Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:10])=[CH:4][N:3]=1.[C:21]([O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30])([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]([C:5]1[C:6]([OH:8])=[N:7][C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:32])=[N:3][CH:4]=1)=[O:10]
Reactant: Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(=O)Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of 2-amino-N-[(2,4-dichlorophenyl)methyl]-4-hydroxypyrimidine-5-carboxamide (317 mg), 4-tert-butoxy-4-oxobutanoic acid (529 mg), and N,N-diisopropylethylamine (1.06 mL) in N,N-dimethylformamide (8 mL), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1160 mg) was added at room temperature, and the mixture was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature. Then, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was stirred for 10 minutes. The resulting suspension was filtered. The product collected by filtration was washed with water and dried under reduced pressure to obtain the title compound (430 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH:12]1[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH2:24]Br>CN(C=O)C>[CH2:1]([N:8]1[CH2:24][CH2:23][N:11]([CH:12]2[CH:17]3[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]3)[CH2:13]2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: O=C(NCc1ccccc1)NC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)CCN1C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
To a solution of 1-benzyl-3-(quinuclidin-3-yl)urea (260 mg, 1.00 mmol) in DMF (30 ml) was added NaH [60% dispersion in mineral oil] (96 mg, 2.4 mmol) with ice bath cooling. The resultant mixture was stirred for 2 h before BrCH2CH2Br (0.75 g, 4.0 mmol) was added carefully. The reaction was stirred for an additional 18 h at about 25° C. After HPLC separation, the aqueous layer was lyophilized and purified by prep-TLC (CHCl3 to 5% MeOH in CHCl3 to 5% 2N NH3(MeOH) in CHCl3) to give the title compound (81 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.19-7.22 (m, 4H), 7.11-7.14 (m, 1H), 6.09 (dd, J=15.2, 8.4 Hz, 1H), 5.45 (dd, J=15.6, 4.0 Hz, 1H), 5.30 (dd, J=8.0, 3.6 Hz, 1H), 4.17-4.29 (m, 4H), 3.66-3.75 (m, 2H), 3.47 (d, J=12.4 Hz, 1H), 3.19-3.27 (m, 3H), 2.34 (br s, 1H), 2.22 (d, J=2.4 Hz, 1H), 1.92 (br s, 2H), 1.75 (br s, 1H) ppm. 13C NMR (400 MHz, CDCl3) δ 158.9, 141.1, 140.4, 128.7, 127.4, 127.3, 113.6, 63.6, 57.1, 56.0, 45.6, 43.9, 25.2, 23.0, 18.8 ppm. Purity: 93.8% HPLCMS (210 nm); retention time 1.84 min; (M+1) 286.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:18]([C:20]([CH3:22])=[O:21])[CH3:19].[Na]>C(O)C>[C:20]([C:22]#[C:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)(=[O:21])[CH2:18][CH3:19]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Reactant: CCC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C#CC(=O)CC)cc1

Procedure:
Following the procedure in Example 1 using 7.1 parts of ethyl 2-(4-formylphenoxy)-2,2-dimethylacetate and 4.5 parts of methyl ethyl ketone in 10 parts by volume of ethanol containing 0.1 part of sodium metal provides ethyl 2-[4-(2-propionylethynyl)phenoxy]-2,2-dimethylacetate as an oil (1.5522). This compound has the following structural formula. ##SPC13##
Reaction SMILES: Cl.[OH:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1.[CH2:19](O)[CH3:20]>>[CH2:19]([O:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1)[CH3:20]
Reactant: CCO
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(O)O2
Agent: Cl
Product: CCOC1Cc2cc3ccc(=O)oc3c(OC)c2O1
Reaction time: 2 h

Procedure:
Absolute ethanol was saturated with gaseous hydrogen chloride at 0°. To this solution, 5.0 g. (0.214 mole) of 2-hydroxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one was added, and the reaction was allowed to proceed at 25° for 2.0 hours. The solvent was evaporated, and the residue was passed through a column consisting of 150 g. silica (upper layer) and 50 g. of neutral alumina (lower layer) using benzene/ethyl acetate, 4:1. Fractions containing the product were combined and evaporated to afford pure 2-ethoxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one as a white solid. Recrystallization from ethanol yielded an analytical sample, mp 119°-120°.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:14]2=[O:31])=[C:10]([F:34])[CH:9]=1)=O)(=[O:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrC(Br)(Br)Br>C(Cl)Cl>[F:34][C:10]1[CH:9]=[C:8]([C:6]2[O:3][C:1]([CH3:2])=[N:4][N:5]=2)[CH:33]=[CH:32][C:11]=1[O:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)[C:14]1=[O:31]
Reactant: CC(=O)NNC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Agent: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)o1
Temperature: 0 °C
Yield: 73.6 %

Procedure:
(S)-tert-butyl 4-(3-(4-(2-acetylhydrazinecarbonyl)-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (960 mg, 2.01 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. under nitrogen. 1H-imidazole (341 mg, 5.02 mmol), triphenylphosphine (1158 mg, 4.41 mmol) and perbromomethane (1464 mg, 4.41 mmol) were added and the reaction was allowed to warm to ambient temperature overnight. The reaction was partitioned between water and EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (680 mg, 1.48 mmol, 73.6% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].S(OC)(O[CH3:31])(=O)=O>C(O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH3:31])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccc2cccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-benzyloxy-1H-indole (Ref: Dobson, D; Todd, A; Gilmore, J. Synth. Commun. (1991), 21(5), 611–17) (1.29 g, 5.78 mmol) in ethanol (30 mL) was added potassium hydroxide (0.41 g, 7.23 mmol) and dichloromethane (5 mL) of to help solubilize the starting material. The resulting solution was allowed to stir at room temperature for 10 min before evaporating the solvent in vacuo. The residue was taken up in acetone (75 mL) and sodium sulfate (4.9 g, 34.7 mmol) was added followed by dimethyl sulfate via syringe (0.62 mL, 6.3 mmol). The solution was stirred for 1 h, then filtered and evaporated in vacuo. This material was purified by flash chromatography, eluting silica gel with hexane:ethyl acetate (100:0 to 10:1) to give the product. (1.12 g, 82%); Mass spectrum (ion spray): m/z=238.1 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:40])[C@H:5]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:34][C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)[CH2:27][C:28]2[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=2)=[CH:21][CH:20]=1)[CH3:17])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])C>Cl.O>[CH2:13]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][CH2:6][C@@H:5]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:34][C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)[CH2:27][C:28]2[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=2)=[CH:21][CH:20]=1)[CH3:17])[C:4]([OH:40])=[O:3])[CH2:14][CH3:15]
Reactant: CCCN(CCC)CCC[C@H](C(=O)OCC)N(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Solvent: O
Product: CCCN(CCC)CCC[C@H](C(=O)O)N(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (200 mg) of the compound obtained in EXAMPLE 96-4 was dissolved in concentrated hydrochloric acid (3 ml) and water (0.2 ml), and the whole was refluxed under heating for 4 hours. After completion of the reaction, the solvent was distilled off, thereby obtaining a hydrochloride (175.1 mg) of the subject compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:10][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][NH2:32]>O.O1CCOCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:32][CH3:31])[CH:7]=3)[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(F)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: CN
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)ccn1
Yield: 58 %

Procedure:
500 mg (1.24 mmol) of 2-fluoro-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine were dissolved in a mixture of 6 ml of methylamine 40% in water and 12 ml of dioxane and the mixture submitted to microwave irradiation at 130° C. for 2 hours in a sealed vial. The solvent was the removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 9/1), giving 300 mg (58%) of the title compound.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:14][C:13]=1[CH2:31][CH3:32])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[CH2:31][CH3:32]
Reactant: CCc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 18 h
Yield: 61 %

Procedure:
tert-Butyl 4-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I39) (0.500 g, 1.14 mmol) was dissolved in ethanol (20 mL), and a slurry of 10% Pd/C (0.25 g) in ethanol (2 mL) was added. The mixture was stirred under hydrogen for 18 hours, then filtered through celite, washing the celite with ethanol (30 mL). The combined filtrates were evaporated, and chromatography (12 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I40) (0.212 g, 61% yield) as a pink syrup; 1H NMR (400 MHz, CDCl3) δ 690 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.0, 2.1 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.21 (s, 2H), 3.55 (s, 2H), 2.78 (t, J=12.2 Hz, 2H), 2.59-2.46 (m, 3H), 1.78 (d, J=13.2 Hz, 2H), 1.66-1.53 (m, overlaps with water). 1.48 (s, 9H), 1.25 (t, J=7.5 Hz, 3H). LCMS Method C: rt 5.33 min; m/z 249.2 [M-tBu+2H]+, 205.2 [M-Boc+2H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:32]3[CH2:33][CH2:34][CH2:35][C@@H:30]([OH:29])[CH2:31]3)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCCNC1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CN2CCC[C@@H](O)C2)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 5b, 100 mg, 0.23 mmol) in DMF (2 mL) is added (R)-3-hydroxypiperidine hydrochloride (96 mg, 0.70 mmol) and N-ethyldiisopropylamine (362 μL, 2.1 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10](O)(=O)[C:11](C)([CH3:13])[CH3:12].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[NH4+].[OH-]>OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:11]([C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=1)([CH3:13])([CH3:12])[CH3:10]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)c1ccc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 38 %

Procedure:
2-Chloronicotinonitrile (2.1 g, 15.2 mmol), pivalic acid (7.7 g, 75.8 mmol) and silver nitrate (0.5 g, 3.0 mmol) were suspended in 10% aqueous H2SO4 (20 ml). Ammonium persulfate (6.9 g, 30.3 mmol) in H2O (40 ml) was added to the mixture. The mixture was stirred at r.t. for 36 h. NH4OH was added until pH=9. The product was extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 9:1) to give the title substance in 38% yield.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[I:20]N1C(=O)CCC1=O>>[F:9][C:10]1[C:18]([F:19])=[CH:17][C:16]([I:20])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1cccc(F)c1F
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C(O)c1cc(I)cc(F)c1F
Temperature: 2.5 °C
Reaction time: 0.05 h
Yield: 82.8 %

Procedure:
A 500 mL, 3 neck round bottom flask, equipped with an overhead stirrer is charged with trifluoromethanesulfonic acid (100 g), cooled to 0-5° C. in an ice bath, and treated with 2,3-difluorobenzoic acid (18.96 g). To this mixture is added N-iodosuccinimide (32.4 g) portion-wise over a 10 min period. After an additional 3 min, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. After a total of 5 h, the reaction mixture is poured into 600 mL of vigorously stirred crushed ice/water containing 100 mL of 10% sodium sulfite solution. The beige colored precipitate is collected, washed with ice water and dried at 50° C. in a vacuum oven overnight to produce 28.2 g (83%) of the title compound. Physical characteristics: 1H NMR (CDCl3) δ10.35, 8.12, 7.76; MS (ESI−) m/z 283 (M−H)−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared from 4-fluoronitrobenzene (2 g) and 1,2,4-triazole (1 g) as described in Description 61 to give a white solid (2.6 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:47]1[CH2:52][CH2:51][N:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1.[O-]CC.[Na+].Cl>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23]([N:24]5[CH2:25][CH2:26][N:27]([S:62]([C:59]6[CH:60]=[CH:61][C:56]([S:53]([N:50]7[CH2:51][CH2:52][O:47][CH2:48][CH2:49]7)(=[O:55])=[O:54])=[CH:57][CH:58]=6)(=[O:63])=[O:64])[CH2:28][CH2:29]5)=[O:30])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCN(S(=O)(=O)c2ccc(S(=O)(=O)N3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
To a mixture N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.040 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.028 mL, 0.160 mmol) followed by 4-(morpholinosulfonyl)benzene-1-sulfonyl chloride (13.00 mg, 0.040 mmol) and the resulting solution stirred at room temperature for 24 h. The mixture was treated with sodium ethoxide (0.015 mL, 0.040 mmol) and stirred at room temperature for 1 h. The reaction was diluted with water and dichloromethane. The aqueous phase was acidified with 1N HCl and the product extracted into the organic phase. The organic phase was concentrated and the residue was triturated with methanol. The white solids were collected by filtration to give the title compound (2.2 mg, 7% yield). (M+H) calcd for C35H41FN7O10S2: 802.23; found: 802.84. 1H NMR (400 MHz, CDCl3) δ: 11.94 (1 H, s), 8.70 (1 H, s), 8.17 (1H, t, J=6.02 Hz), 7.91 (4 H, s), 7.31 (2 H, dd, J=8.41, 5.40 Hz), 6.96 (2 H, t, J=8.66 Hz), 4.51 (2 H, d, J=6.02 Hz), 4.04-4.22 (4 H, m), 3.67-3.80 (4 H, m), 3.44-3.65 (2 H, m), 2.88-3.20 (8 H, m), 2.50-2.67 (2 H, m), 2.46 (1 H, brs), 1.79-2.06 (4 H, m), 1.58-1.77 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].Cl>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]1[C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=[CH:20][N:21]1[C:4]2=[O:6]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cccn2c(=O)c3cc(I)ccc3nc12
Temperature: 0 °C

Procedure:
A solution of 2-amino-5-iodobenzoic acid (25 g; 95.0 mmol), 2-chloronicotinic acid (14.97 g; 95.0 mmol), concentrated hydrochloric acid (3.17 ml; 38 mmol), and ethanol (150 ml) was heated at reflux for 18 hours, then cooled to 0° C. The precipitate was collected by filtration and the filter cake was washed with fresh ethanol (200 ml). The filter cake was dried in vacuo over phosphorous pentoxide to provide product as a yellow solid: 12.0 g.
Reaction SMILES: C([Li])CCC.[CH:6]1[N:7]=[CH:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=12.[CH2:15]=[O:16].Cl>CCCCCC.CCOCC>[OH:16][CH2:15][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:6][N:7]=1
Reactant: C=O
Reactant: c1ncn2c1CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OCc1ncc2n1CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.58 molar n-butyl lithium in n-hexane (49 ml.) was added over 0.5 hour to a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60° under nitrogen. After 3 hours, gaseous formaldehyde generated by the thermal condensation of paraformaldehyde (6.9 g.) was passed into the red solution. The mixture was allowed to warm to room temperature overnight, acidified with hydrochloric acid and extracted with chloroform. The aqueous layer was basified with an excess of saturated sodium carbonate solution and extracted with chloroform. Concentration and recrystallisation of the residue from ethanol-ethyl acetate-petroleum ether afforded 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (7.7 g.) m.p. 188-199°.
Reaction SMILES: [C:1]1([C:7]2[CH:22]=[CH:21][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([OH:20])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC2N=C(CC3[O:36]C(O)=NN=3)SC=2C=1.OO>C(O)(=O)C.O>[OH:20][C:18]1[O:19][C:15]([C:14]([C:12]2[S:13][C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:22]=[CH:21][C:10]=3[N:11]=2)=[O:36])=[N:16][N:17]=1
Reactant: Oc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reactant: Oc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1nnc(O)o1)c1nc2ccc(-c3ccccc3)cc2s1
Temperature: 50 °C
Yield: 80 %

Procedure:
To a suspension of 5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-ol (25 mg, 0.081 mmol) in acetic acid (1 mL) (prepared according to a similar procedure described for Compound 51a) was added 30% hydrogen peroxide in water (0.17 mL, 1.6 mmol) and the reaction mixture heated at 50° C. for 16 h. The reaction mixture was allowed to cool to rt then diluted with water and filtered. The solid was washed with water and rinsed with ether, then dried under vacuum to afford Compound 88a (21 mg, 80% yield) as a yellow solid. LCMS=0.96 min using analytical method (M), 324.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=1.5 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.5, 1.8 Hz, 1H), 7.89-7.79 (m, 2H), 7.63-7.50 (m, 2H), 7.50-7.41 (m, 1H), 5.76 (s, 1H).
Reaction SMILES: [S:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[NH:3]1.[C:13]1([C:19](S)([CH3:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+]>[C:13]1([C:19]([S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([OH:12])[N:3]=2)([CH3:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(S)c1ccccc1
Reactant: O=C1Cc2ccccc2C(=S)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(O)cc2ccccc12)c1ccccc1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a 50 mL round bottom flask was added 1-thioxo-1,4-dihydro-2H-isoquinolin-3-one (250 mg, 1.41 mmol), and 2-phenylpropan-2-thiol (192 mg, 1.41) followed by a solution of TFA (10 mL, 20% v/v in DCM). The reaction mixture was stirred under Ar for 1 h, neutralized with NaHCO3 (100 mL, sat. aq.), and then extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and then the solvent was removed by rotary evaporation to yield a crude residue. The crude residue was purified via silica gel chromatography to provide the title compound as an orange solid (188 mg, 0.636 mmol, 45%). 1H NMR (400 MHz, CDCl3): δ ppm 8.11 (d, J=8.79 Hz, 1H), 7.55 (t, J=7.47 Hz, 3H), 7.42-7.50 (m, 1H), 7.14-7.29 (m, 5H), 6.74 (s, 1H), 1.95 (s, 6H). LC/MS m/z 296 [M+H].
Reaction SMILES: CI.[F:3][CH:4]([F:13])[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[C:14]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:3][CH:4]([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:14])[CH:7]=1
Reactant: Oc1cccc(OC(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OC(F)F)c1
Yield: 2114.7 %

Procedure:
2.67 g of methyl iodide was stirred on ice in a suspension of 2.00 g of 3-difluoromethoxy phenol and 2.60 g of K2CO3 in DMF (10 ml) at room temperature for two hours. Water was added to the solution and the resulting mixture was extracted with Et2O; the organic layer was washed with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure obtained 46.0 g of the title compound (crude form).