Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.CC(C[AlH]CC(C)C)C>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1
Reactant: O=CC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 1-(2-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyridin-3-yl)piperidine-4-carbaldehyde (232 mg, 0.56 mol) in 20 mL of THF was added DIBAL-H (1.4 mol, 1 M in toluene) dropwise at RT. The mixture was stirred for 1 hour at RT and then quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the product (0.150 g, 0.36 mmol, 60% yield). ESI-MS (M+1): 419 calc. for C25H30N4O2 418. 1H NMR (CD3OD, 400 MHz) δ (ppm): 7.96 (d, J=9.2 Hz, 1H); 7.72-7.70 (m, 1H); 7.64-7.60 (m, 2H); 7.52-7.48 (m, 1H); 7.23-7.16 (m, 3H); 6.87-6.84 (m, 1H); 5.38 (s, 1H); 4.81-4.79 (m, 2H); 4.01-3.98 (m, 2H); 3.79-3.74 (m, 2H); 3.40-3.39 (m, 2H); 2.58-2.51 (m, 2H); 2.11-2.08 (m, 2H); 1.93-1.77 (m, 4H); 1.40-1.36 (m, 3H). PDE10 IC50 (uM): 0.01.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1)[NH2:12]
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: NN
Solvent: CCO
Product: Cn1c(=O)cc(NN)[nH]c1=O
Temperature: 75 °C
Yield: 99.7 %

Procedure:
To a mixture containing 10.0 g (62.28 mmol) of 6-chloro-3-methyluracil in 200 ml of ethanol was added 13.70 ml (436.50 mmol) of hydrazine. The mixture was heated to 75° C. under a nitrogen atmosphere overnight. The solids were filtered, washed with ethanol and dried to afford 9.70 g (99.74%) of product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([C:37]([NH:1][C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]4[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=4)[C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)=[O:19])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:38])[CH2:36][CH2:35]1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)c([N+](=O)[O-])c2s1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (200 mg, 0.421 mmol) in pyridine (4 mL) was added cyclopropanecarbonyl chloride (76 μL, 0.842 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (50 ml), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (97 mg, 42%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:25])=[O:21])=[CH:18][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1

Procedure:
The title compound was prepared from 2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D13) by stirring a DMF solution together with iodomethane and potassium carbonate for 3 hours, followed by dilution with water and extraction into ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)(C)(C)C.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccsc1
Reactant: Cc1c(N)cccc1Cl
Agent: CC(C)(C)ON=O
Product: Cc1c(Cl)cccc1-c1cccs1

Procedure:
3-Chloro-2-methylaniline was treated with t-butylnitrite in excess thiophene as described in J. Chem. Soc., 4257 (1963) to produce 2-(3-chloro-2-methylphenyl)thiophene as an oil. Reaction of the oil with N-bromosuccinimide as described in J. Am. Chem. Soc., 89, 2348 (1967) yielded 2-(2-bromomethyl-3-chlorophenyl)thiophene as an oil, which was reacted without further purification, as described in J. Chem. Soc., 2708 (1955), with diethyl malonate in the presence of tetrabutyl ammonium bromide and potassium hydroxide in dry tetrahydrofuran, producing ethyl [2-carboethoxy-3-[2-chloro-6-(thien-2-yl)phenyl]]propionate. Hydrolysis of the latter with hydrochloric acid in glacial acetic acid provided 3-[2-chloro-6-(thien-2-yl)phenyl]propionic acid; mp 83°-86°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C:11]=3[C:12](=[O:32])[CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].C([O-])(=[O:35])C.[Na+].OO.O>O1CCCC1>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C:11]=3[C:12](=[O:32])[CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH:18]([OH:35])[CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCC=C(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCC(O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3β-acetoxy-5α-cholesta-8(14),24-dien-15-one (220 mg) in tetrahydrofuran (3 ml) was added boranedimethyl sulfide (0.125 ml) dropwise at 0° C. After standing overnight at -20° C., 3N sodium acetate (0.4 ml) was added followed by 30% aqueous H2O2 (0.4 ml) at room temperature. After stirring for 3 h at room temperature, the reaction mixture was poured into water (10 ml) and extracted 3 times with ether (5-ml portions). The combined ether extracts were washed with water (5 ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting oily residue was subjected to silica gel column (15 cm×0.8 cm) chromatography. Using 16% ethyl acetate in hexane as the eluting solvent, fractions 8 ml in volume were collected. The contents of fractions 64-99 were pooled and, after evaporation of the solvent, gave 3β-acetoxy-24 -hydroxy-5α-cholest-8(14)-en-15-one (66 mg) as an oil to which, after dissolving in methanol (3 ml), potassium carbonate (40 mg) was added. After stirring for 4 h at room tempeature, TLC analyses (solvent systems, 70% ethyl acetate in hexane and 50% acetone in benzene) indicated completion of the reaction with one major product (with Rf values of 0.51 and 0.27 in the 2 solvent systems, respectively). The reaction mixture was poured into water (10 ml), extracted 3 times with ether (5 ml portions), and the combined ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue (55 mg) was subjected to chromatography on a silica gel (4 g) column (10 cm×0.8 cm). Using 30% ethyl acetate in hexane as the eluting solvent, fractions 8 ml in volume were collected. The contents of fractions 11-17 were combined and, after evaporation of the solvent, gave 3β,24-dihydroxy-5α-cholest-8(14)-en-15-one (21 mg; 10% yield). The structure was confirmed by I.R., N.M.R., and M.S. analyses.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:11])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:4]([C:5]1[C:6]([NH:7][C:2](=[O:3])[CH3:1])=[CH:8][S:9][CH:10]=1)=[O:11]
Reactant: Nc1ccccc1Cl
Reactant: Cc1nc2cscc2c(=O)o1
Solvent: CC(=O)O
Product: CC(=O)Nc1cscc1C(=O)Nc1ccccc1Cl

Procedure:
To a slurry of 2-methyl-thieno[3,4-d][1,3]oxazin-4-one (1.3 g, 7.78 mmol) and acetic acid (15 mL) was added 2-chloroaniline (1.64 mL, 15.57 mmol). The mixture was refluxed 4 hours, cooled, and concentrated. The residue was partitioned between ethyl acetate and water and the aqueous phase was made basic by careful addition of saturated aqueous sodium bicarbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a black oil. The oil was flash chromatographed on silica gel (30×100 mm) eluting with 10% ethyl acetate/hexane. The first component eluting from the column, 0.363 g of white solid was identified as 3-acetamidothiophene-4-carboxylic acid 2-chlorophenylamide.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3.C([O-])(=O)C.[K+].C(#N)C.O.[CH3:34][C:35]([OH:52])([CH3:51])[CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1>C(Cl)Cl.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>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:40]5[CH:39]=[N:38][N:37]([CH2:36][C:35]([CH3:51])([OH:52])[CH3:34])[CH:41]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2
Temperature: 140 °C
Yield: 32.9 %

Procedure:
To a microwave vial was added 5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine (0.180 g, 0.000462 mol) and potassium acetate (0.1362 g, 0.001387 mol) in acetonitrile (2.0 mL, 0.038 mol) and water (2.0 mL, 0.11 mol). The reaction was thoroughly degassed and purged with N2 for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.05344 g, 4.624E-5 mol) and 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (0.1477 g, 0.0005549 mol) were added and the vial was sealed immediately. The reaction was heated to 140° C. for 20 minutes in the microwave. The mixture was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 213 (68.2 mg) as a colorless solid. MS(ESI+) 449.2. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.38 (dd, J=8.4, 1.7, 1H), 7.27 (d, J=1.7, 1H), 5.82-5.68 (m, 1H), 5.19 (s, 2H), 4.74 (s, 1H), 4.50 (br, 4H), 4.04 (s, 2H), 1.42 (d, J=6.6, 6H), 1.09 (s, 6H)
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:20][CH3:21])[C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH:10]=O.[Cl-].[OH:32][NH3+:33].C([O-])(=O)C.[Na+].O>C(O)C.[Cl-].[Na+].O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:20][CH3:21])[C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH:10]=[N:33][OH:32]
Reactant: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=O
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=NO
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde (275 mg) is dissolved in ethanol (2.5 ml) and thereto are added hydroxylammonium chloride (86 mg) and sodium acetate (102 mg), and the mixture is stirred at 60° C. under nitrogen atmosphere for 1 hour and a half. To the reaction solution are added a saturated brine and water, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=24:1→83:17) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehydeoxime (244 mg). MS (m/z): 459 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]=[CH:11]OC.[ClH:14].[NH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[ClH:14].[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]=[N:16][NH:15][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: NNc1ccncc1
Reactant: COC=Cc1cc(OC)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(F)c(CC=NNc2ccncc2)c1
Yield: 40.8 %

Procedure:
To a solution of 1-fluoro-4-methoxy-2-(2-methoxyvinyl)benzene (20 g) and 4-hydrazinopyridine hydrochloride (17.7 g) in ethanol (300 ml), p-toluene sulfonic acid (3.13 g) was added, with stirring. The reaction mixture was stirred under reflux for 2 hrs, filtered, and the filtrate was concentrated in vacuo. The residue was recrystallized from methanol to yield 13.24 g (41%) of product, mp 219-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22])=[C:13]=S.NC(N)=S.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[F:22][C:21]([F:23])([F:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:12][C:13]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(Nc3ccccc3C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3,4-diaminobenzoic acid (3 mmol) in DMF (10 mL) was charged with 1-isothiocyanato-2-trifluoromethylbenzene (3.3 mmol) and the resulting solution was stirred at RT for 4 h. After thiourea formation was complete, solid K2CO3 (10 mmol) was added to the reaction mixture, and the mixture was heated at 90° C. for 10 h. The reaction mixture was cooled to RT and acidified with 10% aqueous HCl to pH 7. The contents were poured onto ice cold water (30 mL) with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]1[C:33](=[O:34])[N:15]2[C:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11])=O>C(O)C.O>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:4]=1
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27.4 %

Procedure:
Thiourea (0.14 g.) was added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer: 0.8 g.) in ethanol (20 ml.) and water (5 ml.), and stirred at room temperature for 3.5 hours. The resultant solution was concentrated under reduced pressure, and to the residue were added water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (0.6 g.) The product was purified by column chromatography on silica gel (eluent: benzene and ethyl acetate (8:2) to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer: 0.21 g.), mp 165° to 170° C. (dec.)
Reaction SMILES: C(OC([N:8]([C:36]1[N:37]=[C:38]2[CH:44]=[CH:43][N:42]([S:45]([C:48]3[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:39]2=[N:40][CH:41]=1)[CH2:9][C:10]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][N:14]([C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:13]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:13][CH:12]1[C:10](=[O:11])[CH2:9][NH:8][C:36]1[N:37]=[C:38]2[CH:44]=[CH:43][N:42]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=3)(=[O:47])=[O:46])[C:39]2=[N:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CN(C(=O)OCC5c6ccccc6-c6ccccc65)CCC4C)C(=O)OC(C)(C)C)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CN(C(=O)OCC5c6ccccc6-c6ccccc65)CCC4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate (0.627 g, 0.836 mmol, prepared using W from Preparation #20, LL, Z from Example #8, Step A) in DCM (10 mL) was added TFA (1.50 mL, 19.5 mmol) and the resulting mixture was stirred at ambient temperature under nitrogen for about 1 h. The solution was concentrated and the residue was partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (25 mL). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield crude (9H-fluoren-9-yl)methyl 4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)-piperidine-1-carboxylate as an amorphous brown solid. The crude material was added to 1,4-dioxane (5 mL), Lawesson's reagent (0.203 g, 0.502 mmol) was added, and the resulting suspension was heated at about 80° C. for about 20 min. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 1.5% MeOH/DCM to give (9H-fluoren-9-yl)methyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate as an off-white solid (0.21 g, 40%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z: 632 (M+H)+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]#[N:42])[C:10]([NH:12][CH:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([OH:35])=[O:34])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]#[N:42])[C:10]([NH:12][CH:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([OH:35])=[O:34])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(N)n3)[C@H]2SC1
Yield: 70.7 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-n-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.11 g.) and conc. hydrochloric acid (0.73 g.) in methanol (11 ml.) and tetrahydrofuran (5 ml.) was treated in a similar manner to that of Example 9-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-n-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.75 g.).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:23][O:24][CH2:25][C@@H:26]([NH2:28])[CH3:27].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[CH3:23][O:24][CH2:25][C@@H:26]([NH:28][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:27]
Reactant: COC[C@H](C)N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[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
Solvent: O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
In a round-bottomed flask were combined 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.32 mmol) and (S)-1-methoxypropan-2-amine hydrochloride (61 mg, 0.49 mmol). DMF (1.5 mL) was added followed by N,N-diisopropylethylamine (0.15 mL, 0.86 mmol) and HATU (135 mg, 0.36 mmol). The yellow reaction mixture was stirred at room temperature overnight then water was added. The resulting suspension was filtered and the filter cake was washed with water and petroleum ether then dried under high vacuum to provide 129 mg (90%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[CH3:23][O:24][C:25](Cl)=[O:26]>ClC(Cl)C.ClCCl>[CH3:23][O:24][C:25](=[O:26])[NH:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 60 °C
Yield: 86 %

Procedure:
To a stirred solution of 0.20 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 5 mL of dichloroethane was added 0.58 mL of pyridine and 0.55 mL of methylchloroformate, and the mixture was heated to 60° C. for 20 minutes. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried over NaSO4 and the volatiles were removed under reduced pressure to give 208 mg (86% yield) of [3-bromo-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid methyl ester.