Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)[C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[CH3:22])=O)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:11][NH:13][C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=3[CH3:20])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Nc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: COc1cc(CNc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a solution of 3-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-5-methoxy-benzamide (1.2 g, 3.3 mmol, 1.0 eq) in THF (50 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 16.0 mL, 16.0 mmol, 5.0 eq) dropwise. The reaction mixture was heated at 60° C. overnight then cooled to room temperature and quenched with water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 5:1) to give the title compound as a colorless oil (700 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12]>C(OCC)C>[CH2:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[Mg]Br
Reactant: C=Cc1cccc(Br)c1
Solvent: CCOCC
Product: C=Cc1cccc(CC(C)C)c1
Temperature: 25 °C

Procedure:
In a 15-liter separable four-necked flask equipped with a stirrer and a reflux condenser were placed 3 liters of sufficiently dried diethyl ether, 915 g (5 moles) of m-bromostyrene and 31 g of bis(1,3-diphenylphosphino)propanenickel(II) chloride, and the above-mentioned diethyl ether solution of isobutylmagnesium bromide was added thereto dropwise with stirring at room temperature. After the completion of the addition, stirring was continued under the reflux of diethyl ether, until the reaction had been over. After the end of the reaction, the solution was cooled to room temperature, and was then thrown into pieces of ice in order to inactivate remaining isobutylmagnesium bromide. The resultant ether layer was separated by a separating funnel, and was washed with water until it had become a neutral state. Afterward, diethyl ether was distilled off, thereby obtaining 670 g of crude m-isobutylstyrene.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])OC(C)(C)C)[CH3:15])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1.[C:31]([O:44][C@H:45]([CH2:71][O:72][C:73](=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])[CH2:46][S:47][CH2:48][C@@H:49](C(O)=O)[NH:50][C:51](=[O:67])[O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C@H:14]([CH3:15])[NH:16][C:17](=[O:23])[C@@H:49]([NH:50][C:51]([O:52][CH2:53][CH:54]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:60]=2[C:61]2[C:66]1=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:67])[CH2:48][S:47][CH2:46][C@H:45]([O:44][C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:71][O:72][C:73](=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:8]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(CCCOC[C@H](C)NC(=O)OC(C)(C)C)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
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](C)COCCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Reaction time: 1.5 h

Procedure:
To a solution of (S)-tert-butyl 1-(3-(diethoxyphosphoryl)propoxy)propan-2-ylcarbamate (1.3 eq, from the previous step) in DCM (0.22 M) at room temperature was added a solution of 4 M HCl in dioxane (20 eq). The reaction was stirred for 1.5 hours. The reaction mixture was concentrated en vaccuo to give an oil which was evaporated under high vacuum briefly. This residue was taken up in DCM (0.1M). To this solution was added (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), HBTU (1.2 eq), and DIEA (4 eq). The reaction was stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% ethyl acetate in hexanes and then 100% ethyl acetate to give the product as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21].[H-].[Na+]>C1COCC1>[C:5]1([C@H:2]2[NH:1][C:20](=[O:21])[CH2:19][O:4][CH2:3]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COC[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.3 %

Procedure:
To a mixture of (2R)-2-amino-2-phenyl-ethanol (10 g, 72.90 mmol) and triethylamine (18.45 g, 25.41 mL, 182.3 mmol) in THF (207.5 mL) at 0° C., was added 2-chloroacetyl chloride (8.234 g, 5.799 mL, 72.90 mmol) over 5 mins. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer separated, washed successively with water (2×100 mL), brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was then dissolved in THF (145.2 mL) and NaH (60% in mineral oil) (3.499 g, 87.48 mmol) was added portionwise over 5 mins at rt. On complete addition, the resulting mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and diluted with EtOAc (50 mL) and the organic layer separated, washed with sequentially with water (2×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by ISCO column companion system (330 g column, 0-10% MeOH/CH2Cl2). Product fractions were combined and concentrated in vacuo to leave the product as a pale yellow solid (5.2 g, 41% yield); 1H NMR (400.0 MHz, DMSO) d 3.55 (1H, m), 3.96 (1H, m), 4.08 (2H, s), 4.63 (1H, m), 7.29-7.40 (5H, m) and 8.46 (1H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:26](=[O:36])[CH2:25][S:24]1>FC(F)(F)C(O)=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([OH:31])=[O:30])[C:26](=[O:36])[CH2:25][S:24]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=C3SCC(=O)N3CC(=O)OC(C)(C)C)c(Cl)cc2F)c1=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=C3SCC(=O)N3CC(=O)O)c(Cl)cc2F)c1=O
Temperature: 35 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A solution of tert-butyl 2-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}imino}-4-oxo-3-thiazolidineacetate (41.93 g, 76.1 mmol) in trifluoroacetic acid is stirred at room temperature for 3 hours, stirred at 35° C. for 1 hour, and concentrated in vacuc to obtain a yellow liquid. A solution of the yellow liquid in diethyl ether is cooled and filtered to obtain a solid. The solid is washed with diethyl ether and air-dried to give the title product as a white solid (31.6 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH2:21])[CH:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:21][C:13]2[CH:12]=[N:11][C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1cnc2ccccc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A solution of 4-fluorobenzoic acid (2.57 g, 18.3 mmol), quinolin-3-ylamine (2.5 g, 17.4 mmol), O-benzotriazol-1-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (7.3 g, 19.3 mmol) and N,N-diisopropylethylamine (6.4 mL, 36.7 mmol) in acetonitrile (75 mL) was stirred at ambient temperature for ten minutes, then heated at reflux for 20 hours. The solution was cooled to 0° C., and the product crystallized. The product was collected by filtration and washed with acetonitrile, to give a colorless solid, 3.86 g (79%). MS: m/z 267 (MH+). 1H NMR(DMSO-d6): δ 7.39-7.46 (m, 2 H), 7.58-7.71 (m, 2 H), 7.97-8.01 (m, 2 H), 8.11-8.16 (m, 2 H), 8.85 (d, 1 H), 9.15 (d, 1 H) and 10.73 (s, 1 H).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[NH:12][C:11](=[O:13])[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O-].[Na+].CI>CO>[CH3:14][N:12]1[C:11](=[O:13])[O:10][N:9]=[C:8]1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(Cc2ccccc2)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: Cn1c(Cc2ccccc2)noc1=O
Temperature: 0 °C

Procedure:
35.2 g. (0.2 moles) of 3-(phenylmethyl)-1,2,4-oxadiazol-5(4H)-one obtained in Example 1 (a) are dissolved in 100 ml of methanol and 110 ml. (0.22 moles) of 2N sodium methylate solution are added. The solution is evaporated to dryness and the residue is dissolved in 200 ml. of anhydrous dimethylformamide. 35.5 g. (0.25 moles) of methyl iodide are added dropwise while cooling with ice water and stirring. The reaction mixture warms slightly and is stirred overnight at room temperature. The reaction mixture is concentrated and the residue is treated with water and acidified with 2N hydrochloric acid. The crystals are filtered under suction, triturated with sodium bicarbonate solution while still moist, again filtered under suction, and washed with water. 33.6 g. of 4-methyl-3-(phenylmethyl)-1,2,4-oxadiazol-5(4H)-one are obtained, m.p. 105°-107°. After recrystallizing twice from isopropanol the m.p. is 110°-112°.
Reaction SMILES: C([Li])CCC.C(N)(C)C.[C:10]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Cl[CH2:20][S:21][CH2:22]Cl>CCOCC>[C:10]([C:12]([CH3:18])([CH2:20][S:21][CH3:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: ClCSCCl
Reactant: CCOC(=O)C(C)C#N
Agent: [Li]CCCC
Solvent: CC(C)N
Solvent: CCOCC
Product: CCOC(=O)C(C)(C#N)CSC
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (24.2 mL, 60 mmol, 2.5 M solution in hexanes) was added to a solution of iso-propylamine (8.1 mL, 58 mmol) in dry ether (70 mL) under nitrogen at a rate needed to maintain temperature below −60° C. Upon completion, the reaction was allowed to warm to 10° C., re-cooled to −78° C. before addition of ethyl 2-cyanopropanoate (7 g, 55 mmol). After stirring at −78° C. for 90 minutes, chloromethylsulfide (4.61 mL, 55 mmol) was added and the mixture was warmed to room temperature over 14 hours, diluted with ether (350 mL), washed with water (100 mL), brine (100 mL), dried over MgSO4, concentrated under reduced pressure and distilled at 0.04 mm Hg. Yield of yellow liquid 3.95 g. (38%): bp 145° C.; IR (KBr thin film) 1751 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.30 (q, J=7.1 Hz, 2H), 3.08 (d, J=13.9 Hz, 1H), 2.91 (d, J=13.9 Hz, 1H), 2.30 (s, 3H), 1.67 (s, 3H), 1.35 (t, J=7.4 Hz, 3H); ESIMS m/z 187.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C:21]([CH3:30])([C:23]([O:25]C(C)(C)C)=[O:24])[CH3:22])=[O:19])=[C:5]2[OH:31]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C:21]([CH3:22])([C:23]([OH:25])=[O:24])[CH3:30])=[O:19])=[C:5]2[OH:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)O
Yield: 83.4 %

Procedure:
1,1-Dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)-2-methylalaninate (245 mg, 545 μmol) was dissolved in TFA at ambient temperature for 1 hour before it was concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (179 mg) as a white solid. MS (m/z)=394 (M+H)+. Calculated for C19H20ClNO6 393.10.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([S:7]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indoline (14.7 g, 124 mmol) in CH2Cl2 (200 mL) was added dropwise Et3N (19.0 g, 186 mmol) at 0° C. The mixture was stirred at room temperature overnight. The organic layer was washed with water (2×), dried over Na2SO4 and concentrated to dryness under reduced pressure to obtain 1-(phenylsulfonyl)indoline (30.9 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.N1C[CH2:17][CH2:16][CH2:15]1.O.C(Br)C=C>C1C=CC=CC=1>[CH2:17]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:13])[CH:16]=[CH2:15]
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Solvent: O
Solvent: C=CCBr
Solvent: c1ccccc1
Product: C=CCC1C(=O)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 104.1 g (0.59 mole) 3,4-dihydro-7-methoxy-2(1H)naphthalenone in 100 ml dry benzene was added dropwise under nitrogen with stirring at room temperature 62.5 g (0.88 mole) pyrrolidine. After the addition (10-15 min), the reaction mixture was refluxed for 2.5 hr with azeotropic removal of water and then cooled to room temperature. The enamine solution was added dropwise to 143.8 g (1.19 mole) allyl bromide with stirring at a rate sufficient to maintain normal refluxing to provide a heavy precipitate. Benzene (50 ml) was added to facilitate stirring and reflux continued for 4 hr; then, 700 ml of water was added and refluxing resumed. After 2 hr, the reaction mixture was cooled to room temperature and diluted with 100 ml benzene. The benzene layer was separated and the aqueous phase extracted with benzene (2×100 ml). The combined extracts were washed with water (2×100 ml) and dried (Na2SO4). After evaporation of the solvent, the residue was distilled to give 113.5 g (89%) of VIIIa, b.p. 114°-118°/0.1-0.05 mm Hg. NMR: δ 2.40-3.10 (m, 6, allylic and alicyclic), 3.45 (t, 1, C1 --H, J=6.5), 3.75 (s, 3, OCH3), 4.8-6.1 (m, 3, olefinic), 6.7-7.2 (m, 3, ArH). IR: (neat) 1715 cm-1.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:19]=1[C:26]#[N:27])[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:31]I.[Cl-].[NH4+]>O1CCCC1>[CH3:4][C:2]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH2:9][CH2:10][C@@H:11]([O:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:19]=1[C:26]#[N:27])[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[CH3:31])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccoc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(CCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccoc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
The product of Example 41 step (c) (0.68 g) was dissolved in dry tetrahydrofuran (40 ml) and treated with sodium hydride (60% dispersion in oil, 0.3 g) and stirred under nitrogen for 0.5 h. Methyl iodide (3 ml) was added and the reaction mixture stirred at ambient temperature for 48 h. The mixture was then cooled in an ice-bath and carefully treated with saturated ammonium chloride (50 ml) and extracted into ethyl acetate. The organic extract was washed with water, brine, dried over magnesium sulphate and evaporated to give a yellow oil (0.7 g).
Reaction SMILES: [O:1]1[CH2:5][CH:4]([CH2:6]O)[O:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][C:82]([C:95]2[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=2)([C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[S:63])=[C:56](C(=O)C)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCOCC1.[F:107][C:108]([F:120])([F:119])[S:109]([O:112][CH2:113][CH:114]1[CH2:118][O:117][CH2:116][O:115]1)(=[O:111])=[O:110]>C(N(CC)CC)C.N1C=CC=CC=1>[F:120][C:108]([F:107])([F:119])[S:109]([O:112][CH2:113][CH:114]1[CH2:118][O:117][CH2:116][O:115]1)(=[O:111])=[O:110].[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][C:82]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:95]2[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=2)[C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)=[S:63])=[C:56]([CH2:6][CH:4]4[CH2:5][O:1][CH2:2][O:3]4)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCC1COCO1
Reactant: CC(=O)C1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=S(=O)(OCC1COCO1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3COCO3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 100 %

Procedure:
1,3-Dioxolan-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27(a) from 1,3-dioxolan-4-yl-methanol (200 mg), pyridine (0.17 ml) and trifluoromethanesulfonic acid anhydride (596 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (700 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27(b), followed by reacting the resulting reaction product with the 1,3-dioxolan-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27(b). The reaction solution so obtained was post-treated in the same manner as in Example 27(b) and the produced compound was recovered and purified similarly to Example 27(b) to afford the titled compound (728 mg; 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([Cl:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:15]2
Reactant: C#CCN1CCN(C)CC1
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Cl)cc2)C3=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.061 mL, 0.4 mmol), 5-bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.11 g, 0.3 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropylamine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.090 g, 70%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.31 (s, 3H), 2.32-2.74 (m, 8H), 3.54 (s, 2H), 4.18 (s, 2H), 4.74 (s, 2H), 7.22-7.36 (m, 5H), 7.44 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[CH2:21]([O:23][C:24]1[C:25]([C:36](=O)[CH3:37])=[CH:26][C:27]2[CH:28]=[CH:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)[CH3:22]>C1COCC1>[CH2:21]([O:23][C:24]1[C:25](/[C:36](/[CH3:37])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:26][C:27]2[CH:28]=[CH:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)[CH3:22]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1C(C)=O)C=CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of triethyl 2-fluoro-2-phosphonoacetate (0.61 g, 2.50 mmol) in THF (5 mL) at −78° C. was added n-butyllithium (1.6 M in hexane, 1.6 mL, 2.5 mmol). After 10 min, a solution of 1-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-25, 122 mg, 0.50 mmol) in THF (2 mL) was added and the reaction was stirred for 6 b while warming gradually to room temperature. The reaction was then quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[C:3]([C:10]([OH:12])=[O:11])[CH:2]=1.C(N(C(C)C)CC)(C)C.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:43][NH:44][CH2:45][CH2:46][CH3:47].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[CH3:43][N:44]([CH2:45][CH2:46][CH3:47])[C:7]([C:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH:4]=1)[C:10]([OH:12])=[O:11])=[O:9]
Reactant: O=C(O)c1cncc(C(=O)O)c1
Reactant: CCCNC
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cncc(C(=O)O)c1
Reaction time: 0.17 h
Yield: 37.5 %

Procedure:
Add a solution of pyridine-3,5-dicarboxylic acid (220 mg, 1.32 mmol), diisopropylethylamine (918 μL, 5.28 mmol), and DMF (1.5 mL) in dichloromethane (10 mL) to 2-chlorotritylchloride resin (11.0 g, 1.1 mmol) in a peptide synthesis vessel and mix for 3 h. Filter and wash the resin with a 17:2:1 mixture of dichloromethane:methanol:diisopropylethylamine, followed by dichloromethane. Add a solution of methylpropylamine (225 μL, 2.2 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.14 g, 2.2 mmol) in dichloromethane (10 mL) to the resin and mix for 1 h. Filter and wash the resin with dichloromethane (2×10 mL). Add a solution of 5% trifluoroacetic acid in dichloromethane (10 mL) to the resin and let stand for 10 min. Filter the resin and wash with dichloromethane (2×10 mL). Combine the filtrates and concentrate to give the title compound (110 mg, 50%).