Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]([Mg]Br)[CH3:27]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1)[CH3:27]
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: CC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a solution of 200 mg (0.55 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF (5 ml) were added 30 mg (0.055 mmol) Ni(dppp)Cl2 and 330 μl (0.66 mmol, 2M in THF) ethylmagnesiumbromide. The RM was heated to 80° C. for 8 h, followed by quenching with a sat. aq. NH4Cl sol. and extraction with EtOAc (3×20 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 50 mg (0.14 mmol, 25%) Ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 22). [M+H]+ 358.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=O)=[CH:10][CH:9]=[N:8]1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>O>[Cl:24][C:15]1[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[CH:9][C:10]=12
Reactant: O=C(O)c1ccccc1Nc1ccnn1-c1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1c2ccccc2nc2c1cnn2-c1ccccn1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A solution of 2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (62.0 g, 0.221 mol) in phosphorous oxychloride (166 g, 1.08 mol) was heated under reflux for 1 hour. The solution was allowed to cool to room temperature and poured into water. The solution was neutralized by addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (47.4 g, 76% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:23][C:24]1[CH:33]=[CH:32][C:27]([CH:28]=[CH:29][CH2:30]Br)=[CH:26][CH:25]=1>CN(C)C=O.C(Cl)Cl>[Br:23][C:24]1[CH:33]=[CH:32][C:27]([CH:28]=[CH:29][CH2:30][NH:22][CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:26][CH:25]=1
Reactant: BrCC=Cc1ccc(Br)cc1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCC=Cc2ccc(Br)cc2)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (261 mg in a mixture of 3 mL N,N-dimethylformamide and 8 mL methylene chloride) at 0° C. was added a solution of 81 mg of 4-bromocinnamyl bromide in 2 mL methylene chloride and the mixture allowed to warm to room temperature. After 27 hours the reaction was quenched by the addition of water followed by extraction with ethyl acetate. The organic portion was dried over over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (93 mg). m/e=491 (M)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[CH:31]=[C:30]([OH:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cc(O)cc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)Nc2cc(O)cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Yield: 28 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.14 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxybenzenesulfonamide (87 mg, 0.21 mmol), 2M sodium carbonate (216 μl, 0.43 mmol) and tetrakis(triphenylphosphino)palladium(0) (8 mg, 0.01 mmol) according to the method described in Example 3 to give 25 mg (27% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.Br.[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br)[CH3:12]>>[CH2:22]([N:13]([CH2:11][CH3:12])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:6][C:5]2=[CH:7][S:8][CH:9]=[C:4]2[N:3]=1)[CH3:23]
Reactant: Sc1nc2cscc2[nH]1
Reactant: CCN(CC)c1ccccc1CBr
Agent: Br
Product: CCN(CC)c1ccccc1CSc1nc2cscc2[nH]1

Procedure:
1.47 g of 2-mercaptothieno[3,4-d]imidazole are reacted with 3.05 g of 2-diethylaminobenzyl bromide hydrobromide, and the product is worked up in analogy to the procedure described in Example 1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]4[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1>>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]5[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1ccnc(F)c1
Product: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(-c4ccnc(F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 65 mg, 0.181 mmol) and 2-fluoropyridine-4-boronic acid (Frontier Scientific, Logan, USA, 33 mg, 0.236 mmol) to give the title compound as a pink solid. (HPLC: tR 2.55 min (Method A); M+H=375 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.08 (s, 1H), 8.35-8.26 (m, 1H), 8.22-8.13 (m, 1H), 8.10-8.01 (m, 1H), 7.84-7.76 (m, 1H), 7.43-7.35 (m, 1H), 7.29-7.23 (m, 1H), 7.23-7.16 (m, 1H), 6.73 (s, 1H), 3.68 (s, 3H), 3.60 (s, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:13]C)=[C:10]([Br:12])[CH:11]=1)[CH3:2].IC>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([OH:13])=[C:10]([Br:12])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cnc(O)c(Br)c1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
(5-Bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester (5.02 mmol) was dissolved in CHCl3 (17 mL). Silver carbonate (1.58 g, 5.7 mmol) and iodomethane (0.82 mL, 13.14 mmol) were added, and the reaction was stirred at 55° C. for 2.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated and purified by silica gel chromatography (0-60% EtOAc in hexanes) to give (5-bromo-6-hydroxy-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:27][OH:28])=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:28][CH2:27][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(COc2nc(N)nc(-c3ccccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. EI-MS m/e (%): 332 (M+, 100), 303 (34), 120 (31).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1C
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1C

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-o-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=248.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:28][CH:29]([N-]C(C)C)C.ICC>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:28][CH3:29])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (165 mg, intermediate E3) in THF (3.0 ml) was added at −78° C. a solution of LDA (3 eq., 2.8 ml) and stirring was continued for 1 h. The mixture was treated at −78° C. with a solution of iodoethane (67 μl) in THF (2.0 ml) and stirring was continued at the same temperature for 1.5 h and at −20° C. for 16 h. The mixture was quenched with saturated aqueous NH4Cl, extracted with diethyl ether, the organic layer was dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (4:1) to give [(4S,5R)-5-ethyl-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (96 mg) as a colorless foam. MS (ESI): m/z=391.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:27]([NH2:29])=[O:28])[CH3:26])=[O:23])[CH2:18][C:19](=[O:21])[OH:20])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.O.[ClH:31].O1CCOCC1>C(O)(=O)C>[ClH:31].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:27]([NH2:29])=[O:28])[CH3:26])=[O:23])[CH2:18][C:19](=[O:20])[OH:21])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O

Procedure:
12.54 Parts of N-t-butoxycarbonyl-L-methionyl-L-aspartyl-D-alanine amide is dissolved in 107 parts by volume glacial acetic acid and 51.66 parts by volume of a 5.6 M solution of HCl/dioxane. The resultant mixture is stirred for 20 minutes and then stripped under reduced pressure to afford a solid. The solid is triturated with ethyl ether, cooled, and the resultant product washed with cold ethyl ether and vacuum dried. This solid is purified by countercurrent distribution to afford L-methionyl-L-aspartyl-D-alanine amide hydrochloride hydrated with 2/3 mole of water per mole, and represented by the following formula.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=O)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:13]([C:10]1[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]2=[N:8][CH:9]=1)=[O:15])[CH2:29][CH3:30]
Reactant: Cc1cccn2c(=O)c(C(=O)O)cnc12
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2c(C)cccn2c1=O
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A mixture containing 9.2 g (0.045 mol) of 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 7.05 mi (0.05 mol) of triethylamine in 280 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.7 ml (0.045 mol) of methyl chloroformate dissolved in 25 ml of chloroform is dropped to the above mixture at -21 0° C. during 10 minutes. After stirring for 5 minutes, 2.95 g (0.05 mol) of propylamine dissolved in 50 ml of chloroform are dropped to the above solution at a temperature between -21° C. and -19° C. during 45 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 7.8 g (70.7%) of the named compound as snow-white crystals after recrystallization from ethanol, m.p.: 138°-140° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].NCP(=O)(O)O.C(O)(=[O:16])C(C)C.[C:18]([O-:22])(=[O:21])[CH2:19][OH:20]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:19]([OH:16])(=[O:20])[C:18]([OH:22])=[O:21]
Reactant: O=C([O-])CO
Reactant: CC(C)C(=O)O
Reactant: O=C(O)CO
Agent: NCP(=O)(O)O
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 19 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor equipped with Dispersimax Impeller (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.50M), aminomethylphosphonic acid (0.375M), isobutyric acid (0.100M, HPLC internal standard), and flavin mononucleotide (0.01 mM) at pH 8.3, and the solution cooled to 5° C. To the reactor was then added 30 g of E. coli transformant (25.2 IU glycolate oxidase and 39,900 IU catalase), and the mixture stirred at 1000 rpm, which bubbled oxygen through the mixture via the action of the turbine impeller, and at 5° C. under 120 psig of oxygen. The reaction was monitored by taking a 0.40 mL aliquot of the reaction mixture at regular intervals, filtering the aliquot using a Millipore Ultrafree-MC 10,000 NMWL Filter Unit, and analyzing the filtrate by HPLC. After 19 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 8.6%, 8.3%, and 1.1%, respectively, with 57.3% glycolic acid remaining. The recovered activities of microbial glycolate oxidase and catalase were 10% and 68% of their initial values, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:19])[C:13]3=[CH:12][N:11]=2)=[O:9])=[CH:4][C:3]=1[O:20][CH3:21].I[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]I>>[CH2:23]([O:19][C:18]1[C:13]2[N:14]([C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:20][CH3:21])[CH:4]=3)=[O:9])=[N:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:19][C:18]1[C:13]2[N:14]([C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:20][CH3:21])[CH:4]=3)=[O:9])=[N:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: ICCOCCOCCOCCOCCOCCI
Reactant: COc1cc(C(=O)c2ncc3c(O)cccn23)ccc1N
Product: COc1cc(C(=O)c2ncc3c(OCCOCCOCCOCCOCCOCCOc4cccn5c(C(=O)c6ccc(N)c(OC)c6)ncc45)cccn23)ccc1N
Yield: 27 %

Procedure:
By following the process described in Stage A of Example 8, Example 10 is prepared from (4-amino-3-methoxyphenyl)(8-hydroxyimidazo[1,5-a]pyridin-3-yl)-methanone (described in Patent Application WO2006097625) with 1,17-diiodo-3,6,9,12,15-pentaoxaheptadecane (Example R2). After purification by flash chromatography on silica gel (dichloromethane/acetone gradient=90/10 to 70/30), 0.93 g (27%) of a yellow powder is obtained.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][C:16]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:15][CH2:14][CH2:13]2)=[O:11])[N:9]=1)([CH3:4])[CH3:3].Br[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CCOC(C)=O>[OH:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][C:16]2([O:15][CH2:14][CH2:13][N:12]([C:10]([C:8]3[N:9]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:6][CH:7]=3)=[O:11])[CH2:17]2)[CH2:22][CH2:21]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cccc(CCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 66 h
Yield: 88 %

Procedure:
To a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride in a solution of 2-(3-(2-bromoethyl)phenyl)ethanol (1.15 molar equivalents) in acetonitrile (10 volumes) at room temp was added potassium carbonate (4 molar equivalents) followed by water (0.167 volumes. The mixture was stirred at 60° C. for 66 hours, cooled to room temp, filtered, washed with MeCN and concentrated in vacuo to leave a crude orange gum. This gum was dissolved in EtOAc (3 volumes) and washed with 2N HCl (1.1 molar equivalents). The aqueous layer was basified using 2N NaOH (1.5 molar equivalents) and extracted with TBME (2×2 volumes) [an oil appeared at the interface which would not dissolve in TBME]. The combined organics and oil were diluted with EtOAc (1 volume) [oil dissolved], dried (Na2SO4), filtered and concentrated in vacuo to leave an orange gum. Yield: 88% of theoretical.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:37])([CH3:36])NC(=O)C1C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>ClCCl>[Br:38][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:37])([CH3:36])[CH3:25])=[O:9]
Reactant: C[Si](C)(C)NC(=O)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 42 %

Procedure:
458 mg of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide (1.32 mmoles) were silylated in 40 ml of dichloromethane with 397 mg (2.06 mmoles) of N-trimethylsilylbenzamide by refluxing for half an hour and the clear, pale yellow solution was cooled in an ice-bath. Bromination was carried out in half an hour with 378.5 mg (2.13 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 42% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([C:9](=[O:21])[C@@H:10]4[C@H:15]([CH2:16]3)[NH:14][CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([C:9](=[O:21])[C@@H:10]4[C@H:15]([CH2:16]3)[N:14]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN[C@H]3C[C@@H]21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN(S(C)(=O)=O)[C@H]3C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 g of (8aS,12aS,13aS)-3-methoxy-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one (I), obtained as shown in Example 4, in 300 ml of methylene chloride and 10 ml of triethylamine was cooled in an ice bath and 5 ml of methanesulfonyl chloride was added. The mixture was stirred at room temperature for 30 minutes, diluted with 100 ml of hexane, and extracted with water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The residue was crystallized from isopropanol, to give 11 g of (8aS,12aS,13aS)-3-methoxy-12-methanesulfonyl5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one, m.p. 138°-140° C.
Reaction SMILES: IC.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[CH:19]1(C#CC2C=CC(OC)=CC=2C(O)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH3:19][O:17][C:16]([C:13]1([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[CH2:14][CH2:15]1)=[O:18]
Reactant: COc1ccc(C#CC2CC2)c(C(=O)O)c1
Reactant: COc1ccc(C#CC2(C(=O)O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(C#Cc2ccc(OC)cc2)CC1
Reaction time: 4 h

Procedure:
Iodomethane (3.6 g, 0.026 mol) was slowly added to a mixture of 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid and 2-cyclopropylethynyl-5-methoxy-benzoic acid (5.0 g) and potassium carbonate (4.8 g, 0.034 mol) in DMF (100 mL). After stirring for 4 hours, the mixture was diluted with ether (200 mL) and washed with water. The ether layer was dried over sodium sulfate, evaporated to dryness, and the residue was purified by column chromatography to yield 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid methyl ester as a yellow oil (2.2 g). 1H NMR (CDCl3): δ 7.36 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz. 2H), 3.79 (s, 3H), 3.76 (s, 3H), 1.62 (m, 2H), 1.41 (m, 2H). 2-cyclopropylethynyl-5-methoxy-benzoic acid methyl ester (1.0 g). 1H NMR (CDCl3): δ 7.89 (d, J=2.4 Hz, 1H), 7.46 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.8 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 1.43 (m, 1H), 0.86 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[C:14](O)[C:11]([C:12]#[N:13])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:32])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[C:14]([Cl:32])[C:11]([C:12]#[N:13])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(O)cc(-c2cccc(Br)c2)nc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)cc(-c2cccc(Br)c2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6-(3-bromophenyl)-4-hydroxy-2-(4-phenoxyphenyl)nicotinonitrile (38.8 mg, 0.070 mmol) and phosphoryl trichloride (0.5 mL, 5.38 mmol) was heated to 90° C. for 17 h, then concentrated to give crude 6-(3-bromophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile, which was used in the next reaction without purification. MS (ES+) m/z: 461, 463 (M+H); LC retention time: 4.821 min (analytical HPLC Method A).