Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:11].[Ba+2].[OH-].[O:14]1[CH2:18]CCC1>O>[C:1]1([CH2:7][C:8](=[O:9])[C:18]([OH:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][C:8]([OH:9])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: [OH-]
Agent: [Ba+2]
Solvent: O
Product: O=C(O)C(=O)Cc1ccccc1
Product: O=C(O)Cc1ccccc1
Temperature: 5 °C
Yield: 86.8 %
Yield: 1.5 %

Procedure:
A 22.5 mL aliquot of 4.5 mmoles of potassium tricarbonyl [triphenylphosphine] cobaltate was charged to a 100 mL three-neck round bottom flask under nitrogen and cooled to 5° C. Phenylacetyl chloride (0.60 mL; 4.5 mmoles) was added to the flask. The solution containing the preformed cobaltate complex was then charged into a 300 mL autoclave by means of a transfer needle under nitrogen. The autoclave had previously been charged with 18.1 mmoles (3.1 g) of barium hydroxide as a suspension in 22.5 mLs tetrahydrofuran and 5 mLs water. The vessel was sealed, flushed with carbon monoxide, pressurized to 900 psig and heated to 90° C. for nine hours. The autoclave was vented and the contents were poured into a 250 mL separatory funnel. The reaction mixture was acidified with 10% hydrochloric acid and then treated with an excess of iodine. The organic phase was diluted with 100 mLs of diethyl ether and the lower aqueous phase was discarded. The organic phase was washed with saturated sodium thiosulfate until the color of iodine was dispelled. The resultant light yellow diethyl ether phase was washed with 10% sodium hydroxide (3×25 mLs) and the organic phase discarded. Acidification of the combined aqueous sodium hydroxide solution followed by re-extraction with diethyl ether (2×75 mLs) gave a clear solution. The solution was dried over MgSO4 and evaporated to give 0.07 mmoles (1.5% yield) of phenylpyruvic acid and 3.91 mmoles (86.8% yield) of phenylacetic acid as identified by mass spectroscopy and comparison to an authentic sample.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:45][C@H:46]([C:64]([NH:66][C@H:67]([C:72]([OH:74])=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70])=[O:65])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:63])[NH:52][S:53]([C:56]1[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=1)(=[O:55])=[O:54]>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH:45][C@H:46]([C:64]([NH:66][C@H:67]([C:72]([OH:74])=[O:73])[CH2:68][CH:69]([CH3:70])[CH3:71])=[O:65])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:63])[NH:52][S:53]([C:56]1[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=1)(=[O:55])=[O:54])=[O:11])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
In 250 ml of tetrahydrofuran are dissolved 23.7 g (80.4 millimoles) of Z-Ser(But)-OH and 10.2 g of N-hydroxysuccinimide, and the solution is cooled to 0° C. and 16.6 g of dicyclohexylcarbodiimide is added to the solution. The mixture is stirred for 3 hours at the above temperature and then stirred in a low temperature chamber overnight. The formed precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The obtained oily substance is dissolved in 100 ml of dimethylformamide. This solution is mixed with a solution formed by dissolving 35.5 g (80.4 millimoles) of H-Arg(Tos)-Leu-OH prepared according to the process (ii) of Example 8 in 200 ml of dimethylformamide and adding 11.2 ml of triethylamine to the solution, and the mixture is stirred for 6 hours at 6° C., overnight in a low temperature chamber and for 5 hours at room temperature. The insoluble substances are removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with 700 ml of ethyl acetate, washed with 2% citric acid and water and dried with magnesium sulfate. The dried filtrate is concentrated under reduced pressure and ether is added to the residue to effect solidification. The solid is dissolved in a mixed liquid of chloroform and methanol, and the solution is concentrated under reduced pressure. Solidification is effected by ethyl acetate to obtain 41.9 g of intended Z-Ser(But)-Arg(Tos)-Leu-OH (the yield being 73%).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:24]CC)[C:6]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)([PH2:10]=[O:11])[CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+].CO>C1COCC1>[OH:24][C:5]([CH3:27])([C:6]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)([PH2:10]=[O:11])[CH:7]([CH3:9])[CH3:8])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(OCC)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)(O)C(=O)O
Yield: 97.3 %

Procedure:
2-(Ethoxy)(quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (4.5 g) was dissolved in 100 mL THF and 12.5 mL of 2N NaOH was added together with enough methanol to make the solution homogeneous. After 18 hours the THF was removed by evaporation, the residue diluted with 50 mL H2O and washed with 50 mL ethyl acetate. The aqueous phase was then acidified to pH 4, and the product extracted with 50 mL ethyl acetate (2×). The ethyl acetate was washed with 20 mL brine, dried with MgSO4 and evaporated to yield 3.8 g of 2-(hydroxy)(quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid as a yellow oil, MS: 368 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[O:21]=[C:19]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:23])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCCC1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and piperidine using a similar procedure to that described for Example 2, product further purified by mass directed auto-prep.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[O:15][CH3:16].Br[CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[O:15][CH3:16])[CH2:19][CH2:20][CH3:21]
Reactant: COc1cc(C2=NNC(=O)CC2)ccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC

Procedure:
11.0 g of 6-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-3[2H]pyridazinone are heated under reflux together with 8.2 g of 1-bromobutane and 8.3 g of potassium carbonate in 150 ml of anhydrous acetone for 20 hours. Thereafter, the starting compound can no longer be detected by thin-layer chromatography. The suspension is filtered hot, the filter cake is washed out with hot acetone and the filtrates are combined and evaporated in vacuo. The semi-solid residue [6-(4-n-butoxy-3-methoxyphenyl)4,5-dihydro-3[2H]pyridazinone]is taken up in 50 ml of ethanol, 10.0 g of sodium hydroxide in 200 ml of water and 14.6 g of sodium meta-nitrobenzenesulfonate are added and the mixture is heated under reflux for 2 hours. After cooling, it is acidified to pH 1-2 with concentrated hydrochloric acid, the crystalline solid is filtered off with suction and the solution is extracted several times with chloroform. The residue from the chloroform extract is combined with the crystals and the product is recrystallized from ethanol/ethyl acetate. 8.7 g (63.7% of theory) of the title compound of m.p. 193° are obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C#N)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-:25].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:25])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(OC)c1cc(C(C#N)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 26.7 parts of intermediate 9, namely 3-(dimethoxymethyl)-4-nitro-α-phenylbenzeneacetonitrile, 12.3 parts of potassium carbonate and 360 parts of N,N-dimethylacetamide was stirred at room temperature while bubbling air through it. The reaction mixture was poured into water and the whole was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CHCl3 /hexane 80:20). The eluent of the desired fraction was evaporated, yielding 18.1 parts (67.3%) of [3-(dimethoxymethyl)-4-nitrophenyl]phenylmethanone (interm. 10).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[NH2:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([Cl:24])[N:18]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:24][C:19]1[CH:20]=[C:21]([O:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[C:11]([F:12])([F:13])[F:14])[N:22]=[C:17]([NH2:16])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(C(O)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 65.8 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 1-(4-methylphenyl)-2,2,2-trifluoro-ethanol (190 mg, 1 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 209 mg of 4-chloro-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine, yield 66%.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Cl:4][C:5]1[C:6]2[C:7]3[C:8](=[C:27]([CH3:30])[O:28][N:29]=3)[C:9](=[O:26])[N:10]([CH:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([CH2:22]C(O)=O)[CH2:16]3)[C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH3:31][OH:32]>>[CH3:31][O:32][C:2](=[O:3])[NH:1][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:15]([N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:5]([Cl:4])[C:6]=3[C:7]3=[N:29][O:28][C:27]([CH3:30])=[C:8]3[C:9]2=[O:26])[CH2:16]1
Reactant: Cc1onc2c1c(=O)n(C1CCCCC(CC(=O)O)C1)c1cccc(Cl)c21
Reactant: [N-]=C=O
Reactant: CO
Product: COC(=O)NCC1CCCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1

Procedure:
In a manner similar to the preparation of Example 677 (except the intermediate isocyanate was trapped with MeOH instead of TMS ethanol) 0.68 g (1.8 mmols) of a compound from Example 680 was converted to 0.43 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])[C:10]=2[C:11]([NH2:13])=[O:12])[CH:5]=[N:6][CH:7]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[CH:3]=2)[C:10]([C:11]([NH2:13])=[O:12])=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH:15]=1
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cncc(N)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Nc1cncc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In analogy to GP 6b, 100 mg of 2-(5-Amino-pyridin-3-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 3.1; 0.21 mmol, 1 eq.) were dissolved in 1.5 mL pyridine and treated with 37 mg iso-propylsulfonyl chloride (0.26 mmol, 1.25 eq., dissolved in 0.5 mL pyridine). The reaction mixture was stirred at rt overnight, treated with another 1.25 eq. sulfonylchloride (in 0.2 mL pyridine) and stirring was continued at rt overnight. After addition of further 1.25 eq. sulfonylchloride (in 0.2 mL pyridine) and further stirring at rt for 3 days, the resulting mixture diluted with ethyl acetate, washed with water and the organic layers dried. Concentration in vacuo was followed by prepurification by chromatography and subsequent HPLC purification to provide the desired compound.
Reaction SMILES: C(N(C(C)C)CC)(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.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([N:53]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])[C:54]3([C:59]([OH:61])=O)[CH2:58][CH2:57][CH2:56][CH2:55]3)(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C)C=O>[CH3:67][O:66][C:64](=[O:65])[CH2:63][CH2:62][N:53]([C:54]1([C:59](=[O:61])[NH:77][O:76][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:55][CH2:56][CH2:57][CH2:58]1)[S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=2)=[CH:45][CH:46]=1)(=[O:51])=[O:52]
Reactant: NOCc1ccccc1
Reactant: COC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C1(C(=O)NOCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 85.7 %

Procedure:
Diisopropylethylamine (4.3 mL, 24.6 mmole) and (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (11.0 grams, 24.9 mmole) were added sequentially to a solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)-amino]cyclopentane-1-carboxylic acid (10.1 grams, 22.4 mmole) in N,N-dimethylformamide (170 mL). The mixture was stirred for 4 hours. Additional diisopropylethylamine (7.8 mL, 44.6 mmole) and O-benzylhydroxylamine hydrochloride (4.64 grams, 29.1 mmole) were then added and the resulting mixture was stirred at 60° C. for 16 hours. After concentration under vacuum, the residue was taken up in water and acidified with 1 N aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate and the extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give a solid which upon trituration with 7:3:1 hexane/ethyl acetate/methylene chloride provided 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester as a white crystalline solid (10.65 grams, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](O)[CH:6]=[CH:5][C:3]=1[OH:4].[C:10](=[O:13])([O-])[O-].[K+].[K+].S(OC)(O[CH3:20])(=O)=O>CC(C)=O>[CH3:20][O:4][C:3]1[CH:5]=[CH:6][C:7]([O:13][CH3:10])=[CH:8][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(C)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A mixture of 12 g of methylhydroquinone, 45 g of potassium carbonate and 45 g of dimethyl sulphate in 300 ml of anhydrous acetone is heated to reflux for 4 days. After cooling, the reaction mixture is filtered and the filtrate is evaporated under vacuum. The residue is taken up in 150 ml of concentrated aqueous ammonia, the mixture is left stirring for 2 hours, diluted with water and extracted with DCM, the organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a heptane/DCM (50:50; v/v) mixture. 12 g of the expected product are obtained.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH2:2][OH:3].[CH:6]([OH:8])=[O:7]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:1]([OH:5])(=[O:4])[C:6]([OH:8])=[O:7]
Reactant: O=CO
Reactant: O=C([O-])CO
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Reaction time: 4 h

Procedure:
The reaction described in Example 4 was repeated, except that the same amounts of soluble, unimmobilized glycolate oxidase and catalase were added to the reaction mixture. After 4 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 43%, 0%, and 0%, respectively, with a 46% conversion of glycolic acid. The final activities of glycolate oxidase and catalase were <2% and 82% of their initial values, respectively, and no further reaction was observed at longer reaction times.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=O)[CH2:4][CH2:5][C:6](O)=[O:7].[NH2:11][NH2:12]>C(O)C>[CH:2]([C:3]1[CH2:4][CH2:5][C:6](=[O:7])[NH:11][N:12]=1)([CH3:10])[CH3:1]
Reactant: CC(C)C(=O)CCC(=O)O
Reactant: NN
Solvent: CCO
Product: CC(C)C1=NNC(=O)CC1

Procedure:
5-Methyl-4-oxohexanoic acid (3.60 g, 25.0 mmol) and anhydrous hydrazine (0.80 g, 26.0 mmol) were heated for 3 hours in ethanol (36.0 ml) under stirring. After the reaction solution was concentrated under reduced pressure, hexane was added to the residues to precipitate crystals, and the crystals were collected by filtration to give 4,5-dihydro-6-isopropyl-3 (2H)-pyridazinone as crystals. The yield was 3.10 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH2:16][C:17]1[NH:21][N:20]=[C:19]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][C:18]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[NH:21][N:20]=[C:19]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][C:18]=23)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2n[nH]c(NC(=O)c3nc(Br)c(C(F)(F)F)nc3N)c2C1

Procedure:
A mixture comprising 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2)(0.102 g, 0.357 mmol), tert-butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (0.08 g, 0.357 mmol), HATU (0.136 g, 0.357 mmol) and N-methylmorpholine (0.071 ml, 0.713 mmol) in DMF (5 ml) was stirred at RT for 30 minutes. The reaction mixture was diluted with water (15 ml) and the resulting orange precipitate was filtered under vacuum and washed with water (10 ml). Purification of the resulting solid by chromatography on silica eluting with iso-hexane:EtOAc (gradient of 0 to 100% EtOAc) to afforded the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To a solution of 742 mg (2.5 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 50 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg (56.7%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1020.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[NH:13][CH:12]([CH2:19][O:20][CH3:21])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:23]([BH3-])#N.[Na+]>C(#N)C.C=O.C(O)(=O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:23])[CH:12]([CH2:19][O:20][CH3:21])[CH2:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [BH3-]C#N
Reactant: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
To a mixture of the above described (3SR,5SR)-1-benzenesulfonyl-3,5-bis-methoxymethyl-piperazine (1.68 g, 5.343 mmol) in acetonitrile (40 ml) and 36.5% formaldehyde solution in water (0.653 ml, 8.015 mmol) and 5-7 drops of acetic acid at 23° C. was added sodium cyanoborohydride (1.679 g, 26.71 mmol) and the mixture was stirred at 23° C. for 1.5 h. Poured onto water and extracted twice with ethyl acetate, dried the organic layer over sodium sulfate, filtered off, evaporated all volatiles totally and dried in high vacuum to give the title compound as a colorless oil (1.05 g, 60%), pure enough for further steps; MS (ISP) m/e=329.1 [(M+H)+].
Reaction SMILES: [C:1]([NH:8][NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=O.S(Cl)(Cl)=O>ClCCCl.C(Cl)Cl>[CH2:6]([O:5][C:3]([C:1]1[O:20][C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)=[N:9][N:8]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccc(OCC)cc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ccc(OCC)cc2)o1
Yield: 77.2 %

Procedure:
A solution of 22 g of 1-ethoxalyl-2-(4-ethoxybenzoyl)-hydrazine and 28 g of thionyl chloride in 157 ml of anhydrous 1,2-dichloroethane is heated under reflux, whilst stirring vigorously, until the evolution of gas has ceased (that is to say about 4 hours). The solvent and excess thionyl chloride are driven off in vacuo (50° C., 20 mm Hg). The residue is taken up in 150 ml of methylene chloride and the methylene chloride solution is successively washed with 2×30 ml of water, then with 30 ml of a 20% strength potassium bicarbonate solution and then with 2×30 ml of water. It is dried over anhydrous sodium sulphate. The solvent is driven off under reduced pressure (20 mm Hg, 50° C.). The solid residue is then recrystallized from isopropanol. 15.9 g of 2-ethoxycarbonyl-5-(4-ethoxyphenyl)-1,3,4-oxadiazole, which melts at 93° C., are obtained. The structure is confirmed by infrared spectrography.