Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](F)=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].O>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:6][CH2:5][CH:4]([F:7])[F:3])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: OCC(F)F
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 122.5 %

Procedure:
0.6 g 60% NaH was added in portions to a solution of 1.23 g 2,2-difluoroethanol in 20 ml THF and stirred at room temperature for 15 minutes. 2.02 g (3-Chloro-4-fluoro-phenyl)-(7-fluoro-6-nitro-quinazoline-4-yl)-amine was added as a solid and the mixture was heated to 65° C. for 1 hour, then cooled to room temperature. Water was added and the THF was removed under vacuum. The mixture was sonicated and the resulting solids collected by filtration and dried under vacuum overnight to give 2.93 g of crude (3-Chloro-4-fluoro-phenyl)-[7-(2,2-difluoro-ethoxy)-6-nitro-quinazolin-4-yl]-amine.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16](OC(C)(C)C)=[O:17].[O-]CC.[Na+]>CCO.O>[OH:17][N:16]=[C:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: CC(C)(C)ON=O
Reactant: O=C(Cc1cccnc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(C(=NO)c1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of 1-phenyl-2-(pyridine-3-yl)ethanone (0.494 g, 2.505 mmol) in EtOH (36.8 mL) at room temperature was added tert-butyl nitrite (0.586 mL, 4.93 mmol) dropwise followed by sodium ethoxide (0.435 g, 2.55 mmol). The reaction was stirred at room temperature overnight. Upon completion, the solvent was evaporated to give a yellow oil. This oil was then diluted with H2O (25 mL), extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (0.214 g). LCMS m/z=227.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])=[CH:5][NH:4][N:3]=1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O>O1CCOCC1>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:6]1[CH:5]=[N:4][N:3]2[C:15]([OH:20])=[CH:16][C:17]([CH3:19])=[N:1][C:2]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1n[nH]cc1-c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: Cc1cc(O)n2ncc(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
3-Amino-4-(2,4-dichlorophenyl)pyrazole and ethyl acetoacetate (2 equivalents) were dissolved in dioxane and heated under reflux overnight. The mixture was concentrated in vacuo and diluted with ethyl acetate. An off-white solid formed after 2 days standing was collected by vacuum filtration, yielding 3-(2,4-dichlorophenyl)-5-methyl-7-hydroxypyrazolo[2,3-a]pyrimidine (intermediate 1).
Reaction SMILES: [BrH:1].[CH:2]1([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=3[OH:19])[C:10]2=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>[Pd].O>[BrH:1].[CH:2]1([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=3[OH:19])[CH:10]2[OH:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1c2ccc(O)c(O)c2CCC1NC1CCCCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NC1CCCCC1)C2O

Procedure:
Using 1.91 parts of 5 % palladium-on-carbon, 1.89 parts of 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 50 volume parts of water is subjected to catalytic reduction at ordinary temperature and pressure. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst and the filtrate is freeze-dried. The residue is recrystallized from a mixture of ethanol and ethyl acetate, whereby 2-cyclohexylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained as colorless crystals. Yield 1.38 parts; melting point: 230°-236° C (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C2OCCO2)cc1

Procedure:
4-Cyanobenzaldehyde (500 mg, 3.81 mmol), ethylene glycol (828 mg, 13.34 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the residue dissolved in chloroform (50 ml) and washed with saturated sodium bicarbonate solution (2×25 mL) and brine (1×25 mL). The organic phase was then dried (Na2SO4) and evaporated to give 4-(1,3-dioxolan-2-yl)benzenecarbonitrile (40) as an oil which solidified to a white solid (633 mg, 95%). 1H NMR (CDCl3, 300 MHz): δ 4.04, t (1.8 Hz), OCH2; 4.07, t (2.0 Hz), OCH2; 5.82, s, H2; 7.64, d (1.4 Hz), 2×ArH; 7.73, d (1.3 Hz), 2×ArH. ESI (+ve) MS: m/z 176 (M+H, 12%).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N+:20]([O-])=O)[C:6]1=[O:23])[CH:2]=[CH2:3].N1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: C1CCNC1
Reactant: C=CCON1C(=O)c2ccc([N+](=O)[O-])c3cc(Br)cc(c23)C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(Br)cc(c23)C1=O

Procedure:
Following the procedure of Example W1, a mixture of the 2-allyloxy-5-bromo-7-nitro-benzo[de] isoquinoline-1,3-dione from above, pyrrolidine (0.43 g, 6.0 mmol) and triethyl amine (1.2 g, 12 mmol) in DMF (10 mL) was reacted to give 0.91 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 51.6 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (63 mg, 0.15 mmol) and 2-bromo ethanol (90 mg, 0.72 mmol) to give 7-cyclopentyl-2-[1′-(2-hydroxy-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (37 mg, 53%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]=1C1C=CC=CC=1[N+]([O-])=O.[C:23](O)(=O)[CH3:24]>[Fe]>[N:10]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:23][C:24]=2[NH:10][C:8]=1[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:22])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 86 %

Procedure:
To a solution of (2-nitrophenyl)-terephthalamic acid methyl ester (0.23 g, 0.76 mmol) in glacial acetic acid (2.5 mL) was added iron powder (<5 μm mesh, 0.12 g, 2.1 mmol) and the mixture stirred at reflux for 1 h. The mixture was cooled, stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (10 mL), the phases separated and the organic layer washed with saturated NaHCO3 (10 mL). The organic extract was dried (MgSO4), filtered and concentrated to give cyclized methyl 4-(benzimidazol-2-yl)-benzoate (0.163 g, 86%). 1H NMR (CDCl3) δ 3.96 (s, 3H), 7.32 (m, 2H), 7.53 (br, 1H), 7.84 (br, 1H), 8.17 (m, 4H), 9.65 (br, 1H (NH)).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[CH2:4].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl.[NH4+].[Cl-]>[C:15]([Si:12]([CH3:14])([CH3:13])[O:6][CH2:1][CH:2]([OH:5])[CH:3]=[CH2:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(O)CO
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of (+/−)-3-butene-1,2-diol (500 mg, 5.67 mmol) in CH2Cl2 (25 mL) was added imidazole (444 mg, 6.53 mmol). The solution was cooled to 0° C. and t-butyidimethylsilyl chloride (1.0 M in THF, 6.24 mL, 6.24 mmol) was added. The reaction was stirred at 0° C. for 15 minutes and at room temperature for 1 hour and 30 minutes. The mixture was diluted with aqueous NH4Cl and extracted with CH2Cl2 (3×). The organic solution was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (5% EtOAc in hexanes to 100% EtOAc) to provide 827.5 mg of 1-(tert-butyl-dimethyl-silanyloxy)-but-3-en-2-ol. 1H NMR (CDCl3) δ 5.81 (m, 1H), 5.34 (d, 1H), 5.19 (d, 1H), 4.17 (m, 1H), 3.66 (dd, 1H), 3.45 (dd, 1H), 0.90 (s, 9H), 0.08 (s, 6H); MS m/z 202.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)[CH:4]=[N:3]1.[Cl:19]/[CH:20]=[CH:21]/[CH2:22][O:23][NH2:24]>>[Cl:19][CH:20]=[CH:21][CH2:22][O:23]/[N:24]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: CCC(=O)C1C(=O)CC(c2cnn(C)c2)CC1=O
Reactant: NOC/C=C/Cl
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2cnn(C)c2)CC1=O

Procedure:
To 200 ml of an ethanolic solution of 20.0 g (81 mmols) of 5-(1-methyl-1H-pyrazol-4-yl)-2-propionylcyclohexane-1,3-dione was added 210 ml (84 mmols) of 0.4 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine. The mixture was reacted for 8 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give 12.5 g of the product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.CO>O>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1
Reactant: OCc1ccc(CO)o1
Solvent: CO
Solvent: O
Product: OCC1CCC(CO)O1
Temperature: 30 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a 2 gal. stainless steel stirred autoclave was charged 1420.5 g. of 2,5-dihydroxymethylfuran and 113.68 g. of the cationic ruthenium zeolite and 1 gal. of methanol. The system was pressurized with H2 to 3500 psig and heated to 30° C. An exothermic gas uptake was seen and the temperature rose within a minute to 82° C. Cooling water was started to control the exothermic reaction. After 5 hours, gas uptake had essentially ceased and gas chromatographic analysis indicated no starting material was present. Distillation gave 92 percent yield of 2,5-dihydroxymethyl tetrahydrofuran and about 8 percent of a product identified as 5-methyl tetrahydrofuran-2-methanol (hydrogenolysis product).
Reaction SMILES: [F:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([O:21]C)[N:15]=1)[CH3:10].[Na+].[Cl-]>CS(C)=O.C(N(CC)CC)C>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[NH:15][C:16](=[O:21])[CH:17]=[C:18]([N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][F:1])[CH2:4]2)[N:19]=1)[CH3:10]
Reactant: FCC1CNCCO1
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Temperature: 85 °C
Yield: 50.4 %

Procedure:
In a 50 ml round-bottomed flask, 680 mg of 2-fluoromethylmorpholine (Yoshikazu Jinho et al.; J. Med. Chem., 37(17), 2791-2796; 1994) and 0.63 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester (example 8b, step 2b) are placed in 15 ml of DMSO and 1,013 ml of triethylamine. The reaction medium is heated for 18 h at 85° C. The reaction medium is poured into a saturated NaCl solution and the mixture is extracted with 3 times 25 ml of ethyl acetate. The organic extracts are combined and washed with a saturated NaCl solution, dried over magnesium sulfate and evaporated. The compound obtained is chromatographed on silica gel (15-40 μm, Merck), elution being carried out with a gradient of dichloromethane and methanol (98/2 to 95/5 v/v). The fractions containing the expected compound are combined and evaporated, so as to give (±)-[4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid ethyl ester (412 mg).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8](C)[C@@H]2CCCC(=O)[C@H]2N2CCCC2)=[O:7])=[CH:4][CH:3]=1.COC(OC)OC.Cl>CO>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:22]=[CH:23][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCCC(=O)[C@H]1N1CCCC1
Agent: Cl
Solvent: CO
Solvent: COC(OC)OC
Product: NC(=O)c1ccccc1

Procedure:
To a solution of 1.0 g of trans-(±)-4-bromo-N-methyl-N-[3-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzamide, prepared as described in Example 1C above, in fifty ml of dry methanol there is added 5 ml of trimethylorthoformate and 0.5 ml of 4M methanolic hydrogen chloride. The resulting mixture is refluxed for about 16 hours, cooled, and the solvent is removed in vacuo. The residual oil is crystallized from a hot methanol solution thereof diluted with diethyl ether until the mixture becomes cloudy to obtain the titled 4-bromo-N-methyl-N-[3,3-dimethoxy)-2-(1-pyrrolidinyl)cyclohexyl]benzamide, which is converted to a hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[N:3]=1.[H][H]>[Pd].C(O)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2
Reactant: Cc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2c(N)cccc2n1
Yield: 50.4 %

Procedure:
2-Methyl-5-nitroquinoline (25 g, 132.85 mmol) and palladium on carbon (2.5 g) in 8 ml of glacial acetic acid are stirred for 5½ hours in a hydrogen atmosphere at normal pressure. The catalyst is suctioned off and washed with ethyl acetate. The combined filtrates are concentrated by evaporation. Column chromatography of the residue on silica gel with dichloromethane-acetone yields 10.6 g of the product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To a stirred solution of tert-butyl (1R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (Step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml), triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0° C. After ten minutes, 4-methylbenzene-1-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 246-2.55 (m, 4H); 2.90-2.91 (m, 1H); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9 Hz, 2H); 7.77-7.80 (d, J=9 Hz, 2H); ES Mass: 369 [M+1] 370 (100%).
Reaction SMILES: CC(C)([O-])C.[K+].C1(S([CH:16]2[CH2:20][C:19]3([CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[NH:18][CH:17]2[C:27]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)[CH:30]=[C:29]([CH3:43])[N:28]=2)(=O)=O)C=CC=CC=1.C(O)(=O)C>C1COCC1>[CH3:25][N:22]1[CH2:23][CH2:24][C:19]2([N:18]=[C:17]([C:27]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)[CH:30]=[C:29]([CH3:43])[N:28]=3)[CH2:16][CH2:20]2)[C:21]1=[O:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Potassium tert-butoxide (2.22 mL, 3.78 mmol) was added dropwise to a solution of 3-(benzene-sulfonyl)-7-methyl-2-[6-methyl-4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 16) (1 g, 1.89 mmol) in THF (20 mL) at 00° C. under N2 and the reaction was stirred at 0° C. for 1 hour. Acetic acid (0.22 mL, 3.78 mmol) was added and the reaction was stirred for 5 minutes. The solid was filtered off and the solvent was evaporated to afford a crude oil. This was purified using a Biotage SP4, 25 g SNAP cartridge, eluting with 0 to 10% MeOH in EtOAc to afford 7-methyl-2-[6-methyl-4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (641 mg, 1.4892 mmol, 78.9% yield) as a pale yellow oil;
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C:10]([N:12]([C:15]1[C:16]([Cl:26])=[N:17][N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=1)[CH2:13][CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][CH2:9][C:10]([N:12]([C:15]1[C:16]([Cl:26])=[N:17][N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=1)[CH2:13][CH3:14])=[O:11])[CH3:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)CCNC(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCN(C(=O)CCN(C)C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a clean vial with a stir bar tert-butyl(3-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-3-oxopropyl)carbamate (1.5 g, 3.8 mmol) was added and sealed with a septum cap. The headspace was purged with N2, dry DMF (5.4 mL) was added via a syringe, and the reaction was cooled to a temperature of about 0° C. in an ice bath under N2. NaH (60% dispersion in oil, 0.21 g, 5.3 mmol) was carefully added and stirred at a temperature of 0° C. for 30 minutes. Methyl iodide (0.29 mL, 4.6 mmol) was then added and stirred for 30 minutes at a temperature of 0° C. With the addition of methyl iodide, reaction became light yellow slurry. The reaction was warmed up to room temperature and stirred for 2 hours. As reaction warmed up, it turned to bright orange color. The reaction was quenched by the slow addition of water (100 mL). The suspension was vigorously stirred at room temperature for 2 hours. The water was filtered off, and remaining slurry was washed with hexanes. The slurry was then dissolved in methanol and passed through the filter. The resulting solution was concentrated, dried under high vacuum to afford brown, viscous oil (1.6 g, 78%).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9](=O)[CH:8]=1)[CH3:5])([OH:3])=[O:2].[NH:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][N:22]=1)[NH2:20]>Cl.C(O)(=O)C>[S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:19]=[N:20][C:9]2[CH:8]=[C:7]([O:6][CH:4]([C:1]([OH:3])=[O:2])[CH3:5])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[OH:17])=[N:22][CH:23]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Agent: Cl
Solvent: CC(=O)O
Product: CC(Oc1cc(N=Nc2ccc(S(N)(=O)=O)cn2)c(O)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(1-Carboxyethoxy)-1,2-naphthoquinone (0.26 g, 1.06×10-3 mole) and 2-hydrazino-5-sulfamoylpyridine (0.2 g, 1.06×10-3 mole) were added to acetic acid (5 ml), along with 2 to 3 drops of concentrated hydrochloric acid. After stirring for 3 hours, at room temperature, the mixture was filtered to remove traces of solid. The filtrate was poured into distilled water (30 ml) and filtered again. The precipitate was washed with water and air dried; yield 0.26 g (59 percent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1)C1CC1

Procedure:
Example 120 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.64–7.55 (s, 1H), 7.55–7.47 (s, 1H), 7.47–7.37 (br, 1H), 7.36–7.17 (m, 6H), 7.05–6.95 (m, 4H), 6.95–6.87 (br, 1H), 4.81 (s, 1H), 3.47–3.35 (m, 2H), 3.07–2.94 (m, 2H), 2.58–2.41 (m, 3H), 2.15–1.99 (m, 2H), 1.90–1.79 (m, 2H), 1.79–1.60 (m, 4H), 1.59–1.44 (m, 1H), 1.13–0.99 (m, 2H), 0.90–0.75 (m, 2H); ESMS m/e: 532.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].[ClH:33]>C(Cl)Cl>[Cl:33][CH2:31][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17]1
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Reactant: Cl
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CCl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of methyl 2-oxo-3-(2-phenoxy-acetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (0.12 g), in dried methylene chloride (5 ml) was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, methylene chloride was distilled off under reduced pressure from the reaction mixture. The residue was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was distilled off to give oily methyl 2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.085 g).