Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:26]([C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:6]=2)[CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1cccc(B(O)O)c1
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: COCCOC
Solvent: ClCCl
Product: N#Cc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A mixture of 4-bromo-1-trityl-1H-imidazole (0.2 g, 0.51 mmol), 3-cyanophenylboronic acid (0.11 g, 0.77 mmol), and Pd(PPh3)4 (0.06 g, 0.05 mmol) in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial overnight at 120° C. After cooling, the reaction mixture was diluted with dichloromethane (30 mL) and washed with water (50 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography of the crude residue using 2% ethyl acetate in hexanes afforded 0.07 g (34%) 4-(3-cyanophenyl)-1-trityl-1H-imidazole as white foam.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>>[CH2:23]([O:17][C:16]([CH:12]1[CH2:13][C:14](=[O:15])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH2:11]1)=[O:18])[CH3:24]
Reactant: CC(C)c1ccc(N2CC(C(=O)O)CC2=O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CC(=O)N(c2ccc(C(C)C)cc2)C1
Temperature: 57.5 °C
Yield: 100 %

Procedure:
A mixture of 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid obtained in step 1 (0.6 g, 2.42 mmol), thionyl chloride (0.35 g, 2.90 mmol), and ethanol (10 ml) was heated at 55-60° C. for 2 hours. The mixture was cooled and solvent was removed. The residue was dissolved in ethyl acetate (20 ml). The organic layer was washed with saturated NaHCO3 and saturated brine solution (20 ml). The organic layer was dried over Na2SO4 and evaporated to obtain 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid ethyl ester as yellow oil (0.7 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:15])[N:7]2[CH2:12][CH:13]=O.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:7]4[C:8]5[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=5)[CH:4]=[CH:5][C:6]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2c(Br)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Br)cccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To 25 mL of a chloroform solution containing 520 mg of (5-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde and 705 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 112 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 629 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 890 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:9])[CH:7]=[CH2:8]>[OH-].[Na+]>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:9])[CH:7]=[CH2:8]
Reactant: NCC(=O)O
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
7.5 g (0.1 mol) mol) glycine was dissolved in 100 ml 2 N NaOH. The solution was cooled to 0° C. and 10.8 g (0.12 mol) acryloyl chloride was added dropwise over 45 minutes, while the temperature was kept below 10° C. The reaction was allowed to continue for one hour at 10° C. The reaction mixture was extracted 2 times with 50 ml tert. butyl methyl ether. The pH was adjusted to pH=3, using a concentrated hydrochloric acid solution and the reaction mixture was saturated with sodium chloride. The mixture was extracted 5 times with 100 ml n.-pentanol. The pooled n.-pentanol fractions were dried over Na2SO4 and evaporated under reduced pressure, after addition of a small fraction BHT as stabilizer. 4.2 g (32.5%) of N-acryloyl-glycine was isolated (m.p. 124-126° C.). N-acryloyl-glycine is Comparative Monomer 5 (see below).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]3[CH2:23][CH2:22][CH2:21][C:20]=3[C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:45])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]34[O:45][C:20]3([C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:22][CH2:23]4)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C2=C(Cc3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(C23CCCC2(Cc2nc(-c4ccccc4)c(-c4ccccc4)o2)O3)c1
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-1-cyclopenten-1-yl]phenoxy]acetate (1.0 g) in methylene chloride (20 ml) were added m-chloroperbenzoic acid (540 mg) and sodium carbonate (330 mg) at room temperature. After being stirred for 4 hours, the mixture was washed with saturated sodium bicarbonate aqueous solution and brine. The dried solvent was evaporated and the residue was purified by column chromatography on silica gel to give ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-1,2-epoxycyclopentyl]phenoxy]acetate (700 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)cc1F
Yield: 96 %

Procedure:
2′,4′-difluoroacetophenone (5 g, 32 mmol) was reacted with sodium borohydride (1.21 g) in THF (20 mL) and methanol (10 mL) for 1 hr. The resultant mixture was evaporated to dryness and partitioned between methylene chloride and water. The organic layer was separated, dried, and evaporated to give 1-(2′,4′-difluorophenyl)-ethanol as a colorless oil (4.86 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.15 (q, 1H), 2.0 (s, 1H), 1.5 (d, 3H). 1-(2′,4′-difluorophenyl)-ethanol (5.384 g, 34 mmol), t-butyltrimethylsilyl chloride (6.148 g, 40.8 mmol) and imidazole (5.567 g, 81.8 mmol) in DMF (60 mL) were combined and stirred at rt overnight. The resultant mixture was evaporated to dryness in vacuo, and then the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and evaporated to give 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether as a white solid (6.88 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.45 (q, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.05 (q, 1H), 1.32 (d, 3H), 0.88 (s, 9H), 0.05 and 0.01 (each s, each 3H). A 1.6 M solution of n-butyl lithium in hexane (3.75 mL, 6 mmol) was added dropwise to a solution of 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at −50° C. and was stirred at the same temperature for 3 h. The reaction mixture was poured to dry ice; and then was evaporated to dryness. The residue was partitioned between methylene chloride and water, acidified with acetic acid. The organic layer was separated, dried, and evaporated to give 2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5A as white solid (1.57 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.70 (q, 1H), 7.00 (t, 1H), 6.00 (br, 1H), 5.15 (q, 1H), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])=[CH2:18])[CH:12]=1)([CH3:10])=[CH2:9]>CCCCCC>[CH3:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:10])[CH3:9])[CH:12]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: C=C(C)c1cccc(C(=C)C)c1
Reactant: Oc1ccccc1
Solvent: CCCCCC
Product: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.3 %

Procedure:
A 500-ml three-neck reactor was charged with Amberlist-15 (7.5 g, 2.6 mmols), phenol (178.5 g, 633 mmols) and hexane (60 ml). The contents were heated up to 80° C in nitrogen atmosphere. Under agitation, a mixture of m-diisopropenylbenzene (m-DIPeB, 15.0 g, 31.5 mmols) and hexane (60 ml) was fed thereto over 3 hours at 80° C. After completion of the feed, agitation was carried out at 80° C. for 10 minutes and then Amberlist-15 was removed by filtration. The filtrate was analyzed by liquid chromatography. Bisphenol M (α, α″-bis(4-hydroxyphenyl)-1,3-diisopropylbenzene, 29.6 g, yield 90%), the intended product, and the o,p-product, the position isomer of bisphenol M (α-(4-hydroxyphenyl)-α″-(2-hydroxyphenyl)-1,3-diisopropylbenzene, 2.43 g, yield 7.4%), were obtained. After completion of the same aftertreatment and purification operations using p-xylene as those in Example 1, bisphenol M was isolated (22.0 g., isolation yield 67%, purity 99.5%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][S:29]([CH3:28])(=[O:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ncc(F)c(NS(C)(=O)=O)n2)cc1
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.100 g, 0.43 mmol) in anhydrous THF (4 mL) was added LiHMDS (1.07 mL of 1.0M, 1.07 mmol) dropwise at room temperature, and the resulting orange solution was stirred for 20 min. Methanesulfonyl chloride (0.108 g, 0.94 mmol) was added in one portion and the turbid, light orange solution was stirred for 60 min. The reaction was quenched with brine (5 mL) and the THF phase was separated. The aq. phase was extracted w/EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated to an orange gummy residue. The residue was purified by flash chromatography (SiO2, 0→100% EtOac/hexanes) to give 0.034 g (26%) of the title compound as a white solid: mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 5.35 (s, 2H), 3.37 (s, 3H), 2.35 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)+, 310 (M−H)−.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:5](=[N:1][C:2]#[N:3])[S:6][CH3:7])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSC(=NC#N)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.25 g.) in methanol (10 ml.) was added dimethyl (cyanoimido)dithiocarbonate (0.15 g.) and the mixture allowed to stand overnight. The residue, obtained on evaporation of methanol, was subjected to preparative thin layer chromatography on silica gel GF (Uniplate, Analtech Inc., Delaware, USA) using chloroform/methanol (90:10 v/v) for development. Isolation of the appropriate region of the chromatogram and elution with warm ethanol/chloroform (50:50 v/v) and crystallisation of the material extracted from methanol ether gave 2-guanidino-4-[3-(3-cyano-2-methylisothioureido)-cyclohexyl]thiazole, m.p. 216°-218° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:25])[C:26]1[CH:31]=[CH:30][C:29]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:2]=4[F:1])[C:6]=3[CH:14]=2)=[CH:28][CH:27]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Yield: 63 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (500 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (63% yield). M.p. 173-174° C., LCMS: m/z=410.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.39 (t, J=7.1 Hz, 3H), 3.45 (t, J=5.0 Hz, 2H), 3.61-3.66 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 4.49 (s, 2H), 5.32 (bs, 1H), 6.78 (d, J=1.5 Hz, 1H), 6.89-6.96 (m, 1H), 6.99-7.08 (m, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.76 (d, J=1.8 Hz, 2H), 8.02 (d, J=8.6 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:21]O>>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([O:16][CH3:21])=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC1CN(Cc2ccccc2)CC1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CN(Cc2ccccc2)CC1C

Procedure:
1.3 g (4.9 mmol) (3RS,4RS)-1-benzyl-4-methyl-pyrrolidine-3-carboxylic acid (as hydrochloride salt) are dissolved in 10 ml of methanol and combined with 0.6 ml (8.5 mmol) thionyl chloride while cooling with an ice bath. The ice bath is removed and the mixture is refluxed for three hours. Then the mixture is evaporated down i. vac. and combined with 1N sodium hydroxide solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[C:25]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:24][C:18]2[CH2:19][CH:20]([CH2:22][OH:23])[O:21][C:17]=2[C:16]=1[Cl:35]>CC(C)=O>[Cl:14][C:15]1[C:25]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:24][C:18]2[CH2:19][CH:20]([C:22]([OH:3])=[O:23])[O:21][C:17]=2[C:16]=1[Cl:35]
Reactant: CC(C)=O
Reactant: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(CO)C2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
Jones reagent [J. Chem. Soc., 2555 (1953)] (84 ml.) was added dropwise to a stirred, cooled solution of 6,7-dichloro-2,3-dihydro-5-(2-fluorobenzoyl)-2-hydroxymethylbenzofuran (43 g., 0.126 mole) in acetone (700 ml.) at such a rate that the internal temperature did not exceed 25° C. The resultant mixture was stirred for 18 hours at 25° C. The insoluble chromium salts were separated by decantation and washed with acetone. The washings were combined with the filtrate, and the resultant solution was concentrated to 1/5 the original volume and then poured into H2O. This mixture was extracted with methylene chloride and the organic extract was washed several times with aqueous NaCl. The methylene chloride solution was then extracted with 0.5N KOH. Upon standing the aqueous extract deposited the potassium carboxylate salt as a crystalline solid. The solid was dissolved in warm water, acidified with 6N HCl and the resulting solution extracted with ethyl acetate. Drying and evaporation furnished 38 g. of carboxylic acid, m.p. 180°-181° C. This material was used without additional purification for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[CH3:25])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:43][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=3[CH3:25])=[N:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(OC(C)C)c(C#N)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 125 °C

Procedure:
In an oven-dried high-pressure tube, 240 mg (0.58 mmol) of N′-(3-cyano-4-isopropyloxyphenylcarbonyl)-4-bromo-2-methylbenzhydrazide (from Step A) was combined with 40 mL of anhydrous toluene, 300 mg of Lawesson's Reagent (0.74 mmol), and 100 μL of pyridine. The tube was sealed with a plastic/teflon cap and the reaction mixture was heated to 125° C. for 2 h. The resulting mixture was cooled down to rt, solvents were removed under reduced pressure and residual solids were dissolved in 10 mL of pyridine. To this mixture, 0.5 g of phosphorous pentasulfide was added and the mixture heated to 110° C. The reaction mixture was combined with ice-water and extracted 2×100 mL of EtOAc. Combined organic layers were dried over sodium sulfate, and solvents removed under reduced pressure. Pure title compound was isolated by flash chromatography using Biotage 40S (eluant: hexanes/EtOAc-4/1) to yield 239 mg: 1H NMR (500 MHZ, CDCl3) δ 1.49 (d, J=6.5, 6H), 2.65 (s, 3H), 4.79 (sep, J=6.5, 1H), 7.13 (dd, J=9.0, 2.0, 1H), 7.50 (dd, J=9.0, 2.0, 1H), 7.56 (d, J=2.0, 1H), 7.63 (d, J=8.0, 1H), 8.17 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:13](=[O:15])[CH3:14].O>C(Cl)Cl.B(Br)(Br)Br>[C:13]([N:12]([S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH:9]([CH3:11])[CH3:10])=[CH:8][C:3]=1[OH:2])(=[O:15])[CH3:14]
Reactant: COc1cc(C(C)C)ccc1N(C(C)=O)S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)N(c1ccc(C(C)C)cc1O)S(=O)(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
To a solution of 2-(N-acetyl-phenylsulfonylamino)-5-isopropylphenyl methyl ether (2.28 g; prepared in Reference Example 40.) in methylene chloride (15 ml), boron tribromide (1.36 ml) was added at 0° C. The mixture was stirred for 5 hours at 10° C. The reaction mixture was poured into iced water, extracted with ethyl acetate. The organic layer was washed, dried over and concentrated. The residue was purified on silica gel column chromatography (benzene:AcOEt=23:2) and recrystallized from AcOEt-hexane mixture solution to give the title compound (1.55 g) having the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[N:9]([CH2:10][C:11](O)=[O:12])[C:8](=[O:14])[C:7]([NH:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][NH:20][C:19]=4[N:18]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][C@H:29]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C@H:29]([NH:28][C:11](=[O:12])[CH2:10][N:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[CH2:23][CH2:22][CH2:21][NH:20][C:19]=3[N:18]=2)[C:8]1=[O:14])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[CH3:35]
Reactant: CCOC(=O)C[C@H](N)c1cccc(F)c1
Reactant: O=C(O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O
Agent: Cl
Product: CCOC(=O)C[C@H](NC(=O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O)c1cccc(F)c1

Procedure:
Following the procedure described for the preparation of 16-5, the acid 17-7 was coupled with the amine 17-8 to yield the title compound 17-9.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][S:29][CH2:30][CH:31]=[CH2:32])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][S:29][CH2:30][CH:31]=[CH2:32])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 84.8 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.19 g.), tetrahydrofuran (7.5 g.) and methanol (22.5 ml.) were treated in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.), powder.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:22])=[C:16](F)[C:17]=3[O:19][CH3:20])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)[CH2:8][CH2:7]1>CN(C=O)C>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:22])=[C:16]([N:1]4[CH2:5][CH:4]=[CH:3][CH2:2]4)[C:17]=3[O:19][CH3:20])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: C1=CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CN(C)C=O
Product: COc1c(N2CC=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
3-Pyrroline (1 g; 14.5 mmol) and acid 52 (2.1 g; 7.2 mmol) in DMF (10 mL) were heated at 100° C. overnight. After cooling, the reaction mixture was filtered and washed with water. Acid 119 was isolated.