Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][OH:48])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.[C:49](O)(=[O:52])[CH:50]=[CH2:51]>ClCCl.CN(C)C1C=CN=CC=1>[C:49]([O:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:32]2[CH:33]=[CH:34][C:29]([C@H:26]3[CH2:25][CH2:24][C@H:23]([CH2:22][CH2:21][CH:17]4[O:18][CH2:19][CH2:20][O:16]4)[CH2:28][CH2:27]3)=[CH:30][CH:31]=2)=[CH:36][CH:37]=1)(=[O:52])[CH:50]=[CH2:51]
Reactant: OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC4OCCO4)CC3)cc2)cc1
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC4OCCO4)CC3)cc2)cc1
Reaction time: 8 h

Procedure:
3.38 g of dicyclohexylcarbodiimide in 5 ml of dichloromethane was added dropwise while stirring at 0°-5° C. within 5 minutes to a solution of 6.2 g of 6-[4'-[trans-4-(2-[1,3]dioxolan-2-yl ethyl)cyclohexyl]-biphenyl-4-yloxy]-hexan-1-ol, 1.48 g of acrylic acid and 1.67 g of 4-dimethylamino-pyridine in 50 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and then concentrated. Chromatography of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 5.14 g of 6-[4'-[trans-4-(2-[1,3]dioxolan-2-yl-ethyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate.
Reaction SMILES: C(OC([N:6]1[CH:10]=[CH:9][S:8][CH:7]1[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)C.ClC1C(=O)C(=O)C(Cl)=C(Cl)C=1Cl>ClCCl>[S:8]1[CH:9]=[CH:10][NH:6][C:7]1=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)C1SC=CN1C(=O)OCC
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C1NC=CS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 44A (12.9 g, 40.7 mmoles) in dichloromethane (100.0 ml) was added tetrachloro-1,2-benzoquinone (10.0 g, 40.7 mmoles) in portions at about 0° C., such that the mixture always had time to decolorize to a yellow-orange color. The mixture was then stirred for about 1 hour at 0° C. and was then washed with saturated aqueous sodium bicarbonate solution (200.0 ml) and brine (100.0 ml). The organic layer was dried over MgSO4, filtered, concentrated in vacuum and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to provide the title compound.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([C:21](=[O:40])[NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])[CH2:28][CH2:27]2)[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH3:18])[C:8](=[O:19])[C:7]=2[CH:20]=1.NC1C=CC(C2OC3C([C:61](=O)[NH:62][CH2:63]CCN4CCN(C5C=CC=CC=5OC)CC4)=CC=CC=3C(=O)C=2C)=CC=1>O.[OH-].[Na+]>[CH3:61][N:62]([CH3:63])[C:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:6]3[C:5]([C:21](=[O:40])[NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])[CH2:28][CH2:27]4)=[CH:4][CH:3]=[CH:20][C:7]=3[C:8](=[O:19])[C:9]=2[CH3:18])=[CH:17][CH:16]=1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc(N)cc4)oc23)CC1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cc(N(C)C)cc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc(N(C)C)cc4)oc23)CC1

Procedure:
The title compound was prepared by the same method as described for compound of Example 97, but using the compound prepared in Example 124 instead of compound of Example 94. The reaction mixture was diluted with water and 3N aqueous sodium hydroxide solution, under vigorous stirring. The precipitated solid was filtered by suction, washed with water, desiccated and purified by flash chromatography on silica gel eluting with ethyl acetate - methanol (8.5:1.5). Evaporation in vacuo of the collected fractions yielded the title compound which melted at 146°-150° C. after crystallization from acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:1][C:2]1[C:3]([C:8]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(COC(=O)c2ncccc2OCc2cccc(OC)c2)c1

Procedure:
In analogy with Example 38a), 10 g of the product were obtained, as a colorless oil which was subjected to further reaction, from 8.4 g (60 mmol) of 3-hydroxypyridine-2-carboxylic acid and 3-methoxybenzyl chloride following chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27]([CH2:29][NH2:30])[OH:28]>C1COCC1>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:30]/[CH2:29][CH2:27][OH:28])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(/C=N/CCO)c(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
The title compound was synthesized by reacting 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 with ethanolamine in THF.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][N:25]=1.C(N(CC)CC)C.Cl.C([O-])(O)=O.[Na+]>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:23]([F:34])([F:22])[F:33])=[N:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(C(F)(F)F)nc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 6-trifluoromethylnicotinoyl chloride (0.65 g, 3.10 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The mixture was neutralized with sat. aq. NaHCO3. The product was isolated by filtration, washed with water (50 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-trifluoromethyl-nicotinamide as a white solid (0.73 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.39 min (97.69%); mp: 240-242° C.; 1H NMR (DMSO-d6) δ 1.92-2.12 (m, 1H), 2.29-2.44 (m, 1H), 2.54-2.70 (m, 1H), 2.81-3.09 (m, 1H), 4.32 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 5.11 (dd, J=5.0, 13.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.40-8.60 (m, 1H), 9.22 (s, 1H), 9.56 (t, J=5.8 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.49, 31.21, 42.87, 47.14, 51.60, 120.60 (q, J=2.9 Hz), 121.41 (q, J=272 Hz), 122.23, 123.00, 127.20, 130.54, 132.78, 137.49, 142.45, 143.13, 148.1 (q, J=34 Hz), 149.02, 163.74, 167.89, 170.98, 172.85; LCMS: MH=447; Anal Calcd for C21H17N4O4F3+0.25H2O: C, 55.94; H, 3.91; N, 12.43. Found: C, 55.97; H, 3.49; N, 12.28.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Temperature: 68 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300 mg, 0.72 mmol, 1 equiv), 4-iodo-1-phenylbutan-1-one (198.5 mg, 0.72 mmol, 1 equiv) and potassium carbonate (199 mg, 1.44 mmol, 2 equiv) in N,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the preparative thin layer chromatography in 8% methanol in dichloromethane to afford the title compound (268 mg, 65.5%); MS for C35H41N3O4 m/z 568.31 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][SiH2:5][CH:6]=[C:7]([CH3:9])[CH3:8].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+]>CN(C=O)C>[C:10]([O:13][CH2:2][CH2:3][CH2:4][SiH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])(=[O:12])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: CC(C)=C[SiH2]CCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCC[SiH2]C=C(C)C
Temperature: 120 °C
Yield: 75 %

Procedure:
As shown in the Reaction Scheme 8, a mixture of 3-chloropropyldimethylvinylsilane (1.0 g, 6.15 mmol) and sodium acetate (1.01 g, 12.3 mmol) was dissolved in 17 mL of N,N′-dimethylformamide (DMF), and the resulting solution was heated at 120° C. for 12 hours. After the reaction, the organic layer was extracted with distilled water and ether. After evaporating the solvent, the resulting residue was purified by column chromatography (n-Hex:EA=10:1, Rf=0.36) to give 859 mg (75% yield) of pure 3-acetoxypropyldimethylvinylsilane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:40])[C@H:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][O:26][C:25]3=[O:31])[C:16]#[N:17])[CH:8]=[CH:9][CH:10]=1)=[O:4].N#N>CC(=O)C(C)(C)C.CCOC(C)=O>[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:40])[C@H:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][O:26][C:25]3=[O:31])[C:16]#[N:17])[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(CCCC[C@@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)Nc2ccc3c(c2)C(=O)OC3)c1
Agent: N#N
Solvent: CC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C[C@H](Nc2ccc3c(c2)C(=O)OC3)C(=O)N[C@H](C#N)CCCCc2cccc(C(=O)O)c2)c1
Temperature: 100 °C

Procedure:
A solution of N-(5-(3-methoxycarbonylphenyl)-1(S)-cyanopentyl]-3-methyl-Nα-(3-oxo-1,3-dihydro-isobenzofuran-5-yl)-L-phenylalaninamide (0.354 g, 0.67 mmol) in pinacolone (15 mL) is deoxygenated with bubbling N2 for 5 min., after which time Lil (0.90 g, 6.74 mmol) is added in one portion. The solution is then heated to 100° C. for 28 h. After cooling, it is diluted with EtOAc (100 mL), and washed with 1 N HCl (100 mL), and brine (50 mL), then dried (MgSO4), evaporated and chromatographed (2% MeOH/CH2Cl2, 0% to 0.05% acetic acid) to yield N-(5-(3-carboxyphenyl)-1(S)-cyanopentyl]-3-methyl-Nα-(3-oxo-1,3-dihydro-isobenzofuran-5-yl)-L-phenylalaninamide, as a light yellow solid; m.p. 91-94° C.
Reaction SMILES: [CH:1]1([N:7]([CH3:21])[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:12]=[CH:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl>[CH:1]1([N:7]([CH3:21])[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N+:17]([O-:27])[CH:18]=[CH:19][CH:20]=3)[N:12]=[CH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCCCC1
Solvent: ClC(Cl)Cl
Product: CN(C(=O)n1cnc(-c2ccc[n+]([O-])c2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
To a stirred solution of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-1H-imidazole-1-carboxamide (90 mg, 0.317 mmol) in chloroform (5 mL) was added 3-chlorobenzoperoxoic acid (149 mg, 0.475 mmol) in one portion. The reaction was allowed to stir at room temperature for 20 h. TLC showed the reaction to be complete and the mixture was evaporated to dryness. The residue was triturated with ether and the resulting white crystals were filtered off and dried in air. Recrystallisation from hot isopropanol gave a white powder (46 mg, 46%).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]([OH:12])[CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3](=[O:12])[CH2:2]1
Reactant: OC1COc2ccccc2OC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1COc2ccccc2OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 3,4-dihydro-2H-1,5-benzodioxepin-3-ol (1 g, 6.02 mmol) in dichloromethane (20 ml) was added Dess-Martin periodinane (2.8 g, 6.60 mmol). The mixture was stirred overnight at 25° C., and then purified by flash chromatography on a Biotage Horizon, 40M column, eluting with 1 column volume of 100% dichloromethane, followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes, to provide the title compound (964 mg, 5.87 mmol, 98% yield). 1H NMR (500 MHz, CDCl3): δ 6.99 (m, 4H), 4.72 (s, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8]([O:12][C:13]([C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:17][CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)=[CH:17][CH:16]=1)=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccc(OCCCCCCBr)cc1
Reactant: Cc1cc(C)on1
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)OC(C)(C)C)cc2)on1
Yield: 23 %

Procedure:
[I; R is CH3, n is 5, X is O, Ar is 4--(CH3)3 --COOCC6H4 ], m.p. 76° C., in 23% yield from 3,5-dimethylisoxazole and 6-(4-tertiary-butyloxycarbonylphenoxy)hexyl bromide; MIC vs. rhinovirus Type 2 in vitro=6.2 μg/ml.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:17][C:18]([OH:22])([C:20]#[CH:21])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:20][C:18]([CH3:19])([OH:22])[CH3:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(O)C#Cc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 25.5 g (0.094 mole) of 3,5-dichloroiodobenzene, 550 ml dry triethylamine, 12 g (0.14 mole) of 2-methyl-2-hydroxy-3-butyne, 0.42 g (0.0019 mole) palladium (II) acetate, and 1 g (0.0038 mole) of triphenylphosphine was heated to reflux under nitrogen for four hours. The resulting mixture was cooled, diluted with ether and washed with two 500-ml portions of 3N hydrochloric acid. The ether layer was separated, dried over anhydrous magnesium sulfate, and evaporated in vacuo to yield the crude product as an oily residue. The purified product was obtained by distillation to yield 7.95 g, bp 115°-125° C./0.0001 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7](=[CH:23][N:24]([CH3:26])[CH3:25])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=C1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O

Procedure:
A mixture of 18.6 g (61 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl acetal was gently heated (ca 50° C.) for 12 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give a yellow solid, mp 170°-171° C. Recrystallization from ether gave yellow prisms, mp 170°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[CH:7]=[C:6](Br)[CH:5]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2B(O)O)[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:10]([C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:30]=2[N:21]=[CH:22][CH:23]=[CH:24]3)[CH:7]=1)[C:3]([O:2][CH3:1])=[O:20])=[O:11])[CH2:14][CH3:15]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2cccc3cccnc23)c1
Temperature: 22.5 °C
Yield: 77.7 %

Procedure:
A mixture of methyl-3-bromo-5-[(dipropylamino)carbonyl]benzoate (XLVIII, 200 mg, 0.58 mmol), 8-quinolineboronic acid (200.6 mg, 1.2 mmol), sodium carbonate (870 Micro Liter of a 2 M mixture in water, 1.74 mmol) in toluene (6 mL) is degassed under reduced pressure for 15 minutes and purged with argon. Palladium tetrakis(triphenylphosphine) (139 mg, 0.12 mmol) is added and the reaction mixture is degassed under reduced pressure for 15 minutes and purged with argon. The reaction mixture is heated at reflux overnight, cooled to 20-25 degrees C. and diluted with chloroform. The organic phase is separated and washed with water (3×50 mL), and saline, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (silica, ethyl acetate/hexanes, 1.3/1) gives methyl 3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoate (XLIX, 176 mg), NMR (300 MHz, CDCl3): delta 8.91, 8.42, 8.21, 8.09, 7.95, 7.86, 7.77, 7.64, 3.94, 3.49, 3.34, 1.64, 0.99 and 0.84.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:27]=[CH:26][C:10]([O:11][CH2:12][CH:13]([NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Cl)[CH:20]=2)[OH:18])[CH3:14])=[CH:9][CH:8]=1)=[O:4]>CO>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:27]=[CH:26][C:10]([O:11][CH2:12][CH:13]([NH:15][CH2:16][CH:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:18])[CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Solvent: CO
Product: COC(=O)CCc1ccc(OCC(C)NCC(O)c2ccccc2)cc1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
2.2 g of 2-{2-[4-(2-methoxycarbonylethenyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 53) were dissolved in 200 ml of methanol and hydrogenated by bubbling hydrogen through the solution at atmospheric pressure and at room temperature in the presence of 0.5 g of 10% w/w palladium-on-charcoal for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was dissolved in ethyl acetate, and the resulting solution was washed with an aqueous solution of potassium carbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The product thus obtained was recrystallized from a mixture of ethyl acetate and hexane, to give 1.2 g of the title compound as crystals, melting at 103°-104° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1([F:19])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])(C)(C)[CH3:2].C([O-])(O)=O.[Na+].ClC(OCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.O1CCOCC1>[CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1([F:19])[CH2:15][CH2:16][CH2:17][CH2:18]1)[C:10]([OH:12])=[O:11])=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)NC(CC1(F)CCCC1)C(=O)O
Reaction time: 2 h

Procedure:
2-tert-Butoxycarbonylamino-3-(1-fluorocyclopentyl)-propionic acid (200 mg, 0.73 mmol) was kept in 4M HCl in dioxane (3 mL) for 20 min The mixture was then freeze-dried and left under a vacuum for 2 h. The solid residue was dissolved in dioxane-H2O 1:1 (12 mL). NaHCO3 (2.18 mmol, 3 eq.) and then ethyl chloroformate (0.87 mmol 1.2 eq.) dissolved in of dioxane (1 mL) were added. The reaction mixture was stirred for 20 min until completed according LC-MS. The mixture was acidified by citric acid (10% aq.) to pH 5. The product was extracted with DCM (20 mL) and EtOAc (20 mL). The organic layers were combined, dried (MgSO4) and concentrated. The afforded crude was used without further purification in the next step.
Reaction SMILES: C1(=O)[N:5]([CH:6]([C:9]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][NH:13]3)[CH2:7][CH3:8])C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH:6]([C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][NH:13]2)[CH2:7][CH3:8]
Reactant: CCC(c1c(C)ccc2[nH]nc(-c3ccccc3)c12)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: CCC(N)c1c(C)ccc2[nH]nc(-c3ccccc3)c12
Yield: 92.4 %

Procedure:
By the procedure similar to that described in Example 33, 1-phthalimidopropyl-3-phenyl-5-methylindazole (5.0 g) and hydrazine hydrate (1.5 g) were treated to obtain 3.1 g of 1-aminopropyl-3-phenyl-5-methylindazole as an oily product. The product was converted by a conventional way to its hydrochloride having a melting point between 161°-163° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)NC=C2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]([CH3:23])[CH:21]=O.C(=O)(OC)OC>CCCCCCC.O.C(OCC)(=O)C>[CH3:19][N:20]1[C:23]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:21]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 10 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A 500 mL, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with 5-nitroindole (20.0 g, 12.3 mmol), potassium carbonate (4.0 g, 29 mmol), N,N-dimethylformamide (80 mL) and dimethyl carbonate (22 mL, 26.14 mmol). The resulting mixture was heated to reflux. The reaction was monitored by HPLC or TLC (solvent system: 30% ethyl acetate in heptane). An analysis of the reaction mixture after 3 h at reflux, by the above methods, failed to detect any remaining 5-nitroindole. The reaction mixture was then cooled to 10±5° C. and diluted with water (160 mL) which resulted in the formation of a yellow precipitate. After the mixture was stirred at room temperature for 2 h, the solid was collected by filtration, then was washed with water (100 mL) and dried under high vacuum at 60-65° C. for 24 h to give 1-methyl-4-nitroindole (21.1 g, 97.1%) as a yellow solid.