Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([O:11]C)([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][C:7]#[CH:8].C([Li])CCC.[CH2:18]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1.CCCCCC>[OH:28][CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([O:9][CH3:10])=[O:11]
Reactant: O=Cc1ccccc1Cc1ccccc1
Reactant: C#CCCCC(OC)(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)CCCC#CC(O)c1ccccc1Cc1ccccc1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred mixture of 2.19 g (12.73 mmol) 1,1,1-trimethoxy-5-hexyne in 15 ml dry tetrahydrofuran (THF) at -78° under nitrogen was added 8.37 ml of 1.52M n-butyllithium (12.73 mmol) in hexane dropwise. The mixture was stirred at -78° for 1 hour and 2.0 g of 2-benzylbenzaldehyde (10.20 mmol) in 10 ml dry THF was added dropwise at -78°. The mixture was stirred at room temperature for 12 hours and poured into water. The reaction mixture was extracted with ether (2×75 ml) and the combined organic layers were washed with water (50 ml), saturated sodium chloride (50 ml), and dried (MgSO4). Filtration and evaporation left an oil that was purified by flash chromatography to give the title compound in 56% yield (2.02 g). NMR (CDCl3, 200 MHz) δ: 1.80 (m, 2H), 2.25-2.50 (m, 5H), 3.67 (s, 3H), 4.18 (br s, 2H), 5.60 (s, 1H), 7.12-7.75 (m, 9H). Mass spectrum: m/z=322 (M+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCc1ccccc1
Reactant: BrCCCCBr
Product: BrCCCCOCCCCc1ccccc1

Procedure:
(2.44 g), T.l.c. [K] Rf 0.68, from 1,4-dibromobutane (8.6 g) and benzenebutanol (2 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].[C:12]1([CH3:21])[C:13]([C:18](Cl)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.Cl>O>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([NH:1][C:18](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:21])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1C(=O)NC(C(=O)O)C(C)(C)C
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
Racemic tert-butylglycine (502 mg, 3.83 mmol) was dissolved in water (10 mL) containing NaOH (153 mg, 3.83 mmol). This solution was cooled to 5° C. and treated with o-toluoyl chloride (0.501 mL, 3.83 mmol) followed by additional NaOH (153 mg, 3.83 mmol). The mixture was warmed to ambient temperature, stirred for 1.5 hours, recooled to 5° C., and treated with 1M HCl (pH 3). The thick precipitate that formed was collected by filtration and washed with cold water to provide 550 mg of the desired product as a white solid.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.S(Cl)([Cl:14])=O.O1CCOCC1>CN(C)C=O>[Cl:14][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=S1(=O)N=Cc2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(Cl)c2ccccc21
Reaction time: 8 h

Procedure:
100 g (545 mM) of benzisothiazole-1,1-dioxide 100 ml. of thionyl chloride, 4 ml. of dimethylformamide (catalyst) and 400 ml. of dioxane are refluxed overnight. Thionyl chloride (50 ml.) and dimethylformamide (1 ml.) are added to the reaction mixture which is again refluxed overnight. The reaction mixture is evaporated to dryness and the residue recrystallized from toluene to obtain 73.4 g of 3-chloro-1,2-benzisothiazole-1,1-dioxide, m.p. 140°-145°.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22](O)=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([F:25])[CH:3]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:31][CH2:32][CH:27]([NH:26][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][C:8]2[C:7]4[C:2]([F:1])=[CH:3][C:4]([F:25])=[CH:5][C:6]=4[O:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:28][CH2:29]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6cc(F)cc(F)c56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 115) and amine 14.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]1[O:19][CH2:18][CH2:17][O:16]1)(=[O:9])=[O:8])[CH3:2].CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1.Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]([S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]1[O:16][CH2:17][CH2:18][O:19]1)(=[O:8])=[O:9])[CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C1OCCO1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1sccc1C1OCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
To a solution of the product from Example 10, Step A (2.80 g, 8.72 mmol) in anhydrous DMF (40 mL) at 0° C. was added a solution of potassium t-butoxide in t-butanol (1M, 9.16 mL, 9.16 mmol) followed by 4-methoxybenzyl chloride (1.78 g, 11.34 mmol). The solution was stirred at ambient temperature for 4 h, poured into 2N HCl (50 mL), diluted with water (150 mL) and extracted with ethyl acetate (2×120 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a viscous oil (3.91 g) which was used in the next step.
Reaction SMILES: [C:1]([C@@H:4]([O:12][C:13](=[O:44])[CH2:14][C@H:15]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:16]([CH3:35])([CH3:34])[C:17](=[O:33])[C@H:18]([CH3:32])[C@@H:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@@H](C)C=C)[CH2:5]/[CH:6]=C(/C)\CC=C)(=[O:3])[CH3:2].[C:45]1([CH3:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:1]([C@H:4]1[O:12][C:13](=[O:44])[CH2:14][C@H:15]([O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38])[C:16]([CH3:34])([CH3:35])[C:17](=[O:33])[C@H:18]([CH3:32])[C@@H:19]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27])[C@@H:45]([CH3:51])[CH:50]=[CH:49][CH2:48][C:47]([CH3:46])=[CH:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CC/C(C)=C\C[C@H](OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=C)C(C)=O
Reactant: Cc1ccccc1
Agent: CC(=O)[C@@H]1C/C=C(/C)C/C=C/[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CC(=O)[C@@H]1CC=C(C)CC=C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reaction time: 0.5 h

Procedure:
A solution of 50.0 mg (76.8 μmol) of (3S,6R,7S,8S)-3,7-bis-(tert-butyl-dimethyl-silanyloxy)-4,4,6,8-tetramethyl-5-oxo-dec-9-enoic acid (Z)-(S)-1-acetyl-4-methyl-hepta-3,6-dienyl ester in 200 ml toluene was heated at reflux. 10.8 mg (11.5 μmol) of [RuCl2(PCy3)(ImH2Mes)(3-phenyl-indenylidene)] was added and the resulting yellowish solution stirred at reflux. After 30 min, a 50 ml sample was evaporated to dryness and to remove residual toluene, redissolved in 25 ml ethanol and evaporated to dryness to yield the title compound with 80% purity (HPLC method described in Example 4).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:10][CH2:11][C:12](OCC)=[O:13])[CH:7]=[CH:6][CH:5]([O:8][CH3:9])[O:4]1.[H-].C([Al+]CC(C)C)C(C)C.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1([CH2:10][CH2:11][CH:12]=[O:13])[CH:7]=[CH:6][CH:5]([O:8][CH3:9])[O:4]1
Reactant: CCOC(=O)CCC1(OC)C=CC(OC)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC1C=CC(CCC=O)(OC)O1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 48.9 g. of 2,5-dihydro-2,5-dimethoxy-2-(2'-carbethoxyethyl)furan (Example 1) in 800 ml. of toluene was added 263 ml. of 0.89M diisobutylaluminum hydride in toluene during 90 minutes at -75°C. The solution was stirred at -75°C. for 30 minutes and then treated with 5.0 ml. of methanol. The stirred solution is treated with 100 ml. of water, and the resulting mixture is stirred at 0°-5°C. for 15 minutes, saturated with sodium sulfate, and filtered through Celite with the aid of ethyl acetate. The filtrate is washed with brine, dried over magnesium sulfate, and concentrated. The residue is distilled to provide a light yellow liquid, b.p. 76°-78°C. (0.25 mm.), ν max 1725 (aldehyde carbonyl group) and 1015 cm-1 (dimethoxydihydrofuran group).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1>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.O1CCOCC1>[C:5]([C:4]1[CH:3]=[C:2]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cccc(-c2cccc(C#N)c2)c1
Temperature: 105 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
A mixture of 3-bromobenzonitrile (910 mg), Pd(Ph3P)4 (290 mg), (Me3Sn)2 (1.64 g) and dioxane (20 mL) was sealed under argon in a pressure tube. The tube was then heated at 100-110° C. for 3 hours with stirring and another 15 hours at 80° C. To the reaction mixture was added 1-bromo-3-methylbenzene (940 mg), Pd(PPh3)4 (290 mg) and dioxane (5 mL) under argon. The sealed tube was heated at 135-140° C. with stirring for two days. The catalyst was filtered off and the filtrate was poured into water and extracted with ethyl acetate (3×). The organic layer was washed with brine, dried over Mg2SO4, concentrated and purified on silica gel column (ethyl acetate/hexane, 1:3) to afford 0.64 g of 3-(3-cyanophenyl)-1-methylbenzene.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][CH3:13])=[CH:7][C:6]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:6]1[CH:7]=[C:8]([S:12][CH3:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: CSc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CSc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 44.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylthio)phenyl)ethanone (4.64 g, 17.0 mmol) and thiourea (1.29 g, 17.0 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (4.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(methylthio)phenyl)thiazol-2-amine (1.9 g) as light yellow solids in 45% yield: 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 2H), 6.26 (s, 1H), 2.47 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[NH:19][CH3:20]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:19]([CH3:20])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1cccc(OC)c1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with 3-methoxy-N-methylaniline (933 mg, 6.8 mmol) using method A to give 4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as an off white solid. Yield: 398 mg (55%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 6.88 (ddd, J=8.5, 2.5, 1.0 Hz, 1H), 6.67-6.64 (m, 2H), 3.69 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[Cl:16][C:17]1[N:18]([C:22]2[CH2:26][CH2:25][CH2:24][N:23]=2)[CH2:19][CH2:20][CH:21]=1>>[ClH:16].[N:23]1[CH2:24][CH2:25][CH2:26][C:22]=1[N:18]1[CH2:19][CH2:20][CH:21]=[C:17]1[N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: ClC1=CCCN1C1=NCCC1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: Cl
Product: C1=C(N2c3ccccc3Oc3ccccc32)N(C2=NCCC2)CC1

Procedure:
Reaction of phenoxazine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 257.5°-263° C. (corr.), from ethanol-ether.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4](Cl)[N:3]=1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: Nc1cccnc1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Nc2cccnc2)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
A mixture of 4-(2,6-dichloro-5-nitro-4-pyrimidinyl)morpholine (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) (1.89 g, 3.6 mmol) and 3-aminopyridine (0.68 g, 7.2 mmol) in THF at −70° C. was treated with 7.2 mL of LiHMDS (1M solution in THF, 2 eq.) and the mixture was stirred at that temperature for 1.5 hrs, and then allowed to warm to room temperature. The solvent was removed and the crude product was extracted with 0.5 M HCl. After filtration, the aqueous solution was made basic with sat. Na2CO3, to give a precipitate, which was collected by filtration, and dried, to give 1.12 g (52% yield) of 2-chloro-6-(4-morpholinyl)-5-nitro-N-(3-pyridinyl)-4-pyrimidinamine: mp (aq. MeOH)>310° C.; 1H NMR (CDCl3) δ 10.19 (br s, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.45 (dd, J=4.8, 1.4 Hz, 1H), 8.12 (ddd, J=8.3, 2.6, 1.5 Hz, 1H), 7.35 (dd, J=8.4, 4.8 Hz, 1H), 3.81 (m, 4H), 3.61 (m, 4H).
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCC.[Al+3].[C:22]([O-])(=[O:40])[CH2:23]CCCCCCCCCCCCCCCC.C([O-])(=[O:60])CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Na+]>C([O-])(=O)CCCCCCCCCCCCCCCCC.[Al+3].C([O-])(=O)CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Pb+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>[C:13]1(=[O:60])[O:40][CH2:22][CH2:23][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Al+3]
Agent: [Na+]
Agent: [Pb+2]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To demonstrate the improved yields and increased reaction rates obtained utilizing the mixed metal catalysts of this invention, batch polymerizations were identically conducted using (a) a mixed metal catalyst comprised of aluminum stearate and sodium stearate (1.1 molar ratio), (b) aluminum stearate catalyst, and (c) lead stearate catalyst. These reactions were conducted in accordance with the procedure employed in Example II utilizing 74 grams poly(ethylene brassylate) and 0.5 mole percent of the catalyst. Reactions were carried out at 310°-320° C. and 0.1-0.5 mm Hg for four hours. The amount of distillate (crude ethylene brassylate) recovered was recorded after the first hour of reaction. With the mixed metal catalyst, 45 mls ethylene brassylate was obtained after one hour and the overall yield was 95.9 percent. With the aluminum stearate, 36 mls crude ethylene brassylate was obtained in the first hour and the overall yield was only 78 percent. Using lead stearate only 25 mls distillate was obtained after one hour and the yield of crude ethylene brassylate was 69.1 percent.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.P([O-])([O-])([O:18][C:19](=O)[NH2:20])=O.S([O-])([O-])(=O)=O.[Mg+2]>[Cl-].[Mn+2].[Cl-].C(O)(=O)C>[NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][O:10][C:19](=[O:18])[NH2:20])[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: NC(=O)OP(=O)([O-])[O-]
Agent: [Mn+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.2 h

Procedure:
7-amino-3-hydroxymethylceph-3-em-4-carboxylic acid (40 μg), [14C] carbamoyl phosphate (150 μg, 7.5 μCi), magnesium sulphate (20 μg), manganese chloride (20 μg) and pipes buffer (0.5 μmole, pH 6.75) were incubated with 0-transcarbamoylase as described in Example 9(i). After incubation the mixture was acidified with glacial acetic acid (10 μl), clarified by centrifugation and the supernatant dried by rotary evaporation. This material was taken up in acetate/formate buffer [glacial acetic acid (5 ml), formic acid (0.2 ml) in methanol/water (40:60 v/v, 1 liter), pH adjusted to 3.9 with 4 N sodium hydroxide] (30 μl) and a portion (10 μl) was applied to a Partisil 10 SAX column (250 mm×4.6 mm) and eluted with the same buffer at 100 psi (1 ml/minute). The U.V. absorption at 260 nm and radioactivity of the eluate were monitored. A new U.V. absorption peak was detected after 12 minutes which also contained radioactivity. This peak corresponded to that obtained with authentic title compound. The conversion of cephalosporin starting material into title compound was 13%.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:12]=[N:11]2)[C:7](O)=[O:8])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:62][C:63]1[CH:67]=[CH:66][N:65]([CH2:68][C:69]([CH3:72])([OH:71])[CH3:70])[N:64]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])[CH:12]=[N:11]2)[C:7]([NH:62][C:63]2[CH:67]=[CH:66][N:65]([CH2:68][C:69]([OH:71])([CH3:70])[CH3:72])[N:64]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 29, 151.8 mg, 0.43 mmol) in N,N-dimethylformamide (1.67 mL, 0.26M) at 25° C. was treated with N,N-diisopropylethylamine (0.21 mL, 1.29 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.28 g, 0.64 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 0.08 g, 0.51 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 12 g, 75-100% gradient ethyl acetate/hexanes) afforded 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (107 mg, 51%) as an off-white solid; ES+-HRMS m/e calcd for C24H27N5O4F2 [M+H+] 488.2104 found 488.2103. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (br s, 3H) 1.07 (br s, 3H) 1.45-1.66 (m, 1H) 1.69-1.89 (m, 4H) 1.88-2.03 (m, 1H) 2.02-2.41 (m, 3H) 3.90 (s, 2H) 4.67 (s, 1H) 5.35 (dd, J=10.1, 4.4 Hz, 1H) 6.02 (d, J=2.9 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.34-7.44 (m, 2H) 7.44-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.27 (d, J=2.9 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][I:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(OCCOCCO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCCOCCI)c1ccccc1
Reaction time: 14 h
Yield: 64.1 %

Procedure:
To a solution of 2,2′-oxydiethanol (2.12 g) in pyridine (20 mL) was added benzoic anhydride (4.52 g) by small portions under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 18 hrs. Pyridine was evaporated under reduced pressure and the obtained residue was diluted with diethyl ether (20 mL). 5% Aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with diethyl ether (100 mL×3). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5→40/60). The object fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the obtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in dichloromethane (10 mL) were added 1-iodopyrrolidine-2,5-dione (2.70 g) and triphenylphosphine (3.14 g) by small portions under ice-cooling, and the mixture was stirred for 14 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (120 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=100/0→60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(2-iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent oil.