Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:5]2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1NCc2cc(Br)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
Under nitrogen atmosphere, 70 mg of 5-bromo-1-oxo-isoindoline was dissolved in 2 ml of tetrahydrofuran, cooled down to 0° C., and then 4 mg of N,N-dimethylaminopyridine and 144 mg of di-tert-butylcarbonate were added. The mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 51.2 mg of the above compound as a white solid.
Reaction SMILES: C([C@H]1COC(=O)N1C(=O)[CH2:15][C@@H:16]([C:22]1[CH:48]=[CH:47][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:50]O.[Li+].[OH-].Cl.C1[CH2:59][O:58]CC1>O>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[CH2:27][O:26][C:25]2[CH:47]=[CH:48][C:22]([C@@H:16]([C:17]3[CH:21]=[CH:20][O:19][N:18]=3)[CH2:15][C:59]([OH:58])=[O:50])=[CH:23][CH:24]=2)[CH2:39][CH2:38]1)=[O:41])([CH3:44])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)c2)CC1
Reactant: C1CCOC1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(COc3ccc([C@H](CC(=O)O)c4ccon4)cc3)c2)CC1
Reaction time: 2 h

Procedure:
To a solution of the oxazolidinone (34.4) (8.9 mg, 0.013 mmol) dissolved in THF (0.5 mL), was added a 30% hydrogen peroxide solution (15.0 μL, 0.130 mmol) followed by a 2 M LiOH solution (33.0 μL, 0.065 mmol). The resulting slurry was stirred for two hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH 3. The mixture was then extracted with EtOAc (3×10 mL), and the organic layer was washed with an acidic sodium sulfite solution (1×5 mL) and brine (1×5 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 34 (2.60 mg). MS ESI (pos.): m/e 505.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.33 (1 H, d, J=1.6 Hz), 7.40 (1 H, s), 7.20-7.34 (3 H, m), 7.13 (2 H, d), 6.86 (2 H, d, J=9.0 Hz), 6.16 (1 H, d, J=1.6 Hz), 6.03 (1 H, br. s.), 4.99 (2 H, s), 4.44 (1 H, t, J=7.8 Hz), 3.90-3.98 (2 H, m, J=2.7 Hz), 3.50 (2H, t, J=5.7 Hz), 3.09 (1 H, dd, J=16.4, 8.2 Hz), 2.84 (1 H, dd, J=16.4, 7.4 Hz), 2.37-2.45 (2 H, m, J=2.0 Hz), 1.37 (9 H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([NH2:21])=[CH:19][C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:20]([NH:21][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([Cl:36])[CH:38]=3)=[CH:19][C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][N:16]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a solution of 0.300 g (0.780 mmol) of (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester in methylene chloride (3 mL) under argon, cooled to 0° C., is added 0.136 mL (0.780 mmol) of N,N-diisopropylethylamine followed by 0.110 mL (0.858 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at 0° C. for 15 min then warmed to room temperature and stirred for 2 days during which time the solvent evaporates. The residue is dissolved in methylene chloride (3 mL) and an additional 0.136 mL (0.780 mmol) of N,N-diisopropylethylamine and 0.110 mL (0.858 mmol) of 3-chlorobenzoyl chloride is added. The reaction is stirred overnight at room temperature. The mixture is diluted with ethyl acetate and washed with water followed by aqueous ammonium chloride and then aqueous sodium carbonate. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography to give 0.186 g (46.0%) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl]-carbamic acid tert-butyl ester as a beige foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:40][CH:39]=1.[I-].[K+]>CN(C=O)C>[F:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[CH2:49][CH2:48][N:47]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:46][CH2:45]2)=[CH:42][CH:43]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (5.8 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.3 g), diisopropylethyl amine (4.9 ml), 1-(4-fluorophenyl)piperazine (4.1 g) and potassium iodide (0.3 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 13.5 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, brine, and then dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 4.0 g of 6,7-dihydro-5-[3-(4-(4-fluorophenyl)-1-piperazinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The product was flushed thru alumina with ether. The hydrochloride was prepared in ether with ethereal HCl. The precipitate was filtered and washed with pentane, m.p. 161°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[C:44]#[N:45]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:26]([NH:40][C:41]3[CH:48]=[CH:47][CH:46]=[C:43]([C:44]#[N:45])[CH:42]=3)=[O:32])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(F)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)Nc3cccc(C#N)c3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 290.9 %

Procedure:
To a stirred solution of (+)-(R)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, example 1 h) in dichloromethane (2 ml) was added triphosgene (22 mg). A solution of sodium carbonate (43 mg) in water (2 ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all the starting material had reacted. 3-Aminobenzonitrile (48 mg, CAS 2237-30-1) was then added and the reaction mixture was stirred at room temperature for a further 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: 0% to 80% EtOAc in hexanes) to give (R)-2-{4-[3-(3-cyano-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (95 mg, quant.) as a white solid. MS (ISP): 439.2 ([M−H]−).
Reaction SMILES: [CH3:1][I:2].[O:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][S:12][N:13]=2)[CH2:5][CH2:4]1>CC(C)=O>[I-:2].[O:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:10]([C:14]3[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=3)=[N:11][S:12][N:13]=2)[CH2:7][CH2:8]1
Reactant: c1cncc(-c2nsnc2N2CCOCC2)c1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nsnc2N2CCOCC2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 8 mmol) and 3-(4-morpholino-1, 2,5-thiadiazol-3-yl)pyridine (680 mg, 2.7 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 1.0 g (94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:3]1OC.C[Si]([C:24]#[N:25])(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:24]([CH:3]1[C:2]([CH3:19])([CH3:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:25]
Reactant: C[Si](C)(C)C#N
Reactant: COC1N(C(=O)OCc2ccccc2)CCC1(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-(methyloxy)-1-pyrrolidinecarboxylate (0.0426 mol, 11.2 g) in 200 ml methylene chloride under argon. After the solution was cooled to −78° C., trimethylsilyl cyanide (0.0640 mol, 6.32 g) was added followed by boron triflouride etherate (0.0640 mol, 9.09 g). After 1 hr of stirring, the reaction was quenched with saturated aqueous sodium bicarbonate and allowed to warm to 20° C. After 2 hr of vigorous stirring, the aqueous phase was separated and extracted with methylene chloride (2×100 ml). All organics were combined, dried over MgSO4, filtered and concentrated yielding 10.8 g (98%) of phenylmethyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=259 m/z (MH+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.44-7.35 (m, 5H), 5.21 and 5.20 (s, 2H), 4.26 and 4.17 (s, 1H), 3.64-3.51 (m, 2H), 2.01-1.95 (m, 1H), 1.80-1.74 (m, 1H), 1.36 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])=[C:13]([CH2:16][S:17][CH3:18])[CH2:14][S:15][C@H:10]12)=O>CO.CCOCC>[ClH:3].[NH2:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:19]([O:21][CH2:22][C:23]([Cl:25])([Cl:24])[Cl:26])=[O:20])=[C:13]([CH2:16][S:17][CH3:18])[CH2:14][S:15][C@H:10]12
Reactant: CSCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: CSCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Product: Cl
Reaction time: 0.02 h

Procedure:
Phosphorus oxychloride (0.5 ml. 5.47 mmole) was added dropwise over 3 min. to a stirred suspension of 2,2,2-trichloroethyl 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylate (1.05 g., 2.5 mmole) in dry methanol (10 ml.). During the addition the starting material went into solution and the temperature of the mixture reached a maximum of ca.45°. After 1 min. a white solid came out of solution and the mixture rapidly set solid. The mixture was diluted with ether (10 ml.), stirred briefly and the product collected, washed with ether (ca. 25 ml.) and dried to furnish the title hydrochloride as a feathery white solid (941 mg., 88%), m.p. 169° to 172° (dec.) [α]D + 5.25°, λmax. (MeOH) 272.5 nm. (ε 6,640), νmax. ca. 2600 (N+H3), 1775 (azetidin-2-one) and 1720 cm-1 (CO2CH2CCl3), τ 4.69 (1H,d, J 5 Hz; C7 -H), 4.88 and 5.01 (2H,AB-q, J 12 Hz; CH2CCl3), 4.90 (1H,d, J 5 Hz; C6 -H), 6.14 and 6.39 (2H,AB-q,J17 Hz C2 -CH2), 6.23 (2H,s; CH2SCH3) and 7.97 (3H,s; SCH3) (Found: C, 31.2; H, 3.3; Cl, 33.0; N, 6.6; S, 15.0. C11H 14 Cl4N2O3S2 (428.2) requires C, 30.85, H, 3.3; Cl, 33.1; N, 6.55; S, 15.0%). Electrophoresis showed a single spot, RX 1.56 (X=cephalexin) which migrated towards the cathode and which gave a mauve colour upon spraying with 0.5% (W/V) ninhydrin in ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([NH2:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[CH3:20][C:21](N(C)C)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:14]=[C:20]([CH3:21])[N:8]2[CH2:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: CC(C)(C)CNc1nc(Cl)ncc1N
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cnc(Cl)nc2n1CC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4.2 g of 2-chloro-N4-(2,2-dimethyl-propyl)-pyrimidine-4,5-diamine in 40 ml of DMA was added 1.6 ml of POCl3. The solution was stirred at 100° C. for 2 hours, cooled and extracted with ethyl acetate and saturated NaHCO3 solution. The organic phases were dried over sodium sulfate and evaporated to dryness yielding 2-chloro-9-(2,2-dimethyl-propyl)-8-methyl-9H-purine as a brown oil.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]=2[CH:27]1[C:38]([OH:40])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:41][C:42]1[CH:43]=[C:44]([CH:46]=[C:47]([F:53])[C:48]=1[Si:49]([CH3:52])([CH3:51])[CH3:50])[NH2:45].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:53][C:47]1[CH:46]=[C:44]([NH:45][C:38]([CH:27]2[N:26]([C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]2=3)=[O:40])[CH:43]=[C:42]([F:41])[C:48]=1[Si:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: C[Si](C)(C)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
T3P (3.84 mL, 6.45 mmol) was added to a solution of 6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylic acid (1.326 g, 4.3 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.866 g, 4.30 mmol), DIEA (3.74 mL, 21.50 mmol) and DMAP (0.578 g, 4.73 mmol) in ethyl acetate (31 mL) at room temperature, and the mixture was stirred at 65° C. for 15 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was washed with cooled hexane to give tert-butyl 5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.69 g, 3.44 mmol, 80%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.O>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[CH:3][C:2]=1[C:29]1[CH:30]=[CH:31][S:27][CH:28]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1-c1ccsc1
Reaction time: 12 h
Yield: 49.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-bromo-4-methoxy-benzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added thiophene-3-boronic acid (0.09 g, 0.67 mmol) and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction was then poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, methylene chloride then 30-40% ethyl acetate/hexanes) afforded 0.1 g (50%) of 3-(4-methoxy-3-thiophen-3-ylbenzylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:25](=[O:26])[N:24]([CH:27]([CH3:29])[CH3:28])[C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=2[N:21]([CH:34]([CH3:36])[CH3:35])[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:25](=[O:26])[N:24]([CH:27]([CH3:29])[CH3:28])[C:23]3[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=3[N:21]([CH:34]([CH3:36])[CH3:35])[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)N1C(=O)C(N)C(=O)N(C(C)C)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC(C)N1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(C(C)C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-α-hydro-1H-1,5-benzodiazepine (Example 8-P), the title compound was prepared as a white solid (melting point=232-233° C.). Purification was by flash chromatography eluting with EtOAc/hexanes (4:1 gradient to 6:1). Rf=0.31 (4:1 EtOAc/hexanes).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:6][CH:7]=2)=[N:29][CH:30]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromo-5-fluoropyridine in Step 4. LC-MS Method 2 tR=1.197, m/z=435.1; 1H NMR (CDCl3) 1.21-1.37 (m, 2H), 1.48 (d, 3H), 1.81-1.95 (m, 2H), 2.18 (m, 1H), 2.20-2.31 (m, 2H), 2.85 (m, 1H), 3.52 (t, 2H), 5.65 (m, 1H), 6.95 (d, 2H), 7.22 (m, 3H), 7.28 (m, 2H), 7.40 (m, 1H), 7.58 (m, 3H), 8.42 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]2[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 275.3 %

Procedure:
To a solution (100 ml) of ethyl 4-benzyloxy-1H-indole-2-carboxylate (12.0 g) in DMF was added sodium hydride (1.6 g) and the mixture was stirred at room temperature for 10 min. To this reaction mixture was added methyl iodide (2.2 g) and the mixture was stirred for one more hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13.2 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[CH2:20]([I:23])[CH:21]=[CH2:22]>CN(C=O)C>[I-:23].[CH2:20]([N+:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1)[CH:21]=[CH2:22]
Reactant: CN1CCN(c2nc3ccc([N+](=O)[O-])cc3o2)CC1
Reactant: C=CCI
Solvent: CN(C)C=O
Product: C=CC[N+]1(C)CCN(c2nc3ccc([N+](=O)[O-])cc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
Under cooling with ice, 50 mg of 2-(4-methyl-1-piperazinyl)-6-nitrobenzoxazole dissolved in 5 ml of DMF was mixed with 0.021 ml of allyl iodide, and the reaction was carried out for 1 hour at the same temperature and then for 19 hours at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by Sephadex LH-20 (Pharmacia) (chloroform:methanol=1:1) to obtain 67 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:9][C:8]1[CH:7]=[CH:6][C:5](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1ccc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1O
Yield: 53.8 %

Procedure:
A mixture of 1-[2-[3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoylamino]ethyl]-4-(3-indolyl)piperidine (2 g) and p-toluenesulfonic acid monohydrate (1.05 g) in methanol (40 ml) was refluxed for 30 minutes under an inert atmosphere. After the solvent was removed under reduced pressure, the residue was treated with water (100 ml), adjusted to pH 10.0 with a sodium carbonate solution and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel (31 g) and eluted with a mixture of chloroform and methanol (8:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 1-[2-{3-(4-hydroxy-3-methoxyphenyl)-(E)-propenoylamino}ethyl]-4-(3-indolyl)piperidine (0.89 g).