, 2H) 7.52-7.78 (m, 3H) 11.15 (s, 1H)
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44](O)=[O:45])[CH2:33]1)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:47][C:48]1[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][C:49]=1[O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[C@H:34]([C:44]([N:54]2[CH2:53][CH2:52][CH:51]([O:50][C:49]3[CH:57]=[C:58]([CH3:61])[CH:59]=[CH:60][C:48]=3[Cl:47])[CH2:56][CH2:55]2)=[O:45])[CH2:33]1)=[O:30])=[O:26])([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(Cl)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(OC2CCN(C(=O)[C@@H]3C[C@@H](NC(=O)CNC(=O)OC(C)(C)C)CN3C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.6 %

Procedure:
N-Methylmorpholine (60 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 200 mg), 4-(2-chloro-5-methylphenoxy)piperidine (117 mg) and, 1-hydroxybenzotriazole (70 mg) in tetrahydrofuran (6 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at room temperature for 14 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated in vacuo. The residue was washed with hexane to give the titled compound (309 mg) as a white foam: 1H NMR (400 MHz, CDCl3) δ 1.43-1.46 (18H), 1.89 (br s, 4H), 2.16 (br s, 2H), 2.32 (s, 3H), 3.34-3.60 (m, 3H), 3.70-4.00 (m, 5H), 4.49 (br s, 0.5H), 4.62 (m, 2H), 4.79 (br s, 0.5H), 5.11 (br s, 1H), 6.34 (br s, 1H), 6.77 (m, 2H), and 7.24 (m, 1H). Anal. Calcd for C29H43Cl1N4O7: C, 58.53; H, 7.28; N, 9.41; Cl, 5.96. Found: C, 58.21; H, 7.35; N, 9.25; Cl, 6.03; IR (KBr) 3319, 2978, 2933, 1699, 1666, 1404, 1252, 1165, 1061 cm−1; mass spectrum (EI+) m/e 594 (M).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11].ClC1C=CC(C(C2C=CC(F)=CC=2)O)=CC=1F>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)([OH:11])[CH3:9])=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Fc1ccc(Br)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1
Product: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared starting from 5.00 g (28.57 mmol) of 4-bromofluorobenzene and 4.86 g (31.43 mmol) of 4-chloroacetophenone in analogy to the synthesis of the compound from Example 176A. A difference was that a preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9/1) was carried out before the purification of the crude product by preparative HPLC. 5.23 g (73% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([C:9]3[C:10]([O:23][C:24]4[N:32]=[C:31]5[C:27]([N:28](C6CCCCO6)[CH:29]=[N:30]5)=[CH:26][N:25]=4)=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:21])[CH3:20])[C@@H:14]([CH3:22])[CH2:13][CH2:12]4)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[N:25]1[CH:26]=[C:27]2[C:31]([N:30]=[CH:29][NH:28]2)=[N:32][C:24]=1[O:23][C:10]1[C:9]([C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH:8]=2)=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][C@H:14]([CH3:22])[N:15]2[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ncc4c(ncn4C4CCCCO4)n3)c2CC[C@@H]1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ncc4[nH]cnc4n3)c2CC[C@@H]1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A 100-mL, round-bottom flask was charged with 1-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.150 g, 0.29 mmol), HCl (6 M aqueous solution, 3 mL) and methanol (20 mL). The resulting solution stirred overnight at 40° C. After cooling to room temperature, the pH of the reaction mixture was adjusted to 7-8 with saturated aqueous sodium carbonate solution. The resulting mixture was concentrated to remove the methanol and ethyl acetate was added. The aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (37% acetonitrile up to 58% in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-1-(5-(7H-purin-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.030 g, 24%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.86-1.00 (m, 4H), 1.16 (d, J=6.30 Hz, 3H), 1.21-1.49 (m, 1H), 2.18-2.47 (m, 5H), 2.63-2.72 (m, 1H), 3.52-3.59 (m, 1H), 4.72-4.80 (m, 1H), 7.19-7.30 (m, 1H), 7.56 (d, J=8.40 Hz, 1H), 7.60 (s, 1H), 7.99 (s, 1H), 8.41 (s, 1H), 8.79 (s, 1H). MS (ESI, pos. ion) m/z 430 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([OH:34])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:25]=1)=[O:23].Cl>C(OCC)(=O)C>[C:30]([C:28]1[CH:29]=[C:24]([C:22](=[O:23])[CH2:21][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:25]=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[OH:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1OCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A mixture of 19.4 g (125 mmol) of 4-hydroxy-3-methoxy-benzaldehyde, 1.88 g (12.5 mmol) of sodium iodide and 34.5 g (250 mmol) of potassium carbonate in 1000 ml of ethyl acetate is stirred for 30 minutes. Then 43.6 g (125 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone is added and stirring at room temperature is continued for 16 hours. Then the mixture is acidified with 2N HCl and extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated. Crystallization of the crude product from dichloro-methane/hexane yields 36.85 g of compound 101, m.p. 99-100° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][C:23]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24]5)=[O:19])[CH2:13][C:12]=3[CH:33]=2)=[CH:4][C:3]=1[N+:34]([O-])=O.[H][H]>[Pd].C(O)(=O)C>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([N:20]4[CH:21]5[CH2:27][CH2:26][CH:25]4[CH2:24][C:23]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:22]5)=[O:19])[CH2:13][C:12]=3[CH:33]=2)[CH:6]=[N:7][C:2]=1[NH2:1]
Reactant: Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cnc1N
Yield: 92 %

Procedure:
A slurry of 8-{[7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (1.1 g, 2.2 mmol), Pd/C (5% wt./wt., 0.20 g) and acetic acid (40 mL) was subjected to an atmosphere of hydrogen (45 PSI) using a Parr apparatus. After 2 hours the reaction mixture was filtered through Celite and concentrated to give 8-{[7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (0.95, 92% yield) as an orange oil. MS (ES) for C23H26F3N5O3: 478 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:34][C:35]1[C:36]([O:43][CH3:44])=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:34][C:35]1[C:36]([O:43][CH3:44])=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COc1ccc(CCl)c(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)c(OC)n1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
5-Benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.03 g) was dissolved in dimethylformamide (27 mL), and sodium hydride (0.20 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 min. A solution of 3-chloromethyl-2,6-dimethoxypyridine (0.95 g) in dimethylformamide (6 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.43 g).