Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:10]=[CH:11][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(O)(=O)=O.[K+]>ClCCl>[Si:1]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])[CH:10]=[CH:11][CH:12]=[C:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si:23]([CH3:24])([CH3:25])[CH3:26])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(C(O)C=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(=CC=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Yield: 66 %

Procedure:
To a solution of 1.00 g of 5-[4,7-bis(t-butyldimethylsilyloxy)-1-hydroxy-2-heptenyl]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 559 dissolved in 10 ml of dichloromethane was added under ice-cooling and stirring 497 mg of dimethylaminopyridene, and then 147 μl of methanesulfonyl chloride was added dropwise. The temperature of the mixture was gradually elevated to room temperature, and then stirred for 6 hours. Saturated aqueous potassium hydrogensulfate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate and with saturated aqueous sodium chloride in the order mentioned, and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel chromatography to give 644 mg (yield 66%) of low polarity isomer and 255 mg (yield 26%) of high polarity isomer of 5-[4,7-bis(t-butyldimethylsilyloxy)-2-heptenylidene]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([OH:16])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 65 °C

Procedure:
The above ester (1.0 g, 3.8 mmol) was dissolved in 2N NaOH (20 mL) and heated to 65° C. for 2 h. The resulting clear mixture was cooled to ambient temperature and the solids were filtered off. The filtrate was then acidified with 1N HCl to pH=1 and the resulting yellow precipitate was collected as the desired product (0.73 g, 82%). 1H NMR (DMSO-d6) δ 13.52 (br s, 1 H), 8.86 (s, 1 H), 8.51 (s, 1 H), 7.99-7.96 (m, 2 H), 7.55-7.51 (m, 2 H); MS (ESI+) m/z 234 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=1.[CH:19]1([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)[CH:13]=1
Reactant: Fc1cc(Br)ccn1
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N#CC1(c2cc(Br)ccn2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
LiHMDS (1M in toluene, 17.7 mL, 17.7 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) solution of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol) and cyclobutanecarbonitrile (1.39 g, 17.1 mmol, 3 eq) in toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 5 h, quenched by addition of a saturated solution of NaHCO3 (50 mL) and filtered through a pad of celite. The filtrate is extracted with EtOAc (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5) to afford 933 mg of the title compound as a yellow oil: ESI-MS: 237.0/239.0 [M+H]+; tR=4.27 min (System 1); TLC: Rf=0.30 (Hex/EtOAc, 9:1).
Reaction SMILES: [CH3:1][C:2]([CH:4](O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH3:3][C:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:1]
Reactant: C=C(C)C(O)Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C#Cc1ccccc1

Procedure:
A solution of 100 mmol of 2-methyl-4-phenylbut-1-en-3-ol (16.02 g) in 90 mL of tetrahydrofuran and 210 mL of carbon tetrachloride was mixed with 300 mmol (78.70 g) of dry triphenylphosphine. The solution was heated to boiling under reflux for 2 hours, whereupon a precipitate formed. After cooling, 400 mL of pentane was added and the precipitate was separated by filtration. The solvent was removed from the filtrate under reduced pressure and the residue was fractionally distilled to give 2-methyl-4-phenylbut-1-en-3-yne havng the formula: ##STR27##
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[O:13]1[C:21]2[CH:20]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1>>[CH:10]1([CH2:9][O:8][C:5]2[CH:4]=[N:3][C:2]([C:14]3[O:13][C:21]4[CH:20]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])[N:18]=[CH:17][C:16]=4[N:15]=3)=[N:7][CH:6]=2)[CH2:12][CH2:11]1
Reactant: Clc1ncc(OCC2CC2)cn1
Reactant: C[C@@H](COc1cc2ocnc2cn1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1cc2oc(-c3ncc(OCC4CC4)cn3)nc2cn1)NC(=O)OC(C)(C)C

Procedure:
Using 2-chloro-5-(cyclopropylmethoxy)pyrimidine and tert-butyl ((2S)-1-([1,3]oxazolo[4,5-c]pyridin-6-yloxy)propan-2-yl)carbamate, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[Na].C([O-])(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc(Nc2ccc(Br)cn2)cc1
Temperature: 0 °C

Procedure:
5 g (21.1 mmol) of 2,5-dibromopyridine, 4.4 ml of 4-fluoroaniline, 4.10 g (42.3 mmol) of sodium-tert-butanolate, 200 mg (0.8 mmol) of palladium(II)acetate and 200 mg (0.3 mmol) of R-(+)-BINAP were dissolved in 60 ml of dioxane and stirred at reflux temperature for 1 h. The mixture was poured into ice-water and extracted with ethyl acetate. The organic phases were dried and evaporated, and the residue was purified by column chromatography (silica gel, n-heptane/ethyl acetate 5:2). Yield: 2.10 g.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 92.6 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5 (10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (79.0 mg, 92%).
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[NH:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19]>O>[OH:19][CH2:18][CH2:17][N:16]([C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1)[CH2:20][CH2:21][OH:22]
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Reactant: OCCNCCO
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)cc1N(CCO)CCO
Temperature: 140 °C

Procedure:
3-Methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) was treated with diethanolamine (10 mL), and the mixture was heated to 140° C. for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was recrystalized from ethanol to give the title compound (53 mg); mp 204°-205° C.; NMR: 5.90 (s,1); MS: m/z=277(+1). Analysis for C14H16NO4 : Calculated: C, 60.80; H, 5.84; N, 10.14; Found: C, 61.29; H, 5.29; N, 11.74.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 37897.4 %

Procedure:
3-Methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c (53 mg, 0.174 mmol) and 5-chloro-1,3-dihydro-indol-2-one (29 g, 0.84 mmol) was dissolved in 0.9 ml of ethanol under stirring, and added with piperidine (0.1 ml, 1.0 mmol) to the solution at room temperature. The mixture was heated to reflux for 2 hours in an oil bath and lots of precipitates were formed. Then the ice-salt bath was removed, and the reaction mixture was naturally cooled down to room temperature, filtered to obtain the title compound (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 10 (30 g, yield 38%) as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:9]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1.C[O-].[Na+].CO.[C:31](O)(=[O:33])C>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:33][CH3:31])=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:9]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1
Reactant: CC(=O)O
Reactant: COCCOc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(OC)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-methoxyethoxy)-3H-quinazolin-4-one (0.42 g, 1.22 mmol) in DMF (10 mL) was added a solution of sodium methoxide in methanol (25 wt %, 2.8 g, 12.8 mmol) and the reaction mixture was stirred at 70° C. for 16 hours, then cooled to room temperature. Water (1 mL) was added, the mixture was neutralized to pH approximately 6 with acetic acid, diluted with water (50 mL), and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo, to give 0.30 g of crude compound. Further purification by crystallization in acetone:Et2O (1:3) gave the title compound as a white solid. Yield: 91 mg (15%). 1H NMR (400 MHz, CDCl3): δ 10.08 (br s, 1H), 7.60 (br s, 2H), 6.87 (d, J=1.95 Hz, 2H), 6.55 (d, J=1.95 Hz, 2H), 4.25 (t, J=4.88 Hz, 2H), 3.93 (s, 3H), 3.83 (d, J=4.29 Hz, 2H), 3.44 (s, 3H), 2.64 (s, 6H). MS (ES+) m/z: 356.11 (M+1)+
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>C(OCC)C>[CH2:4]([NH:5][C:12]([NH:11][CH2:10][CH2:9][Cl:8])=[O:13])[CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)CCN
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: CC(C)(C)CCNC(=O)NCCCl
Reaction time: 2 h

Procedure:
A 5 g quantity of 3,3-dimethyl butylamine (0.5 mol) was dissolved in 30 ml of anhydrous diethyl ether and stirred on an ice bath. 2-Chloroethyl isocyanate (5.25 g, 0.5 mol) dissolved in 15 ml of ether was added maintaining a temperature of 10° C. or less, and stirring continued for 2 hrs. Filtering the product and washing with four 5 ml portions of chilled ether afforded 6.2 g (60%) which melted at 84° C. (decomposes). IR analysis showed peaks at 1625/cm (C=O) and 1580/cm (N--C=O). NMR: singlet (9H) at 0.9 ppm, multiplet (2H) at 1.3 ppm, multiplet (2H) at 3.2 ppm, multiplet (4H) at 3.5 ppm, singlet (1H) at 5.5 ppm, and singlet (1H) at 5.7 ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH2:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH:5][C:52]([C:51]1[C:55]([CH3:59])=[CH:56][CH:57]=[CH:58][C:50]=1[Cl:49])=[O:53]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
To a suspension of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.125 mmol, 46 mg), HBTU (0.125 mmol, 47.5 mg) and 2-chloro-6-methylbenzoic acid (0.137 mmol, 25 mg) in DMF (2 mL) was added diisopropylethylamine (0.312 mmol, 44 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 72 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 42 mg (70% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a oily residue. ES-HRMS m/e calcd for C25H26ClN3O5 (M+Na) 506.1454, found 506.1459.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:62][C@@H:63]1[C:81](=[O:82])[N:65]2[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]3[N:76]([NH2:77])[N:75]=[N:74][N:73]=3)[CH2:68][S:69][C@H:64]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])/[C:27]([NH:62][C@@H:63]2[C:81](=[O:82])[N:65]3[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]4[N:76]([NH2:77])[N:75]=[N:74][N:73]=4)[CH2:68][S:69][C@H:64]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: CNC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.7 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(N-methylcarbamoyl)methoxyiminoacetic acid (3.25 g, 6.5 mmol), 1-hydroxybenzotriazole (0.97 g, 7.15 mmol) and N,N'-dicyclohexylcarbodiimide (1.41 g, 6.83 mmol) in dimethylacetamide (34 ml) was stirred at room temperature for 4 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.57 g, 7.8 mmol) and triethylamine (1.73 g, 17.2 mmol) in dimethylacetamide (20 ml) and water (2.4 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(N-methylcarbamoyl)methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (4.1 g, 78%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC([O-])(C)C.[K+].O=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1>C1COCC1>[C:1]([CH:3]=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1)#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.47 %

Procedure:
Diethyl cyanomethylphosphonate (4.247 mL, 26.99 mmol) was suspended in THF (135.0 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (32.39 mL, 32.39 mmol) was added portion-wise and stirred at 0° C. for 10 minutes. tert-Butyl 3-oxopyrrolidine-1-carboxylate (5 g, 26.99 mmol) was added dropwise as a solution in THF (25 mL). The resulting mixture was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue partitioned between saturated aqueous NH4Cl and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was passed through a pad of Celite® and silica, eluting with DCM to furnish tert-butyl 3-(cyanomethylene)pyrrolidine-1-carboxylate (2.5 g, 12.00 mmol, 44.47% yield. 1H NMR (CDCl3) δ 5.8 (s, 1H), 4.26 (t, 2H), 3.85 (s, 2H), 2.28 (t, 2H), 2.06-1.96 (m, 1H), 1.54 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]#[N:21]>CN(C)C=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:21]
Reactant: N#CCCl
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC#N)c1
Temperature: 0 °C
Yield: 6461 %

Procedure:
Methyl 3-hydroxybenzoate (10.00 g, 65.72 mmol) was dissolved in dimethylformamide (100 ml). With stirring the solution under ice-cooling, potassium carbonate (13.63 g, 98.58 mmol) and chloroacetonitrile (4.99 ml, 78.86 mmol) were added in that order, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into ice-water and the crystals precipitated were collected by filtration. The resulting crystals were dissolved in chloroform, and the solution was washed with 5% potassium carbonate aqueous solution, 10% citric acid aqueous solution and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. By crystallizing the resulting residue from diethyl etherhexane, methyl 3-cyanomethoxybenzoate (811.80 g, 94%) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][C:5](N(OC)C)=[O:6])[CH2:3][CH2:2]1.[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>O1CCCC1>[CH:1]1([CH2:4][C:5](=[O:6])[CH2:13][CH:12]=[CH2:11])[CH2:3][CH2:2]1
Reactant: C=CC[Mg]Br
Reactant: CON(C)C(=O)CC1CC1
Solvent: C1CCOC1
Product: C=CCC(=O)CC1CC1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (C63) (48 g, 0.3 mol) in tetrahydrofuran (900 mL) was added a solution of allylmagnesium bromide (1.0 M in diethyl ether, 1.5 L, 1.5 mol) drop-wise at −60° C. The mixture was stirred at −60° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (120 mL). The reaction was extracted with dichloromethane (2×500 mL), and the organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried and concentrated in vacuo to give the product as a yellow oil, which was used directly in the following step.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30]C)=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:27][O:26][C:25]1[C:3](=[O:2])[C:4]([CH3:32])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:23](=[O:30])[C:24]=1[O:28][CH3:29]
Reactant: COc1c(C)c(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 48.8 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-phenoxybenzoic acid (0.220 g, 0.502 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.688 g, 1.26 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.100 g, 0.245 mmol, 49%).