Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:56][C@@H:57]([CH2:68][CH3:69])[CH2:58][O:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.C1COCC1.CN(C=O)C>[C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38](=[O:39])[NH:56][C@@H:57]([CH2:68][CH3:69])[CH2:58][O:59][CH2:60][C:61](=[O:62])[O:63][C:64]([CH3:65])([CH3:67])[CH3:66])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC[C@H](N)COCC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC)COCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and (S)-tert-butyl 2-(2-aminobutoxy)acetate (1.5 eq, from the previous step) in 2:1 THF/DMF (0.13 M) was added EDCI (1.3 eq), HOBT (1.3 eq), and DIEA (5 eq). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 2:1 saturated aqueous NaHCO3/water, brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH3:22])[C:13]=2[CH3:23])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:24]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OC(=O)C)(=O)C>[CH2:40]([N:37]([CH2:38][CH3:39])[C:33]1[CH:34]=[CH:35][C:36]([C:10]2([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][CH3:22])[C:13]=3[CH3:23])[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][N:6]=3)[C:1](=[O:2])[O:11]2)=[C:31]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:32]=1)[CH3:41]
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Reactant: CCCCCCOc1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCOc1cc(N(CC)CC)ccc1C1(c2c(C)n(CC)c3ccccc23)OC(=O)c2cccnc21
Temperature: 25 °C

Procedure:
Into 200 ml of acetic anhydride, 15.4 g of (1-ethyl-2-methylindol-3-yl) (3-carboxypyridin-2-yl) ketone and 13.7 g of 1-n-hexyloxy-3-diethylaminobenzene were added, and the resultant mixture was stirred for 3 hours to 60° to 65° C. After cooling the reaction mixture to room temperature, the cooled reaction mixture was treated by the same manner as in Synthetic Example 1 and as a result, 18.9 of the objective compound of the melting point of 154° to 156° C. as pale blue crystals was obtained. The elementary analytical data of the product were as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=1.Cl.CN1C(C)(C)CCCC1(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: Cc1nn(C)cc1N
Agent: CN1C(C)(C)CCCC1(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1Nc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 6-bromo-4-chloro-3-nitro-quinoline (Stage A.4, 3.0 g, 20.43 mmol) and 4-amino-1,3-dimethylpyrazole.HCl (ChemCollect, Remscheid, Germany, 1.85 g, 12.53 mmol) in DMA (45 ml) was added 1,2,2,6,6-pentamethylpiperidine (6.67 ml, 36.5 mmol). The RM was stirred at 50° C. for 4.5 h. Then the RM was cooled down to rt and quenched with H2O. The suspension was filtered, the solid cake was washed with H2O and dried under vacuum, before being dissolved in EtOAc. The solution was washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an orange solid (HPLC tR 2.55 min (Method A); M+H=362; M−H=360 MS-ES)
Reaction SMILES: [NH:1]([C:57]([O:59][CH2:60][CH:61]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:67]2[C:62]1=[CH:63][CH:64]=[CH:65][CH:66]=2)=[O:58])[C@@H:2]([C:15]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49]CC1C=CC=CC=1)=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(=O)([O-])O.[Na+].Cl>C(Cl)(Cl)Cl.CCCCCCC.FC(F)(F)C(O)=O>[NH:1]([C:57]([O:59][CH2:60][CH:61]1[C:62]2[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:68]2[C:73]1=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:58])[C@@H:2]([C:15]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 12.5 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
The crude crystals (1.23 g) of Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in a mixture of chloroform (12 mL) and heptane (12 mL), and 3% trifluoroacetic acid/(chloroform-heptane=1:1) solution was added dropwise under ice-cooling. The reaction mixture was stirred in a water bath at 10-15° C. for 3 hr, and 2.5% aqueous sodium hydrogen carbonate solution (18 mL) and chloroform (18 mL) were added. 0.1N Hydrochloric acid was added, and the aqueous layer was adjusted to pH 2. The aqueous layer was removed, and the organic layer was washed 3 times with purified water (10 mL). The combined organic layers were concentrated under reduced pressure, and heptane (30 mL) was added to the residue. The precipitated crystals were washed at 40° C. and collected by filtration to give Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OH (800 mg, 93%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CO>[CH3:29][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (6.4 g, 15.6 mmol) was dissolved in MeOH (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with EtOAc (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide a white solid. The compound was recrystallized from CH3CN (85 mL) to afford the product (4.50 g, 75%) as colorless needles after drying at 50° C. under vacuum for 6 h: Rf=0.14 in 35% EtOAc/hexanes; mp 129-130° C.; 1H NMR (400 MHz, CDCl3) δ 7.98-7.96 (m, 2H), 7.44-7.41 (m, 3H), 6.91-6.79 (m, 4H), 4.16 (t, J=8.8 Hz, 2H), 2.99 (t, J=8.8 Hz, 2H), 2.38 (s, 3H), 1.53 (s, 6H); 13C (100 MHz, CDCl3) δ 177.2, 159.7, 154.7, 148.3, 145.3, 132.4, 130.1, 128.7, 127.2, 126.1, 122.1, 114.9, 79.9, 67.0, 26.1, 25.1, 10.2; IR (CHCl3) 2991, 1775, 1718, 1554, 1506, 1469, 1237, 1145, 1023 cm−1; HRMS (TOF) m/e calcd. for C22H24NO5 (M++1) 382.1654, found 382.1628.
Reaction SMILES: Cl.[P:2]([O:14][CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]3[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])[CH2:20][CH2:19]1)=[O:17])([O:9]C(C)(C)C)([O:4]C(C)(C)C)=[O:3].C(OCC)C>O1CCOCC1>[P:2]([OH:4])([OH:9])([O:14][CH2:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]3[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])[CH2:22][CH2:23]1)=[O:17])=[O:3]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)COP(=O)(OC(C)(C)C)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)COP(=O)(O)O)CC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
4M Hydrogen chloride in 1,4 dioxane (1.95 ml) was added to a stirred solution of di-tert-butyl 2-[4-(4-[3-chloro-2-fluoroanilino]-7-methoxyquinazolin-6-yloxy)piperidin-1-yl]-2-oxoethyl phosphate (0.951 g) in 1,4-dioxane (16 ml). The mixture was stirred overnight and diethyl ether (50 ml) was then added. The resulting precipitate was collected by filtration and dried to give the title product as a white solid (0.77 g); NMR Spectrum: (DMSO d6) 1.60–1.76 (m, 2H), 2.11 (m, 2H), 3.38 (m, 2H), 3.69 (m, 1H), 3.91 (m, 1H), 4.02 (s, 3H), 4.53 (m, 2H), 5.02 (m, 1H), 7.37 (m, 2H), 7.55 (m, 1H), 7.65 (m, 1H), 8.53 (s, 1H), 8.81 (s, 1H), 11.86 (br s, 1H); Mass Spectrum: (M+H)+ 541.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.[OH-].[Na+].O1CCO[CH2:28][CH2:27]1>O>[OH:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]3[CH:20]4[CH2:27][CH2:28][CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]=13)[O:7][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:23])([CH3:22])[CH2:15][CH2:14]2
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCCC3CC1
Reaction time: 15 h

Procedure:
To a solution of 3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester (235 mg, 0.68 mmol) in 5 mL of dioxane was added a solution of NaOH (41 mg, 1.02 mmol) in 400 mL water. The resulting suspension was vigorously stirred for 15 h and quenched by adding 50 mL of saturated NaH2PO4 solution. The mixture was extracted with EtOAc (3×50 mL) and the organic layers were dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel to afford 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-propano-2H-benzo[h]chromen-2-yl)-propionic acid as a white sticky solid (184 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.71 (ws, 1 H), 6.41 (s, 1 H), 3.54 (m, 1 H), 3.38 (m, 1 H), 2.73 )m, 2 H), 2.56 (m, 2 H), 2.10-1.62 (m, 12 H), 0.95 (m, 5 H); 13C-NMR δ (ppm): 180.1, 144.0, 142.9, 132.8 128.9, 118.5, 112.7, 74.0, 34.48, 34.0, 32.0, 31.9, 31.8, 29.5, 28.7, 28.6, 26.4, 26.3, 26.0, 23.9, 23.3, 22.7, 22.3; MS (ESI) m/z: 331 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[N:7][C:6]=12.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[N:7][C:6]=23)[CH:23]=1)=[O:18]
Reactant: FC(F)(F)c1cnc2c(Br)cnn2c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
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
Product: COC(=O)c1cc(-c2cnn3cc(C(F)(F)F)cnc23)c(C)s1
Temperature: 85 °C
Yield: 46.8 %

Procedure:
3-Bromo-6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (200 mg, 0.752 mmol), methyl-5-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (297 mg, 1.05 mmol), Pd(PPh3)4 (43.4 mg, 0.038 mmol), and 2 M sodium carbonate (aq) (750 μL, 1.50 mmol) were placed in a sealed tube. 1,4-dioxane (3.75 mL) was added and the reaction purged with N2 for 5 min. The reaction was heated to 85° C. for 7 h. After consumption of starting material, the reaction was cooled to room temperature, diluted with water and extracted 3× with ethyl acetate. The organic layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-70% EtOAc/Hex) to afford the title compound (120 mg, 0.352 mmol). LRMS (APCI) calc'd for (C14H10F3N3O2S) [M+H]+, 342.0; found 342.0.
Reaction SMILES: C([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)(OCC)=O.[OH-].[K+]>C(O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9]3[CH2:26][CH2:27][NH:6][CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCCCCCCCn1c2c(c3cc(Br)ccc31)CN(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCn1c2c(c3cc(Br)ccc31)CNCC2
Yield: 74.5 %

Procedure:
To the solution of 2-carbethoxy-8-bromo-5-n-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (4b) in ethanol was added the aqueous solution of potassium hydroxide. The mixture was refluxed for 16 h. The reaction mixture was concentrated to remove ethanol and extracted with DCM for three times (15 mL×3). The DCM layer was washed with brine, dried with Na2SO4, filtered and concentrated to give brow residue. This residue was purified by silica gel column chromatography to give yellow oil. Yield: 74.5%.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:39]=[CH:24][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:22]=3[CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccs2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (82 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (20 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (61 mg) and triethylamine (279 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 60) (86 mg) as yellow crystals.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.ClCCl.CO>O>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:20][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)cc2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 90.6 %

Procedure:
Boron tribromide (1.0 M, 3.91 mL, 3.91 mmol) was added dropwise into a cold (−78° C.) mixture of 4-(4′-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (1.6 g, 3.91 mmol), and dichloromethane (20 mL). The reaction mixture was allowed to come gradually to room temperature and stirred for 10 hours. Then, the mixture was cooled to 0° C. and methyl alcohol (5 mL) was added dropwise. After stirring for 10 minutes the mixture was poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether/hexanes gave an off-white solid (1.4 g, 90% yield): mp 189-191; MS m/e 396 (M+H)+;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].F>[Cr].[Co]>[CH3:8][C:4]1[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=[C:6]([C:10]([CH3:11])=[O:12])[CH:5]=1
Reactant: Cc1cccc(C)c1O
Reactant: CC(=O)OC(C)=O
Agent: [Co]
Agent: [Cr]
Agent: F
Product: CC(=O)c1cc(C)c(O)c(C)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(36.6 g, 0.30 mol) of 2,6-dimethylphenol are mixed in an Hastelloy C autoclave with 0.315 mol of acetic anhydride and 9 mols of hydrogen fluoride. The temperature is raised to 50° C. and the reaction runs for 3 hours. After extraction and wash, 47.4 g of a gray to purple solid mass of 3,5-dimethyl-4-hydroxyacetophenone is obtained. This solid is then esterified by refluxing with 4 mols of acetic anhydride for 19 hours. After removal of acetic acid and acetic anhydride by vacuum distillation the 3,5-dimethyl-4-acetoxyacetophenone is flash distilled to yield 47.7 g of a slightly yellow liquid. 0.1 mol of the 3,5-dimethyl-4-acetoxyacetophenone, 1.2 g of 5% Pd/C as catalyst and 100 ml ethanol are mixed in an autoclave and the autoclave is charged with hydrogen gas at a pressure of 215-220 mm Hg PSIG and the reaction is run for about 2 1/2 hours at a temperature of about 25°-30° C. Additional catalyst is added as needed. The catalyst is then removed and the ethanol evaporated to yield 21.5 g of a colorless oil which is 1-(3',5'-dimethyl-4'-acetoxyphenyl)ethanol. 0.168 mol of 1-(3',5'-dimethyl-4'-acetoxyphenyl)ethanol is added to a flask with 0.35 g KHSO4 and 0.5 g t-butyl catechol. The flask is heated to 185° to 190° C. at 1.5 to 2.0 mm Hg. A colorless liquid is distilled. After the addition of 0.15 g of t-butyl catechol, and redistillation, 26.1 g of 3,5- dimethyl-4-acetoxystyrene monomer is produced. The compound has a boiling point of 90°-91° C. at 0.5 mm of Hg and the yield is 81.8%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][OH:15].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:22]([O:15][CH2:14][C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1cnc2ccc(Cl)nc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-hydroxyethanone (128 mg, 0.5 mmol) in DMF (5 mL) was added imidazole (68 mg, 1.0 mmol) and tert-butyldimethylsilyl chloride (90 mg, 0.6 mmol) at 0° C. The mixture was stirred for 3 h, poured into NaHCO3 (saturated), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated, and purified by chromatography to afford product (87 mg, 47%) as a light yellow oil: ESI MS m/z 371 [M+H]+.