Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3](=[O:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[NH2:2].N(C(=O)C(NC1C=CC([C@H]2CC[C@H](CC(OC)=O)CC2)=CC=1)=O)N.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N:51]=[C:52]=S>>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]1[O:19][C:3]([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:11][CH:12]=2)=[O:5])=[N:1][N:2]=1
Reactant: Fc1ccccc1N=C=S
Reactant: CCCS(=O)(=O)c1ccc(NC(=O)C(=O)NN)cc1
Agent: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Product: CCCS(=O)(=O)c1ccc(NC(=O)c2nnc(Nc3ccccc3F)o2)cc1

Procedure:
Following the general procedure of Example 105 but using 2-hydrazino-2-oxo-N-[4-(propylsulfonyl)phenyl]acetamide (Intermediate 97) as starting material in place of methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclohexyl]acetate and using 2-fluorophenylisothiocyanate in place of 2-isothiocyanatopyridine the title compound was obtained as a solid; 1H NMR δ 0.90 (t, 3H), 1.46-1.62 (m, 2H), 3.18-3.27 (m, 2H), 7.12-7.20 (m, 1H), 7.22-7.35 (m, 2H), 7.87 (d, 2H), 7.99-8.10 (m, 3H), 10.90 (s, 1H), 11.50 (s, 1H); MS m/e MH+ 405.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.1 g) and triethylamine (1.0 ml), and 3,4-dichlorobenzoyl chloride (1.0 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH:8]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[P:9]([O:13][CH3:14])([O:11][CH3:12])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:18][O:17][P:15]([CH:8]([P:9]([O:11][CH3:12])([O:13][CH3:14])=[O:10])[CH2:7][C:6]([OH:21])=[O:5])([O:19][CH3:20])=[O:16]
Reactant: COP(=O)(OC)C(CC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COP(=O)(OC)C(CC(=O)O)P(=O)(OC)OC
Temperature: 25 °C
Yield: 105 %

Procedure:
To a solution of 3,3-bis(dimethoxyphosphoryl)propanoic acid t-butyl ester (2.5 g) in dichloromethane (10 ml) was added trifluoroacetic acid. Stirring at room temperature was followed by evaporation of the volatiles in vacuo. Three cycles of vacuum evaporation of 5 ml portions of toluene gave 2.2 g product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1>C(O)C.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(/C=C/C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CCC(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]-N-phenylacrylic acid amide (70 mg, 0.17 mmol, 1 eq) and Pd(OH)2 (2.5 mg) in ethanol (1 ml) and THF (0.4 ml) is stirred for 20 h at RT under a hydrogen atmosphere. Filtration and concentration of the reaction mixture on a rotary evaporator yields the desired product in quantitative yield (70 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:17])=O>C(Cl)(Cl)Cl.CN(C)C1C=CC(C)=CC=1>[Cl:17][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[CH:9]=2)[N:4]=[C:3]([CH2:2][Cl:1])[N:12]=1
Reactant: Cc1ccc2nc(CCl)[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Product: Cc1ccc2nc(CCl)nc(Cl)c2c1

Procedure:
2. 114.1 g of 2-chloromethyl-6-methyl-3H-quina-zolin-4-one are dissolved in 1.11 of chloroform and 120 ml of N,N,4-trimethylaniline, treated with 53 ml of phosphorus oxychloride and heated at reflux temperature for 20 h. The reaction mixture is evaporated in a vacuum. The residue is dissolved in 1.0 l of ethyl acetate and washed in succession with 2N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic extracts are concentrated to about 0.51 in a vacuum. The mixture is left to crystallize at -25° C. overnight. The crystal slurry is filtered, the crystals are washed with ethyl acetate (-25° C.) and dried in a vacuum. 89.9 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline of m.p. 111°-112° C. are obtained. A further 11.1 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline of m.p. 114°-116° C. can be obtained from the mother liquor.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: Cc1nccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nccnc1NN
Temperature: 90 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Hydrazine hydrate (9.66 mL, 311.14 mmol) was added to 2-chloro-3-methylpyrazine (CAS no. 95-58-9) (8 g, 62.23 mmol) in ethanol (25 mL). The resulting solution was stirred at 90° C. for 16 hours. The resulting solution was evaporated to dryness and the crude product was purified by crystallisation from toluene (125 mL) to afford 2-hydrazinyl-3-methylpyrazine (6.2 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 2.24 (3H, s), 7.61 (1H, d), 7.61 (1H, d), 7.87 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reaction time: 18 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (906 mg), sodium hydride (120 mg, of a 60% dispersion in mineral oil) and dry dimethylformamide (30 ml) was stirred at ambient temperature under nitrogen for 30 minutes. Ethyl bromoacetate (0.5 g) in dimethylformamide (10 ml) was added over 5 minutes at 0-5° C. with stirring. The mixture was stirred for 30 minutes at ambient temperature and then allowed to stand for 18 hours. The mixture was evaporated under vacuum and the residue was triturated with water and ether. The solid obtained was collected by filtration, washed with water and then with ether to give ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate, m.p. 161-161.3° C.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[NH:11][C:12]([CH:17]=O)=[C:13]([O:15][CH3:16])[CH:14]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[CH:3]=1.[CH3:26][C:27]1[NH:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.Cl>CO.CCOCC>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[CH:14]=[C:13]([O:15][CH3:16])/[C:12](=[CH:17]/[C:29]4[NH:28][C:27]([CH3:26])=[CH:31][C:30]=4[CH3:32])/[N:11]=3)[N:5]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[CH:3]=1
Reactant: COc1cc(-c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)[nH]c1C=O
Reactant: Cc1c[nH]c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC1=CC(c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)=N/C1=C\c1[nH]c(C)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a solution of tert-butyl 2-chloro-5-(5-formyl-4-methoxy-1H-pyrrol-2-yl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (11 mg) and 2,4-dimethyl-1H-pyrrole (3.5 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 10 min and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 60% EtOAc/hexanes to give 10 mg of the title compound as a dark solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:22](Cl)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(N(CC)CC)C>[CH:13]1([C:22]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: O=C(Cl)C1C=Cc2ccccc21
Solvent: CCN(CC)CC
Product: O=C(C1C=Cc2ccccc21)N1CCCCC1CN1CCCC1
Yield: 32.2 %

Procedure:
From 2.36 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.5 g of indene-1-carbonyl chloride and 4.88 ml of triethylamine. 1.4 g of 1-(indene-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine was obtained using a procedure similar to that in Example 2. In a mixed solvent of methanol, water and ethanol (2:1:1), this compound was catalytically reduced with 10% palladium on carbon. After completion of the reduction, the catalyst was filtered off. After evaporation of the solvent, the residue was treated with a 4N 1,4-dioxane solution of hydrogen chloride to obtain 1.05 g of the title compound, melting at 218°-221° C.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][C@@H:31]([C@H:33]([OH:35])[CH3:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:35][C@@H:33]([C@@H:31]1[CH2:30][O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:36])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32]1)[CH3:34]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (178 mg, 0.35 mmol) synthesized in Example (95b) was dissolved in methylene chloride (5 mL) and subsequently cooled to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 0.69 mL, 0.69 mmol) was added under nitrogen atmosphere. The temperature was raised naturally, followed by stirring at room temperature for 30 minutes, and subsequently a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (70 mL). The organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (132 mg, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[CH:17]1[O:29][C@H:28]([CH3:30])[C@H:23]([O:24]C(=O)C)[C@@H:18]1[O:19]C(=O)C)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]([C@H:17]2[O:29][C@H:28]([CH3:30])[C@H:23]([OH:24])[C@@H:18]2[OH:19])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC1O[C@H](C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H]1O[C@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
2,5,6-Trichlorobenzimidazole (221 mg, 1.0 mmol) was suspended in acetonitrile (15 ml) and the mixture was stirred at 40° C. BSA (365 μl, 1.5 mmol) was added, and the reaction mixture stirred for 15 min. A solution of 3 (260 mg, 1.0 mmol) in acetonitrile (5 ml) and TMSOTf (290 μl, 1.5 mmol) was added to the clear solution, and the mixture was allowed to stand at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved with dichloromethane (50 ml). The solution was washed with a saturated aqueous solution of sodium bicarbonate (10 ml) and with water (3×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up with the minimum amount of dichloromethane and chromatographed on a silica gel column (eluent: gradient of methanol (0-1.6%) in dichloromethane). Fractions having a UV-absorbing spot that also charred under H2SO4 and heating were pooled and concentrated to a foam which was dissolved in ethanol 90 (11 ml). To the stirred solution was added sodium carbonate (216 mg, 2.0 mmol) and the reaction mixture was stirred overnight. The mixture was then evaporated under reduced pressure, dissolved in a 2:1 mixture of ethyl acetate and dichloromethane, and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. Compound 4 crystallized from a 2% methanolic solution of dichloromethane (120 mg, 56%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([NH2:15])[N:4]2[N:3]=1.[O-:16][CH2:17][CH3:18].[Na+]>C(O)C>[CH2:17]([O:16][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([NH2:15])[N:4]2[N:3]=1)[CH3:18]
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c2c1CCCC2
Yield: 47.1 %

Procedure:
6-Chloro-7,8,9,10-tetrahydro-[1,2,4]triazolo[3,4-a]phthalazin-3-ylamine (W2.018, 1.0 g) was dissolved in ethanol (50 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (1.34 g) and stirred at 60° C. for 1 h. After the solvent had been drawn off, the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 491 mg of the title compound were obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14].CS(O)(=O)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][CH:16]([O:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12])[CH3:17])[CH3:14]
Reactant: O=C1N[C@H](c2ccccc2)[C@@H]1O
Reactant: C=COCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 3.41 g (20.9 mmol) of cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL of THF at 0° C. was added 5 mL of ethyl vinyl ether and 20 mg (0.2 mmol) of methanesulfonic acid. The mixture was stirred at 0° C. for 20 min, diluted with 20 mL of saturated aqueous sodium bicarbonate, and extracted with three 40 mL portions of ethyl acetate. The combined ethyl acetate layers wre dried over sodium sulfate and concentrated to give 4.87 g (99%) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one as a colorless oil.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)Cl>[I:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C:6]=1[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1n[nH]c(C)c1I
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C)c(I)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a 50 ml reaction vessel under argon, a solution of crude 4-iodo-3,5-dimethyl-1H-pyrazole x52 (1.15 g, 5.2 mmol) in 25 ml of dry CH2Cl2 is added to 4-methylbenzenesulfonyl chloride (1.18 g, 6.2 mmol). Pyridine (0.42 ml, 5.2 mmol) is added and the mixture is stirred for 16 h at room temperature. The organic phase is washed with water, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silicagel (CH2Cl2/hexane: 70/30 (v/v)) to afford 4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44 g).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[C:19]1[CH:20]=[C:21]2[O:27][C:26](=[O:28])[N:25]([CH3:29])[C:22]2=[N:23][CH:24]=1>O1CCCC1.[Zn].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>[CH3:29][N:25]1[C:22]2=[N:23][CH:24]=[C:19]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:20]=[C:21]2[O:27][C:26]1=[O:28]
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cn1c(=O)oc2cc(Cc3ccccc3)cnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Zinc (227 mg, 3.48 mmol) is suspended in tetrahydrofuran (10 ml) and 1,2-dibromoethane (0.22 ml, 0.2 mmol) is added. The mixture is heated at 60° C. for 3 minutes, the solution is allowed to cool until the temperature is 35° C., and trimethylsilyl chloride (0.06 ml, 0.5 mmol) is slowly added. Stirring is maintained for 30 minutes and then benzyl bromide (0.11 ml, 0.9 mmol) is added. Wait a further 30 minutes before introducing 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one (200 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium (4 mg). Heat at 50° C. for 20 minutes. After the solution has been cooled, the zinc is removed by filtration, the flitrate is taken up in water, and then a 10% aqueous hydrochloric acid solution is added until the aqueous phase becomes clear. Extraction is carried out with dichloromethane. The organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off under reduced pressure. The title product is purified by chromatography on silica gel (eluant: dichloromethane). The yield obtained is 91%. ##STR51##
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:17][CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH3:31]>>[C:20]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:8]([CH3:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:30][CH3:31])=[CH:12][C:11]=2[O:17][CH3:18])[C:6]=1[CH3:19])(=[O:22])[CH3:21]
Reactant: CCBr
Reactant: COc1cc(O)ccc1-n1c(C)c(C(C)=O)c(C(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 330 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[NH2:26][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:27]=[CH:28][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[C:22]([NH2:25])[N:21]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine (100 mg, 0.27 mmol) described in Example 13 in trifluoroacetic acid (3 mL) was added thioanisole (126 μL) at room temperature, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0° C., which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (72.4 mg, 95%).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][CH:24]([F:46])[C:25]1[O:29][C:28]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:27][CH:26]=1.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1>>[F:23][CH:24]([F:46])[C:25]1[O:29][C:28]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([NH:47][CH2:48][C:49]4[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=4)=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 59 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-((5-(difluoromethyl)furan-2-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 59% yield: mp 142-143° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.60-8.53 (m, 1H), 8.51-8.44 (m, 1H), 7.72-7.62 (m, 1H), 7.28-7.19 (m, 1H), 6.59-6.57 (m, 1H), 6.54 (t, JH-F=54.2 Hz, 1H), 6.33-6.59 (m, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.46 (s, 2H), 4.10-4.03 (m, 2H), 3.61-3.53 (m, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.1, 153.5, 151.4, 149.2, 148.8, 135.6, 133.9, 123.6, 117.1, 111.3, 109.7, 108.1, 105.0, 42.3, 42.0, 41.3, 40.4, 17.2; MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[N:20][CH:21]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:3][CH:4]2[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)=[N:20][CH:21]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
NaH (0.250 g, 6.25 mmol) was added to a mixture of ethyl 4-hydroxycyclohexanoate (0.916 ml, 5.68 mmol), and 5-bromo-2-fluoropyridine (0.585 mL, 5.68 mmol) in DMF (15 mL) at room temperature under an Argon atmosphere. The reaction mixture was heated to 80° C. for 2.5 hours. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 (50 mL), and extracted with ethyl acetate (50 mL) and diethyl ether (50 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (hexanes/ethyl Acetate) to afford ethyl 4-[(5-bromopyridin-2-yl)oxy]cyclohexanecarboxylate. MS ESI calc'd. for C14H19BrNO3 [M+H]+ 328 and 330. found 328 and 330.