Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:5]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@H:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:5]1
Reactant: CCOC(=O)CC[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a stirred solution of tert-butyl (2R,4S)-4-azido-2-(3-ethoxy-3-oxopropyl)pyrrolidine-1-carboxylate (562 mg, 1.20 mmol, step 4 of Example 8) in ethanol (10 mL) was added 10 wt. % palladium on carbon (50 mg). The resulting mixture was stirred under hydrogen (4 atom) at room temperature for 3 h. The mixture was filtered through a pad of Celite and the filter cake was washed with ethanol. The combined filtrate was concentrated to give 352 mg (97%) of the title compound as a colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].[ClH:34].C1(OC)C=CC=CC=1.CCOC(C)=O>>[NH2:1][C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].[ClH:34]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)N

Procedure:
Boc-DAla-Phe-Met-OCH3 (9.4 g) was treated with HCl/anisole/EtOAc as described in Step B to give H-DAla-Phe-Met-OCH3.HCl which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:12]=2[N:13]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[N:13]=1
Reactant: COc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(2,4-dichlorophenyl)-5-methoxybenzoxazole (0.5 g, 1.7 mmol) was dissolved in 25 mL dichloromethane. To the solution was added boron tribromide (8 mmol) and the mixture was allowed to stir at room temperature for 48 hours. The mixture was then diluted with 25 mL dichloromethane and washed sequentially with saturated sodium bicarbonate (2×25 mL), followed by brine. The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed under reduced pressure, to provide 2-(2,4-dichlorophenyl)benzoxazol-5-ol, which was purified using flash chromatography.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:13]=[CH:14][C:10]([CH3:9])=[N:11]2)=[CH:3][CH:4]=1
Reactant: Cc1cc[nH]n1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccn(-c2ccc(I)cc2)n1
Temperature: 130 °C
Yield: 28.5 %

Procedure:
A mixture of 1,4-diiodobenzene (4.00 g, 12.1 mmol), 3-methylpyrazole (0.972 g, 12.1 mmol), 8-hydroxyquinoline (0.176 g, 1.21 mmol) and K2CO3 (1.69 g, 12.2 mmol) in DMSO (12 mL) was degassed before being charged with CuI (0.230 g, 1.21 mmol). The mixture in a sealed tube was heated at 130° C. overnight. Water and EtOAc were added. The mixture was filtered. The organic layer was separated, then purified by silica gel column chromatography with hexane followed by 4-6% EtOAc in hexane to give 1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g).
Reaction SMILES: C(NCC=C)C=C.[CH2:8]([N:11](CC=C)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH:9]=[CH2:10]>>[CH2:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:14][CH:13]=1)[CH:9]=[CH2:10]
Reactant: C=CCN(CC=C)c1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1
Agent: C=CCNCC=C
Product: C=CCNc1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
This compound was prepared from the N-2-propenyl-2-propen-1-amine using the coupling protocol outlined in example 258, step 2. The other major product was tert-butyl 1-[4-(diallylamino)phenyl]cyclopropanecarboxylate.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[NH:7][C:6](=O)[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:7]=1
Reactant: O=c1cc(C2CC2)nc(-c2ccccc2C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Temperature: 0 °C
Yield: 76 %

Procedure:
6-Cyclopropyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (12.0 g, 42.8 mmol) in phosphorous oxychloride (40 mL, 428 mmol) was heated at 75-80° C. for 1 hour. The solvent was removed by evaporation and azeotroping three times with toluene. The residue was cooled to 0° C., taken up in ethyl acetate, treated with ice chips and water. The mixture was then washed sequentially with sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, 5:95 ethyl acetate:hexanes (5:95)] provided the title compound (9.71 g, 76% yield) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.12 (m, 2H), 1.30 (m, 2H). 2.02 (m, 1H), 7.24 (s, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.79 (m, 2H) ppm; MS (FIA) 299.1/300.9 (M+H); Rt (Method A) 3.882 minutes.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([N:9]([CH2:21][C:22]2[N:23]=[CH:24][S:25][CH:26]=2)[C:10](=[O:20])[C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:12])[CH:6]=[CH:7][CH:8]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].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]>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH2:21][C:22]3[N:23]=[CH:24][S:25][CH:26]=3)[C:10](=[O:20])[C@H:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH2:12])[CH:4]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N(Cc1cscn1)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C(=O)N(Cc1cscn1)c1cccc(-c2ccc(F)cc2)c1
Temperature: 135 °C
Yield: 9.5 %

Procedure:
Bromide 44.A (200 mg, 0.44 mmol), 4-fluorophenylboronic acid (68 mg, 0.49 mmol), and Pd(dppf)Cl2 were mixed in THF and Na2CO3 (2 M). The resulting mixture was heated in a sealed tube in a microwave at 135° C. for 10 minutes. The organic layer was concentrated and the residue was partially purified on a silica gel column (12 g, 0-10% MeOH:DCM). The fractions containing desired product were combined, concentrated, and purified again on a prepHPLC (C18, ACN:H2O:0.1% TFA, gradient). The desired fractions were combined and concentrated on a rotavap to remove ACN and then partitioned with NaHCO3 (sat)/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 44 (18 mg). LC-MS (+esi, M+H+=432.1). 1H NMR (500 MHz, DICHLOROMETHANE-d2) δ ppm 9.63 (br. s., 1H) 8.71 (d, J=1.96 Hz, 1H) 7.86 (t, J=1.96 Hz, 1H) 7.54-7.64 (m, 3H) 7.40 (t, J=7.82 Hz, 1H) 7.28-7.33 (m, 3H) 7.24-7.28 (m, 1H) 7.22 (d, J=6.85 Hz, 2H) 7.12-7.18 (m, 2H) 7.04 (d, J=1.71 Hz, 1H) 3.84-3.94 (m, 2H) 3.54 (dd, J=9.41, 4.28 Hz, 1H) 3.27 (dd, J=13.94, 4.16 Hz, 1H) 2.85 (dd, J=14.06, 9.41 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][CH2:38][CH:37]1[CH2:46][NH2:47]>CN(C=O)C>[O:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][CH2:38][CH:37]1[CH2:46][NH:47][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OCC(CNCCCc1c[nH]c3ccccc13)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
3-Indolepropionic acid (1.1 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF, and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as an oily solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)c(C)c1
Reaction time: 1.33 h
Yield: 90.4 %

Procedure:
4-Methoxy-2-methylaniline (26.06 g, 190 mmol) and triethylamine (43 ml, 309 mmol) were dissolved in dichloromethane, acetic anhydride (25 ml, 265 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 80 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was filtered, washed with hexane, and dried under reduced pressure to give the title compound (30.78 g, yield 90%) as a pale-pink solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](OC(=O)C(C)=O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([Cl:23])[C:15]=2[F:24])[CH:10]([CH3:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([Cl:23])[C:15]=2[F:24])[C@H:10]([CH3:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)OC1(c2c(F)c(Cl)cc3ccoc23)CCN(Cc2ccccc2)CC1C
Agent: CCCC[SnH](CCCC)CCCC
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1c(F)c(Cl)cc2ccoc12
Yield: 46.8 %

Procedure:
Beginning with 1.07 gm (2.33 mMol) 1-benzyl-3-methyl-4-(methyl oxoacetoxy)-4-(5-chloro-6-fluorobenzofur-7-yl)piperidine, this material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to provide 0.39 gm of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[Br-].[Mg+2].[Br-]>C(Cl)Cl.CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([CH2:9][C:17]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC1(CC(=O)OC)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Temperature: -78 °C
Yield: 102.4 %

Procedure:
To a solution of 1-ethyl-4-hydroxyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (1 g, 3.6 mmol) in 60 mL of dry methylene chloride at -78° C. under nitrogen was added TiCl4 in one portion and then after ~10 minutes, a solution of banzyl magnesium bromide in ether was added in one portion and the reaction mixture was allowed to stir at -78° C. for ~30 minutes. The reacton was quenched with methanol (3 mL) at -78° C. and then poured into water (10 mL). The two layers were separated and the aqueous layer was then extracted with methylene chloride (2×100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was passed through a pad of silica gel, eluting with 10% EtOAc in hexane to give 0.67 g (51.5%) of the product as an oil, which had isomer ratio of 75:25 by HPLC.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH2:12][C:13](O)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[SH:11][CH2:12][C:13]([O:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: O=C(O)CS
Reactant: OCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OCCCc1ccccc1

Procedure:
Into a 100 ml flask equipped with reflux condenser, thermometer, hot plate (including magnetic stirring apparatus within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4 grams of mercaptoacetic acid; and 0.1 grams para-toluene sulphonic acid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([CH:26]=[CH:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2>ClCCl>[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([C:26](=[O:9])[CH2:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1C[C@H]2CCCC[C@]23c2cccn2CCN13
Solvent: ClCCl
Product: O=C1CC=C2N1CCN1C(=O)C[C@H]3CCCC[C@]231
Reaction time: 4 h

Procedure:
A solution of 3.04 g (15 mmol) of m-chloroperbenzoic acid in 30 ml of dichloromethane is added dropwise over a period of 45 minutes at -15°, with stirring, to a solution of 2.3 g (10 mmol) of (+)-(9bR*,13aR*)-2oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole in 30 ml of dichloromethane. The reaction mixture is then stirred for 4 hours at -15°, then diluted with 100 ml of dichloromethane and washed in succession, while ice-cold, with sodium hydrogen sulfite solution (5%) and sodium hydrogen carbonate solution (5%). The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation in vacuo. The (+)-(9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyra zino[2,1-i]indole is obtained in the form of a foam, which can be further reacted without being further purified.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17](=[N:23]O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[O:9][N:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)=[CH:2]1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccsc2)n1
Yield: 38.1 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(thiophen-3-yl)acetic acid (0.568 g; 3.78 mmol), oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF; (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol); N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.343 g (38%) of ethyl 5-(thiophen-3-ylmethyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21]Br)=[O:4].[CH3:23][O:24][C:25](=[O:38])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:27]([CH2:26][C:25]([O:24][CH3:23])=[O:38])[S:28]([C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-6-oxo-1-phenethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (320 mg, 0.746 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (200 mg, 0.821 mmol), sodium iodide (212 mg, 1.49 mmol) and potassium carbonate (206 mg, 1.49 mmol) in DMF (7 mL) was stirred at r.t. for 16 h. Brine (50 mL) was added and the mixture was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes) to give 371 mg of the title compound. MS: (+) m/z 591.13, 593.08 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14])[C:5]([O:7]C)=O.[OH-].[Li+].CN.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[NH:37][CH3:36])[CH:9]=[CH:10][C:11]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14]
Reactant: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C#N)cc2OCC3)c(Cl)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C#N)cc2OCC3)c(Cl)c1

Procedure:
Following Example 91, methyl 3-chloro-4-(8-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoate was saponified with lithium hydroxide in THF and water, then the carboxylic acid was coupled with methylamine, HBTU, DIEA in dichloromethane to give 180. MS: (ESI+) 452.1
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28]Br)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[C:30]([NH:34][CH2:35][CH3:36])([CH3:33])([CH3:32])[CH3:31]>>[C:1]([C:4]1[C:5]([CH2:28][N:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:35][CH3:36])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: CCNC(C)(C)C
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Product: CCN(Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(C)=O)C(C)(C)C

Procedure:
According to the same manner as that described in Example 1, 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline was reacted with N-tert-butyl-N-ethylamine to give 3-acetyl-2-(N-tert-butyl-N-ethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline. This compound was recrystallized from methanol to give colorless prisms. mp. 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][OH:28])[O:24][C:23]4=[O:29])=[CH:17][C:16]=3[F:30])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:31])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:16]([F:30])=[CH:17][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][O:28][S:40]([CH3:39])(=[O:42])=[O:41])[O:24][C:23]4=[O:29])=[CH:19][C:20]=3[F:21])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](CO)OC4=O)cc3F)CC2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)CC2)O1
Reaction time: 2 h
Yield: 93 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (2.19 g, 5 mM) was dissolved in dry dichloromethane (40 ml) under nitrogen at 0°, and treated with triethylamine (0.81 g, 8 mM). Methanesulfonyl chloride (0.687 g, 6 mM) was added, and stirring continued for 2 hours, allowing the temperature to rise to ambient. Aqueous sodium bicarbonate (5%, 20 ml) was added, and stirring continued for 10 minutes. The organic phase was separated, dried (magnesium sulfate), filtered, and evaporated to dryness. The resulting gum was triturated with diethyl ether (50 ml) and solid filtered to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12](=[CH2:13])[C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: C=C(C(=O)OC)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4-dichlorobenzaldehyde (17.5 g) and methyl acrylate (8.6 mL) in acetonitrile (100 ml) was added 1,4-diazabicyclo[2.2.2]octane (3.36 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (18.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (36 mg, 41%).