Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17].Cl>O1CCCC1.O>[CH3:14][O:15][C:16]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
L-Valine (S) (0.213 mol) was dissolved in anhydrous tetrahydrofuran (645 mL) with NaHCO3 (0.640 mol) in water (645 mL). Methylchloroformate (0.235 mol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was acidified to pH 3 with 1N HCl. The aqueous layer was extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 1 as a white solid in 98% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.93 (d, J=7.00 Hz, 3H), 1.00 (d, J=7.00 Hz, 3H), 2.23 (m, 1H), 3.70 (s, 3H), 4.33 (m, 1H), 5.26 (brs, 1H), 8.50 (brs, 1H); and MS (ESI, EI+) m/z=176 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (42 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (134 mg) and diisopropylethylamine (65 mg) in methylene chloride (5 ml) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether, filtered and dried under vacuum to give the title product as a mixture of the 3R and 3S isomers (0.10 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.54-2.07 (m, 4H), 2.95 (s, 3H), 3.10-120 (m, 1H), 3.21-3.37 (m, 2H), 3.50-3.59 (m, 1H), 3.93 (s, 3H), 4.70 (m, 1H), 7.20-7.29 (m, 2H), 7.40-7.55 (m, 2H), 7.89 (s, 1H), 8.37 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][NH2:22]>C(O)C.N1C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[NH:22][CH3:21]
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Reactant: CN
Solvent: c1ccncc1
Solvent: CCO
Product: CNC1=Nc2ccccc2C(O)(c2ccccc2)C1(C)C
Reaction time: 4 h

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (1.43g., 0.005 mole) was dissolved in a mixture of a 33% w/v solution of methylamine in ethanol (40 ml.) and pyridine (0.79g.). The solution was stirred for four hours, after which the methylamine and ethanol were evaporated off to leave a residue, which was recrystallised twice from isopropyl alcohol to give the title compound (0.96g., m.p. 192° - 194° C).
Reaction SMILES: C1[C@H](NCC2[C:12]3[C:13]([N:15]=[C:16]([NH2:18])[NH:17][C:11]=3[N:10]([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=2)=[O:14])[C@@H](O)[C@@H](O)C=1.ClC(CC#N)=O.ClCC#N.C(OC)=O>>[NH2:18][C:16]1[NH:15][C:13](=[O:14])[CH:12]=[C:11]([NH2:10])[N:17]=1
Reactant: Nc1nc(=O)c2c(CN[C@H]3C=C[C@H](O)[C@@H]3O)cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Agent: N#CCC(=O)Cl
Agent: N#CCCl
Solvent: COC=O
Product: Nc1cc(=O)[nH]c(N)n1

Procedure:
A 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine(III) was prepared according to the method reported by Migawa, et al., “A Two Step Synthesis of the Nucleoside q Precursor 2-amino-5-cyanopyrrolo[2-3-dpyrimidine-4-one” Syn. Comm. 26:3317(1996) which involved the synthesis of chloroformylacetonitrile (110) from chloroacetonitrile (109) and methyl formate as shown in FIG. 19. Cyclocon-densation of compound 10 with 2,6-diamino-4-oxopyrimidine afforded to the key intermediate in 65-70% overall yield. Reductive amination of the 5-nitrile with the appropriate anilines or ethyl-p-aminobenzoyl-L-glutamate in the presence of Raney nickel and hydrogen at 50 psi for 5-6 hours afforded the desired analogues which were purified by column chromatography and were obtained in 20-62% yield. This yielded the product generally represented by compound 112. For the classical analogue, compound 407, which is the compound 112 where R2 is p-benzoyl-L-glutamate, saponification of the chromatographically purified ester afforded the desired product. This method was used to synthesize compounds 407-415, which are generally represented by compound 112 in FIG. 19 with the following substitutions:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.P(Cl)(Cl)(Cl)=O.O.CN([CH:19]=[O:20])C>>[N:1]1[CH:2]=[C:3]([CH:19]=[O:20])[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Imidazo[1,2-a]-pyrazine (0.30 g, 2.5 mmol) was dissolved in anhydrous DMF (10.0 mL) and added to a preformed solution of phosphorous oxychloride (0.26 mL, 2.8 mmol) in anhydrous DMF (10.0 mL). The solution was allowed to stir 72 h under nitrogen at RT. The solution was then poured into water (100 mL) and residual organics extracted with diethyl ether (3×30 mL). The remaining aqueous portion was concentrated to dryness under a nitrogen stream to yield the title compound (0.050 g). MS (ESI+) for m/z 148 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14]CC2C=CC=CC=2)=[C:9]([CH2:22][CH3:23])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH2:22][CH3:23])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.3 %

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid tert-butyl ester (9.02 g, 27.6 mmol) in THF (50 mL) and ethanol (50 mL), Pd/C (400 mg, 10% Pd) is added. The slurry is stirred at rt for 24 h under 1 bar of H2. The catalyst is removed by filtration and the filtrate is concentrated, dissolved again in THF (50 mL) and ethanol (50 mL), and again treated with Pd/C (400 mg, 10% Pd). The slurry is stirred at rt for 24 h under 1 bar of H2. The catalyst is again removed by filtration and the filtrate is concentrated and dried to give 3-ethyl-4-hydroxy-5-methyl-benzoic acid tert-butyl ester as a pale yellow oil (7.13 g). LC-MS: tR=1.01 min; 1H NMR (CDCl3): δ 1.28 (t, J=7.8 Hz, 3H), 1.61 (s, 9H), 2.30 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 5.13 (br s, 1H), 7.67 (s, 1H), 7.69 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:22](/[S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:26])([F:11])[F:25])[CH:14]=2)(=[O:21])=[O:20])\[C:23]#[N:24])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1cccc(C(F)(F)F)c1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and 3-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[3-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: C([N:3](CC)[CH:4]=[CH:5][C:6]([C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=O)C.[NH2:30]N>CO.C(O)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:17]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:6]2[NH:30][N:3]=[CH:4][CH:5]=2)[CH:9]=1)=[O:18]
Reactant: CCN(C=CC(=O)c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OC)CC
Reactant: NN
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccn[nH]1
Yield: 78.1 %

Procedure:
To a solution of 1-[3-(3-Diethylamino-acryloyl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (1.5 g, 3.72 mmole) in methanol/acetic acid (50 mL/2.0 mL) mixture was added hydrazine (0.82 g, 37.22 mmole). The reaction mixture was refluxed at 55 C for 20 hrs. The methanol/acetic acid was evaporated from the reaction mixture and the solid was triturated with ether/methanol. The solid was filtered and washed with ether. Next, the solid was dried in vacuo to furnish a colorless solid (1.0 g, 76%). LCMS m/z (%)=345 (M+H, 100), 1H NMR (Bruker, 400 MHz, DMSO-d6) δ: 13.0 (bs, 1H), 8.89 (bs, 1H), 8.37 (bs, 1H), 8.09-810 (d, J=6.05 Hz, 1H), 7.74-7.97 (bs, 1H), 7.52-7.64 (bs, 1H), 7.39-7.40 (d, J=5.94 Hz, 1H), 7.27-7.32 (m, 2H), 7.01-7.09 (m, 2H), 6.73 (s, 1H), 3.82 (s, 3H) (major tautomer).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)(C)[CH3:12].ICC>C1COCC1>[CH2:11]([C:5]1[O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH3:12]
Reactant: [Li]C(C)(C)C
Reactant: c1ccc2occc2c1
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2ccccc2o1

Procedure:
2-Ethylbenzo[b]furan was prepared by the method of example 40A with benzo[b]furan (7.3 mmols), 0.86 g) t-BuLi (1.7 m, 9.4 mmols) iodoethane (4 mmols, 0.9 mls) and THF (15 ml). 1.0 g (95%) of a yellow liquid was isolated.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH:23]2[CH2:25][CH2:26][CH:20]1[CH2:21][CH2:22]2>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([CH2:17][CH2:18][N:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]2[CH2:21][CH2:22]3)[C:8]#[N:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(c1ccccc1)c1cccnc1
Reactant: ClCCN1CC2CCC1CC2
Solvent: Cc1ccccc1
Product: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1cccnc1

Procedure:
α-Phenyl-3-pyridylacetonitrile (U.S. Pat. No. 3,225,054) is reacted with 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in toluene to provide 2-phenyl-2-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. This nitrile is reacted with sodium azide in DMF containing lithium chloride to provide 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. Reaction this tetrazole with acetic anhydride in pyridine provides 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, the oxalate salt melts at 171°-172° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH-:14].[Na+]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(S)cnn(C(C)(C)C)c1=O
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To 75ml of ethanol were added 17.0 g (0.085 mol) of 2-tert.-butyl-5-chloro-4-methyl-3(2H)-pyridazinone and 8.5 g (0.106 mol) of 70% sodium hydrosulfide, and the mixture was stirred under reflux for 4 hours. After cooling, the mixture was poured into 300 ml of ice-water and extracted with 200 ml of ethyl ether. The ether layer was washed with 100 ml of water and dried over anhydrous sodium sulfate. The solvent was then distilled off therefrom to give 16.3 g of a crude product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]2[CH:7]=[CH:8][C:9]3[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]=3[C:4]=2[CH2:3]1.[Br:16]Br.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)C>[Br:16][C:7]1[C:5]2[CH2:6][N:2]([CH3:1])[CH2:3][C:4]=2[C:10]2[NH:11][C:12](=[O:15])[C:13](=[O:14])[C:9]=2[CH:8]=1
Reactant: BrBr
Reactant: CN1Cc2ccc3c(c2C1)NC(=O)C3=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(Br)cc3c(c2C1)NC(=O)C3=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 1,6,7,8-tetrahydro-7-methylbenzo[2,1-b:3,4-c']dipyrrole-2,3-dione (0.5 g, 2.48 mmol) in water (20 ml) was added a solution of bromine (0.7 ml) in ethanol (5 ml). After 5 hours stirring at room temperature the reaction was completed and pH was adjusted to 8 with sat Na2CO3. The precipitated product was filtered off and washed with water, M.p. >300° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][CH:13]=1)=[O:11])[CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>COCCOC.CCOC(C)=O.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>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:15]1[S:16][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13][N:14]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: OB(O)c1ccccc1F
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2ccccc2F)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
Tetrakis(triphenylphosphine)palladium (O) (0.58 g, 0.5 mmol), and a degassed solution of 2.0M Na2CO3 (10 mL) are added to a degassed solution of 2-bromo-1,3-thiazole-5-carboxylic ethyl ester (1.18 g, 5.0 mmol) and 2-fluorophenylboronic acid (0.77 g, 5.5 mmol) in DME (10 mL). The resulting suspension is stirred under argon at 80° C. for 4 hours. The reaction mixture is cooled, diluted with EtOAc, and then washed with two portions of 1.0 M NaOH, then one portion of brine. The combined organic phases are concentrated in vacuo and the resulting oil purified with flash chromatography. Yield 37%. HRMS (FAB) calculated for C12H10FNO2S+H 252.0495, found 252.0496.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(/[CH:15]=[CH:16]/[C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:19][C:17]([CH3:18])(/[CH:16]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC(=O)/C=C/c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(O)/C=C/c1ccccc1
Yield: 100 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.73 g (5 mmol) of trans-4-phenyl-3-buten-2-one in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 8.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.17 g of the desired product (yield 100%). 1H NMR (CDCl3), (ppm): δ 1.23 (3H, t, J=7.1 Hz), 1.42 (3H, s), 2.66 (2H, dd, J=19.5, 15.6 Hz), 4.05 (1H, s), 4.15 (2H, q, J=7.1 Hz), 6.27 (1H, d, J=16.0 Hz), 6.64 (1H, d, J=16.0 Hz), 7.20-7.39 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([N:28]1[CH2:33][C:32](=O)[O:31][C:30](=[O:35])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:21]([N:28]1[CH2:33][C:32](=[O:31])[N:1]([C:2]2[CH:3]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:17]=[CH:18][C:19]=2[F:20])[C:30](=[O:35])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)O1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(Cc2ccccc2)CC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (2.51 g, 9.3 mmol; prepared in a manner similar to that described in Example 23), 4-benzylmorpholin-2,6-dione (2.3 g, 11.2 mmol) and toluene (15 ml) was heated under reflux for 20 hours, then the solvent was removed in vacuo. The residue was dissolved in dimethylacetamide (15 ml) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (3 g, 9.3 mmol) and diisopropylethylamine (1.63 ml, 9.3 mmol) were added sequentially. The mixture was stirred at ambient temperature for 2 hours, then it was added dropwise to stirred, ice-cold water (300 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (4.01 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.6 (s, 4H) (2×ring CH2) 3.75 (s, 2H) (NCH2Ph), 4.35 (s, 2H) (ArCH2—), 7.17–7.5 (m, 8H) (8×ArH), 7.75–8.0 (m, 3H) (3×ArH), 8.25 (d, 1H) (ArH), 12.6 (s, 1H) (CONH); m/z (M+H)+ 457, 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2c(c1)C=C(C=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (4.0 g, 22.7 mmol) and potassium carbonate (6.26 g, 45.3 mmol) in 80 ml of DMF is treated with n-hexyl bromide (4.5 g, 27.2 mmol). The mixture is stirred overnight at room temperature. Additional potassium carbonate (3.1 g, 22.4 mmol) and n-hexyl bromide (1.0 g, 6.1 mmol) are added and, after another overnight reaction, no more starting material is detected in the reaction mixture. The reaction mixture is diluted with water and extracted three times with dichloromethane. The combined organic phases are dried (MgSO4) and evaporated. Purification by silica gel chromatography (10% ethyl acetate/hexane) yields 6-(n-hexyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 36°-38° C., which is converted as described above to 3-(N-hydroxyaminomethyl)-6-(n-hexyloxy)-2H-1-benzopyran.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[S:13][C:6]=12.[H-].[Na+].[CH2:28](Cl)[O:29][CH3:30]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:28][O:29][CH3:30])[CH:18]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4c[nH]cn4)sc23)c(F)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a solution of 7-(2-fluoro-4-nitrophenoxy)-2-(1H-imidazol-4-yl)thieno[3,2-b]pyridine (93) (WO 2006010264) (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0° C. was added NaH (40 mg, 60% dispersion in oil, 1.0 mmol). The mixture was allowed to warm to room temperature over 0.5 h then re-cooled to 0° C. MOMCl (74 mg, 1.1 eq, 0.92 mmol) was added and mixture was allowed to warm to room temperature over 20 hours, concentrated and partitioned between EtOAc and water. The EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (100% hexane to 100% acetone) to afford the title compound 94 (126 mg, 36% yield). MS (m/z): 401.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH2:11](I)[CH3:12]>>[Cl:1][C:2]1[N:7]([CH2:11][CH3:12])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: CCI
Product: CCn1c(Cl)cc(=O)n(C)c1=O

Procedure:
The sub-title compound was prepared by the method of example 9, part a) using 6-chloro-3-methyl uracil and ethyl iodide.
Reaction SMILES: O=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:15])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.O.[CH3:24][NH:25][C:26](=[S:29])[NH:27][NH2:28]>CO>[CH3:24][NH:25][C:26]([NH:27][N:28]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])=[S:29]
Reactant: CNC(=S)NN
Reactant: O=C(Nc1ccccc1)OCCCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=S)NN=C(CCCOC(=O)Nc1ccccc1)c1ccccc1
Reaction time: 21 h
Yield: 83.9 %

Procedure:
Phenyl-carbamic acid 4-oxo-4-phenyl-butyl ester (2.80 g, 9.88 mmol), prepared in the previous step, was suspended in 60 ml of methanol and the mixture warmed to dissolve the solid. While still warm 2.7 ml of 1 N HCl, 2.7 ml of water and 4-methyl-3-thiosemicarbazide (1.04 g, 9.92 mmol) were added and the reaction stirred under nitrogen for 21 hours. The solid formed was removed by filtration and dried under high vacuum to give the title compound (3.07 g, 84%) as a white solid, mp 155-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.C1C2C=CC3C(=CC([CH:38]=[O:39])=C4C=3C=CC=C4)C=2C=CC=1.C(Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH:38]=[O:39])[CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: Clc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
6-Chlorochrysene (Cambridge Chemical, Inc., 70 g, 0.266 mol) was formylated according to the proceudre outlined in 1A, except that CH2Cl2 (2.5 L) was used as the reaction solvent. Chromatography on a plug of SiO2 (1 kg) using EtOAc as the eluting solvent afforded after removal of solvent and drying 19.1 g (25%) of 12-chloro-6-chrysenecarbaldehyde mp 255°-257°, (EtOAc).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].CCOCC>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:20][C:23](=[O:25])[CH3:24])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCc1c(OC(C)=O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a stirred solution of 0.8 g of racemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of pyridine was added 0.37 ml of acetic anhydride. The solution was stirred at room temperature for 5 hours then poured into ice-water and worked up with ether in the usual manner (the combined ether extracts were additionally washed with 1N hydrochloric acid and saturated sodium bicarbonate solutions). The oily product (1.0 g) was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate afforded 0.575 g (63.3%) of racemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a pale-yellow oil.