Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([O:18]CC)=[O:17])=[C:11]([CH3:21])[C:10]1=[O:22])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:25]O.O>>[CH3:21][C:11]1[C:10](=[O:22])[N:9]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:25])[CH:14]=[C:13]([CH3:15])[C:12]=1[C:16]([OH:18])=[O:17]
Reactant: CO
Reactant: CCOC(=O)c1c(C)cn(C(=O)c2ccccc2)c(=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cn(C(C)c2ccccc2)c(=O)c(C)c1C(=O)O
Yield: 7.3 %

Procedure:
To the solution of ethyl 1-benzoyl-3,5-dimethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1.06 g, 3.54 mmol) in methanol/H2O (40 mL, 1:1) was added KOH (0.79 g, 14.16 mmol). The mixture was refluxed overnight. Then the mixture was concentrated under vacuum, diluted with water (5 mL) and acidified with 1 N HCl to pH=2. The mixture was extracted with ethyl acetate. The extractions were combined, dried over Na2SO4, and concentrated to give a residue 3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid as a white solid. (70 mg, yield 7.3%) LRMS (M+H+) m/z: calcd 271.31. found 272.1. The residue was used in the next step.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].Br[CH2:52][CH:53]([OH:56])[CH2:54][OH:55]>O.[OH-].[Na+]>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:52][CH:53]([OH:56])[CH2:54][OH:55])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: OCC(O)CBr
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CC(O)CO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 160 h

Procedure:
N,N'-Bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(2,3-dihydroxypropylaminocarbonyl)-phenyl]urea (0.353 g, 0.257 mmol) was dissolved in a mixture of water (8 ml) and 2M aqueous NaOH (0.9 ml) together with 1-bromo-2,3-dihydroxypropane (0.136 ml, 1.55 mmol). After stirring at room temperature for 160 h, the solution was neutralized using a strongly acidic cation exchange resin. After evaporation, the residue was purified using preparative HPLC. Yield: 100 mg (27%) of the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:44])[CH:10]([NH:23][C:24](=[O:43])[C@@H:25]([S:33]CC2C=CC(OC)=CC=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:12])=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:44])[CH:10]([NH:23][C:24](=[O:43])[CH:25]([SH:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(CS[C@@H](Cc2ccccc2)C(=O)NC(C(=O)NCCc2ccc(Cl)cc2)C(=O)NCCc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(NC(C(=O)NCCc1ccc(Cl)cc1)C(=O)NCCc1ccc(Cl)cc1)C(S)Cc1ccccc1
Reaction time: 3 h
Yield: 80 %

Procedure:
Combine of N,N′-di-(4-chlorophenethyl)-2-((S)-2-(p-methoxybenzylmercapto)-3-phenylpropionylamino)malonamide (0.29 g, 0.43 mmol), mercury (II) acetate (0.171 g, 0.54 mmol), and anisole (0.47 mL) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add trifluoroacetic acid (4 mL). After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Triturate the residue with diethyl ether to give the title compound as a solid (80%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:8][CH2:9][C:10]#[CH:11].C(N(CC)CC)C>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH:3]1[C:2]([C:11]#[C:10][CH2:9][CH2:8][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][N:5]=[CH:4]1
Reactant: Ic1c[nH]cn1
Reactant: C#CCCC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC#Cc1cnc[nH]1)OCc1ccccc1
Temperature: 75 °C
Yield: 68.8 %

Procedure:
Add bis(triphenylphosphine)palladium(II) chloride (0.14 g; 0.1 equiv; 0.20 mmoles) and copper(I) iodide (0.039 mg; 0.1 equiv; 0.20 mmoles) to a deoxygenated solution of 4-iodo-1H-imidazole (0.388 g; 1.0 equiv; 2.00 mmoles), benzyl pent-4-ynoate (0.376 g; 1.0 equiv; 2.00 mmoles), and triethylamine (0.84 mL; 3 equiv; 6.0 mmoles) in dimethylformamide (8 mL). Heat the mixture to 75° C. for 16 hours, then dilute the mixture with water (30 mL) and extract 3× with ethyl acetate. Wash the combined organic extracts with brine, dry over magnesium sulfate, filter, and concentrate to provide the crude product. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford benzyl 5-(1H-imidazol-5-yl)pent-4-ynoate (0.35 g; 69%) as a colorless oil: MS (m/z): 255(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](C(OCC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.NO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.064 mL, 0.46 mmol) and iso-butyl chloroformate (0.030 mL, 0.23 mmol). After stirring at ambient temperature for 30 min, there was added hydroxylamine hydrochloride (16 mg, 0.23 mmol). The reaction was stirred for 1 h and then the volatiles were removed. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 28 mg (27%) of the title compound as a white powder. LRMS (ES−): 562.1 (M−H+TFA)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO.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>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)nc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (5 g, 30.7 mmol), benzeneboronic acid (3.74 g, 30.7 mmol), K2CO3 (12.72 g, 92 mmol) and Pd(PPh3)4 (1.06 g, 0.92 mmol) in toluene (150 ml) and methanol (35 ml) was degassed with nitrogen and heated at 90° C. overnight. The mixture was cooled and water (200 ml) added. The organic layer was separated and the aqueous extracted with EtOAc (×2). The organic layers were combined and dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 40+M) eluent: 100% Hexanes (180 ml), gradient rising from 100% Hexanes to 20% EtOAc in Hexanes (1800 ml), then 20% EtOAc in Hexanes (1000 ml) to give 3 g (48%). 1H NMR (CDCl3): 2.61 (s, 3H), 7.52 (m, 4H), 8.08 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][CH2:10][CH:9]1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11][CH2:10][CH:9]1[CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCC(CO)N1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (30 g) and imidazole (27.8 g) in dimethylformamide (300 ml) was added portionwise t-butyldimethylsilyl chloride (20.4 g) at room temperature. After stirring for 1 hour at room temperature, water (0.9 l) and ethyl acetate (1.4 l) was added to the mixture. After shaking, aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V) to give 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (16.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][C:11](=O)/[C:10]/2=[CH:15]\[N:16](C)C)[CH:5]=[CH:6][C:7]=1[F:8].O.[NH2:20]N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[CH:15]=[N:16][NH:20][C:11]=3[CH2:12][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)/C=C1\C(=O)CCC1c1ccc(F)c(F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc(C2CCc3[nH]ncc32)cc1F
Temperature: 80 °C
Yield: 28 %

Procedure:
To the mixture of (+/−)-(2Z)-3-(3,4-difluorophenyl)-2-((dimethylamino)methylene)cyclopentanone (8.5 g, 34 mmol) in ethanol (200 mL), is added hydrazine hydrate (15 mL) and the mixture is heated to 80° C., overnight. The mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by preparative HPLC using a CXTH instrument with a DAISO 10 μC18 250×50 mm column, a 9 mL injection, a flow rate of 70 mL/min, a wavelength of 214 nm and a mobile phase of 10-80% acetonitrile in 0.1% TFA/H2O to give the title compound as a white solid (2.1 g, 28%). ES/MS m/z 221 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:16][CH:12]([C:13]2([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]3[CH3:17])=[CH:4][C:3]=1[SiH:18]([CH3:20])[CH3:19].C([Li])CCC.CN(C)[CH:28]=[O:29]>C(OCC)C>[C:8]12([C:5]3[CH:6]=[CH:7][C:2]([CH:28]=[O:29])=[C:3]([SiH:18]([CH3:20])[CH3:19])[CH:4]=3)[CH2:16][CH:12]([C:13]1([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]2[CH3:17]
Reactant: CN(C)C=O
Reactant: CC1CCC2CC1(c1ccc(Br)c([SiH](C)C)c1)C2(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1CCC2CC1(c1ccc(C=O)c([SiH](C)C)c1)C2(C)C
Yield: 96.6 %

Procedure:
28.4 g of p-dibromobenzene was dissolved in diethyl ether, and 51.3 g n-butyl lithium was added to react with p-dibromobenzene at 0° C. Then, 31.2 g of (−)-pinanyldimethylsilyl chloride was added and reacted. A mixture obtained after a routine process was purified by distillation under reduced pressure to obtain 1-bromo-4-(−)-pinanyldimethylsilylbenzene. After dissolving 34.85 g of the obtained 1-bromo-4-(−)-pinanyldimethylsilylbenzene in diethyl ether, 42.4 g of n-butyl lithium and 6.9 g of dimethylformamide were successively added and the mixture was reacted. After processing by a routine method, the reaction mixture was purified by silica gel column chromatography to obtain 27.4 g of 4-(−)-pinanyldimethylsilylbenzaldehyde. After dissolving the obtained aldehyde in 200 ml of tetrahydrofuran, the solution was added to a solution of 36.9 g of methyltriphenyl iodide and 40.0 g of n-butyl lithium to obtain (−)-PSSt. The (−)-PSSt was purified by column chromatography using hexane as a developing solvent to obtain 15.0 g of purified (−)-PSSt. The structure was confirmed using NMR and IR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:4]([F:10])[CH:3]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: OC1CCOCC1
Product: Fc1cc(Br)cc(F)c1OC1CCOCC1

Procedure:
The title compound was prepared from 4-bromo-2,6-difluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 292 and 294 M+.
Reaction SMILES: Cl.Cl.CN1CCNCC1.CN1CCNCC1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26](O)=[O:27])=[CH:23][C:22]=2[CH:29]=1.O>C1COCC1.CCOCC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=2[CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: CN1CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
LiA1H4 (3.04 g, 80 mmol) was suspended under stirring at 0° under Ar in anhydrous THF (150 ml), then N-methylpiperazine dihydrochloride (6.92 g, 40 mmol) was added portionwise in 10 minutes. N-methylpiperazine (12 g, 120 mmol) was then added dropwise, the mixture was warmed to RT and stirring continued for 2 hours. The surnatant of this suspension was then added by syringe to a stirred solution at 0° under Ar of 5-chlorobenzofuran-2-carboxylic acid (2.95 g, 15.0 mmol) in anhydrous THF (50 ml). The mixture was refluxed for 4 hours and after cooling to RT the suspension was diluted with Et2O (400 ml). The resulting mixture was poured into water (500 ml) and the organic phase was decanted. The aqueous phase was extracted with Et2O (2×300 ml) and the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml). After drying (MgSO4) and concentration a brown oily residue was obtained. This was chromatographed on silicagel (n-heptane/EtOAc 3/1). The pooled fractions produced after evaporation pure title compound (850 mg, 4.71 mmol, yield 31.4%) as brown needles.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:31][CH2:32][C:33]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:34]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (500 mg, 1.20 mmol) in tetrahydrofuran (10 mL) were added chloroacetyl chloride (168 μL, 1.45 mmol) and triethylamine (253 μL, 1.81 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (418 mg, 71%) as a pale-yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([I:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([I:12])[CH:6]=1)[CH2:11][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1cc(I)cc(C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(I)cc(CN2CCOCC2)c1
Temperature: 70 °C

Procedure:
Dissolve 1-tert-butyl-3-iodo-5-methyl-benzene (1 g, 3.6 mmol, prepared according to Chem. Soc. Perkin Trans. I, 1987, page 859-866) in carbon tetrachloride (20 mL) under nitrogen. Add NBS (0.71 g, 1.1 equiv.) followed by AIBN (0.06 g, 0.1 equiv.) and heat overnight at 70° C. Filter in the morning, washing with hexanes. Concentrate filtrate and use crude. Dissolve this residue in THF (10 mL) under nitrogen and cool to 0° C. Add morpholine (0.64 mL, 2 equiv.) dropwise via syringe and stir 5 minutes with cooling. Remove ice bath and let warm to room temperature. After one hour concentrate to dryness and purify the residue on silica gel (Hexanes→4:1 Hexanes Ethyl Acetate) to give product (0.785 g, 60% over 2 steps). MS (ES), m/z 360.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[NH:10][NH:11][C:12](OCC)=[O:13])=[C:6]([F:18])[C:5]([F:19])=[C:4]([F:20])[C:3]=1[F:21].C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:6]1[C:7]([N:8]2[C:9](=[O:17])[NH:10][NH:11][C:12]2=[O:13])=[C:2]([F:1])[C:3]([F:21])=[C:4]([F:20])[C:5]=1[F:19]
Reactant: CCOC(=O)NNC(=O)Nc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1[nH][nH]c(=O)n1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 70 °C

Procedure:
4-(Pentafluorophenyl)-1-carbethoxysemicarbazide, 2.13 g (0.0068M), and potassium carbonate, 0.938 g (0.0068M), are added to 75 ml of water. The mixture is heated at 70° C. under N2 about 12 hours. The solution is cooled in an ice bath and filtered to remove a trace of starting material. The pH of the solution is adjusted to pH 7 with concentrated HCl and extracted with ethyl acetate to remove a product which is less polar than the urazole in the TLC system, chloroform/ethyl acetate/acetic acid (5/5/1). The pH of the solution is reduced to 1 or 2 with concentrated HCl and then extracted with ethyl acetate. About 1/3 of a volume of toluene is added to the ethyl acetate and the solvents evaporated. The resulting crude solid weighs 0.569 g. The product is purified by two crystallizations from ethyl acetate/toluene (1/3 by vol). The yield of purified material is 0.476 g. It is recrystallized from H2O, mp 223°-225°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]([NH2:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O>CN(C)C=O.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]#[N:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(I)cc(C(N)=O)n1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(I)cc(C#N)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 129B (400 mg) in N,N-dimethylformamide (6 mL) and pyridine (0.6 mL) at (PC was added dropwise oxalyl chloride (0.31 mL). The mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate and washed with saturated NaHCO3 and water extensively. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, and eluted with dichloromethane to provide the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N+:18]([O-:20])=[O:19].CCOC(C)=O>CN(C=O)C>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 50 mL three-necked flask containing 10 mL of DMF and 0.592 g of phenol. The mixture is stirred at room temperature for 1 hour and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of DMF is added. The reaction medium is left at room temperature for 24 hours. 50 mL of EtOAc are added and the mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. The crude product is chromatographed on a silica cartridge (120 g) eluting with heptane/EtOAc (as an EtOAc gradient: 0 to 50%). 1.07 g of expected product 57 are obtained (yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[CH3:16])[C:10]([CH3:19])([CH3:18])[CH:9]=[C:8]2[CH3:20])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[CH3:16])[C:10]([CH3:19])([CH3:18])[CH2:9][C:8]2([C:5]1[CH:6]=[CH:7][CH:12]=[CH:13][CH:14]=1)[CH3:20])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(C)=CC(C)(C)N2C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Friedel-Crafts alkylation of benzene (60 ml) with 1-acetyl-1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (2.3 g) in the presence of AlCl3 (4.4 g) was performed according to the method described in example 3.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([SH:17])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC=CC=1>C(O)C.[OH-].[K+].CN(C)C(=O)C>[CH2:18]([S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Sc1nnc(-c2ccccc2)c2ccccc12
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-phenylphthalazine-1-thiol (238 mg; 1 mmol) in ethanol (30 ml), aqueous KOH (1 molar, 1 ml) and N,N-dimethylacetamide (30 ml) are added. After 10 minutes, benzylchloride (126 mg, 1 mmol) is added, and the mixture is stirred at room temperature overnight. The solution is concentrated, and water (20 ml) is added to the residual to give a precipitate. Filtration gives a light yellow solid (R1=phenyl, R2=phenyl, A=benzene, Y1=CH2, m=0, n=1, p=0, q=0).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O.CC(OC(C)=O)=O.C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[CH3:23][O:22][C:20]1[CH:19]=[C:16](/[CH:17]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)\[C:9]([OH:11])=[O:10])[CH:15]=[C:14]([O:13][CH3:12])[CH:21]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(/C=C(\C(=O)O)c2ccc(F)cc2)cc(OC)c1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of 4-fluorophenyl acetic acid (0.928 g, 6.02 mmol), 3,5 dimethoxybenzaldehyde (1 g, 6.02 mmole), Ac2O (1 ml) and triethylamine (0.5 ml) was heated at 100° C. for 12 hours. Upon completion (as monitored by TLC using hexane-ethyl acetate (3:2), the reaction mixture was cooled to room temperature and concentrated HCL (5 ml) was added. The precipitate was dissolved in CH2Cl2 (100 ml), washed with 10% aqueous NaOH (3×50 ml) and the basic solution was acidified (PH-1) with concentrated HCL. After stirring, the precipitate was collected and dried to get the product (1.5 g, 82.87%).