Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:16])[NH:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].[CH3:17][C:18]([O:20][CH2:21][C@H:22]1[O:27][C@H:26](Br)[C@H:25]([O:29][C:30]([CH3:32])=[O:31])[C@@H:24]([O:33][C:34]([CH3:36])=[O:35])[C@@H:23]1[O:37][C:38]([CH3:40])=[O:39])=[O:19]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:26]3[O:27][C@H:22]([CH2:21][O:20][C:18](=[O:19])[CH3:17])[C@@H:23]([O:37][C:38](=[O:39])[CH3:40])[C@H:24]([O:33][C:34](=[O:35])[CH3:36])[C@H:25]3[O:29][C:30](=[O:31])[CH3:32])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a suspension of 4-[(4-ethylphenyl)methyl]-5-methyl-1,2-dihydro-3H-pyrazol-3-one (0.65 g) and acetobromo-α-D-glucose (1.2 g) in tetrahydrofuran (15 mL) was added silver carbonate (0.83 g), and the mixture was stirred at 60° C. overnight under light shielding. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran), and successively by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give 4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:17])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl

Procedure:
A mixture of 2-(4-chlorophenoxy)-2-methylpropionic acid (15.0 g) and thionyl chloride (70 ml) was boiled under reflux for 1 hour. The thionyl chloride was distilled off and the residue distilled under vacuum to give 2-(4-chlorophenoxy)-2-methylpropionyl chloride, b.p. 84-87° C. at 0.07 mbar. A solution of this chloride (14.17 g) in dichloromethane (50 ml) was added dropwise to a mixture of 1-(3-aminopropyl)imidazole (7.63 g), triethylamine (6.78 g) and dichloromethane (100 ml) at below 0° C. with stirring. After the addition, the mixtures was allowed to warm up to ambient temperature and stirred at this temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (100 ml) was added and the mixture stirred for 1 hour. The mixture was separated and the aqueous layer was washed with dichloromethane. The combined organic layers were dried and evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(4-chlorophenoxy)-N-[3-(imidazol-1-yl)propyl]-2-methylpropionamide, m.p. 83-84° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH2:6][CH:7]=[CH2:8])[CH3:2].C(OC(=O)C(C)/C=C\C)C>[Pd].C([O-])([O-])=O.[Ca+2]>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH:6]=[C:7]=[CH2:8])[CH3:2]
Reactant: C=CCC(C)C(=O)OCC
Agent: [Pd]
Agent: C/C=C\C(C)C(=O)OCC
Agent: O=C([O-])[O-]
Product: C=C=CC(C)C(=O)OCC

Procedure:
FIG. 7 is an illustration of the GLC curve for a mixture of ethyl-2-methyl-4-pentenoate and ethyl-2-methyl-cis-3-pentenoate produced by the hydrogenation of ethyl-2-methyl-3,4-pentadienoate with a Pd/CaCO3 catalyst according to Example XVII.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)=[N:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])(=[O:3])[NH2:2].[ClH:38]>C(OCC)(=O)C>[ClH:38].[ClH:38].[CH:35]([S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:5]1[N:6]=[C:7]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[NH:8][C:9](=[O:10])[C:4]=1[C:1]([NH2:2])=[O:3])(=[O:34])=[O:33])([CH3:37])[CH3:36]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)[nH]c(=O)c1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCNC2)[nH]c(=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 3-[(5-carbamoyl-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-2-yl)amino]piperidine-1-carboxylate (Example 28) (299 mg) and ethyl acetate (3 mL), 4M hydrogen chloride in ethyl acetate (2.7 mL) was added under ice cooling and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide dihydrochloride (194 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.CC(C)([O-])C.[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: CNc1ccccn1
Reactant: Cc1cccc(Br)n1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(N(C)c2ccccn2)n1
Yield: 95 %

Procedure:
To a flask were added 0.75 g 2-(methylamino)pyridine, 1.0 g 2-bromo-6-methylpyridine, 0.95 g sodium tert-butoxide, 0.16 g 1,1′-bis(diphenylphosphino)ferrocene and 50 ml toluene. The mixture was purged thoroughly with nitrogen and 0.14 g of tris(dibenzylideneacetone)d2-propanollladium(0) was added and the mixture was heated to 80 C under nitrogen for 16 hours. After cooling to 22 C and quenching with 50 ml water, the product was extracted twice with ethyl acetate and washed twice with water. After filtration and solvent removal, the product was purified by silica gel chromatography using 35% ethyl acetate in hexane resulting in an orange oil. This was dissolved in 75 ml tert-butyl methyl ether and extracted into 75 ml 1M hydrochloric acid. After basification with 3M sodium hydroxide solution, the product was extracted with 75 ml tert-butyl methyl ether. Following removal of solvent, 1.1 g of a yellow oil was obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:18]1[N:19]([CH3:32])[C:20](=[O:31])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])[N:23]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][N:3]([CH3:16])[C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:18]3[N:19]([CH3:32])[C:20](=[O:31])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:30])[N:23]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: CN(C)c1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Yield: 46.1 %

Procedure:
A solution of (2S)-2-(4-(dimethylamino)phenyl)morpholine hydrochloride (0.20 g, 0.64 mmol), 2-chloro-1-methyl-6-oxo-4-(3-fluoropyridin-4-yl)-1,6-dihydropyrimidine (0.12 g, 0.53 mmol), and triethylamine (0.19 g, 1.92 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was evaporated off in vacuo and the residue treated with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford 2-((2S)-2-(4-(dimethylamino)phenyl)morpholin-4-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.10 g, 50%) as yellow crystals
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCO>CN(C=O)C.[Cl-].[Na+].O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[CH2:19][CH2:18]1
Reactant: CS(=O)(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NS(C)(=O)=O)c2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
N-(5-fluoro-2-nitrophenyl)methanesulfonamide (1.33 g, 5.68 mmol) was dissolved in DMF (10 mL) and N-methylpiperazine (2.00 g, 20 mmol) was added. The reaction mixture was stirred at 20° C. for 1 h, and then heated with a heat gun for 5 min to reach boiling of DMF (150° C.), then left stirring for another hour. The reaction mixture was then poured into brine and extracted with toluene (10 mL×2), EtOAc (20 mL×2) and CH2Cl2 (20 mL×2), NaHCO3 was then added to the water phase and then the water phase was extracted with CH2Cl2 (20 mL×2). The organic phases were combined and dried (MgSO4) and concentrated to give a semi solid. EtOH was added and left over night and then filtered off to give 1.503 g (4.78 mmol) in 84% yield. MS (posES-FIA) m/z=found: 315; Calc M=314.10; Anal (C12 H18 N4 O4 S), C, H, N, S.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][Mg]Cl>C1COCC1>[O:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([CH3:13])([OH:3])[CH3:2])[C:12]=2[O:11][CH2:10]1
Reactant: CC(=O)c1cccc2c1OCO2
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
25.5 g of 4-acetylbenzo[1,3]dioxole is mixed with 57.2 ml of methylmagnesium chloride solution (3M in THF) in 375 ml of THF at room temperature under argon. It is stirred for 16 hours at room temperature and added to ice/2H hydrochloric acid. It is extracted with ethyl acetate, and the organic phase is washed with water and brine, and it is dried (Na2SO4). 27.89 g of 1-[benzo(1,3)dioxol-4-yl]-1-methylethanol is obtained as a brown oil
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:22][CH:23]=1)=[O:42]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Yield: 46.9 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 1.04 mmol) obtained in the last step and triethylamine (1.4 mL) were dissolved in dichloromethane (15 mL). In an ice bath, a dichloromethane solution (10 mL) of 2-naphthoyl chloride (210 mg, 1.1 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was removed under reduced pressure, and the resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 226 mg, at a total yield over two steps of reactions of 46.9%.
Reaction SMILES: [C:1]1([C:11]([C:13]2[CH:41]=[CH:40][C:16]3[N:17]([CH2:21][CH2:22][O:23][C:24]4[CH:39]=[CH:38][C:27]([CH2:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=4)[C:18](=[O:20])[S:19][C:15]=3[CH:14]=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([CH2:11][C:13]2[CH:41]=[CH:40][C:16]3[N:17]([CH2:21][CH2:22][O:23][C:24]4[CH:39]=[CH:38][C:27]([CH2:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=4)[C:18](=[O:20])[S:19][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc5ccccc45)ccc32)cc1)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(Cc4cccc5ccccc45)ccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Example 48, starting from the compound obtained in Example 49. The recrystallisation solvent is toluene.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:5])[CH3:2].CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[CH3:28][NH:29][C:30](=[O:42])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[NH2:32]>ClCCl.CN(C)C=O>[CH3:28][NH:29][C:30](=[O:42])[C@H:31]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[NH:32][C:8](=[O:10])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CCOC(=O)CC(CC(C)C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CC(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 0 °C
Reaction time: 60 h

Procedure:
A mixture of 3-(ethoxycarbonyl)-2-(2-methylpropyl)propanoic acid (17.4 g., 0.087 mol.), N-methylmorpholine (28.7 mls., 0.26 mol.) and dimethylformamide (0.25 ml.) was dissolved in dry dichloromethane (200 mls.) and the resulting mixture was cooled to 0° C. To the reaction mixture was added a solution of oxalyl chloride (7.6 mls., 0.087 mol.) in dry dichloromethane (50 mls.). The mixture was heated under reflux for 10 minutes and then cooled to -70° C. To the reaction mixture was added O-methyl-L-tyrosine N-methylamide (20.0 g., 0.096 mol.) in dry dichloromethane (100 mls.) over a period of 30 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 2.5 days. The mixture was filtered and the filtrate washed with saturated sodium bicarbonate solution (2×200 mls.), dilute citric acid (2×150 mls.) and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation in vacuo to yield N-[3-(ethoxycarbonyl)-2-(2-methylpropyl)propanoyl]-O-methyl-L-tyrosine N-methylamide, as a mixture of isomers (20.7 g.), in the form of a solid.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:22]=1)(=O)C.C(O)(=O)C.S(=O)(=O)(O)O>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:22]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2

Procedure:
Reflux 200 mg. of 8-acetamido-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid for 16 hours in a mixture of 5 cc. of acetic acid and 5 cc. of 50% aqueous sulfuric acid. Dilute with water and separate the solids by filtration. Wash with water and dry to obtain the title product.
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Mg]Br>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:4]([C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:2]=1[F:1])=[O:5]
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reactant: COc1ccc([Mg]Br)c(OC)c1
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(OC)c1

Procedure:
Prepared according to Method A step B from 2-fluoro-3-trifluoromethyl-N-methoxy-N-methylbenzamide (4.42 g, 17.6 mmol) and 2,4-dimethoxyphenylmagnesium bromide (32 mL, 0.5 M in THF) to give 1.67 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=O.[O-]CC.[Na+].CC(O)=O.O>C(O)C>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:14]([C:13]([F:20])([F:19])[F:12])[N:6]=[C:4]2[OH:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(=O)c1cc(Cl)ccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Oc1nc(C(F)(F)F)nc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 92.7 %

Procedure:
2-Amino-5-chlorobenzamide (Avocado) (1.00 g, 5.86 mmol, 1.0 eq.) and ethyl trifluoroacetate (4.19 mL, 35.2 mmol, 6.0 eq.) were dissolved in 50 mL of ethanol at rt under nitrogen and followed by the addition of 3.09 M sodium ethoxide in ethanol (11.38 mL, 35.2 mmol, 6.0 eq.) The mixture was refluxed 20 hours. Cooled to rt. Added 10 mL of 10% HOAc/H2O. Solids formed which were filtered, rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo to give 1.35 g of amber solids. LCMS detects (M+H)+=249.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(O)(=O)C.BrBr.[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>C(OCC)C>[CH2:15]([O:17][P:18]([CH:8]1[C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]1[CH3:1])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: CN1CC(=O)NC1=O
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methylhydantoin (20.25 g, 180 mmole) and acetic acid (100 ml) is heated to 90° C. Bromine (10 ml, 195 mmole) is introduced dropwise at such a rate that instant decolorization occurred. After the addition is completed, the reaction mixture is stirred at 90° C. for 60 minute and at room temperature overnight. The acetic acid is decanted from white precipitate and removed in vacuo. The residue is combined with the precipitate and suspended in diethylether (200 ml). Triethylphosphite (32 ml, 180 mmole) is added portionwise with stirring and cooling. A solution resulted which on continued stirring, yield trace of white precipitate. The mixture is diluted with diethyl ether and allowed to stand overnight. Decanted the solvent, and pumped in vacuum oven to give white crystal ylide, (3-Methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester: 16.57 g (36.8%) MS (ES+): (M+H)=251.0
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[O:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])[CH:22]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3O)no1
Yield: 106.4 %

Procedure:
To a solution of tert-butyl (3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)isoxazol-5-yl)methylcarbamate (210 mg, 0.5 mmol) in THF (5 mL) was added 10% Pd/C (100 mg). The reaction mixture was then filtered and concentrated to afford tert-butyl((3-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)isoxazol-5-yl)methyl)carbamate (180 mg, 99%) as a light yellow solid, which was used directly in the next step. ESI-MS (EI+, m/z): 339.1 [M+H]+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:39]=[C:38]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)[CH:37]=[CH:36][C:35]=1[C:54]1[CH:62]=[C:61]2[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]2=[O:63])=[CH:56][CH:55]=1>>[F:33][C:34]1[CH:39]=[C:38]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)[CH:37]=[CH:36][C:35]=1[C:54]1[CH:62]=[C:61]2[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:70])[CH3:71])[C:65]([OH:67])=[O:66])[C:60]2=[O:63])=[CH:56][CH:55]=1
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(F)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(F)c2)cc1
Yield: 81 %

Procedure:
The compound of example 610 was prepared analogous to compound of example 98 by hydrolysis of compound of example 609.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:33]4[C:29](=[O:39])[C:30]5[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:32]4=[O:34])[CH2:6][CH2:7]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)c5ccccc5C4=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1) and phthalimide as starting compounds.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14]>C(Cl)Cl.[O-2].[O-2].[Mn+4].O=[Mn]=O>[F:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14]
Reactant: Cc1noc2c(F)c(F)c(CO)cc12
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1noc2c(F)c(F)c(C=O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.5 %

Procedure:
A mixture of (6,7-difluoro-3-methyl-1,2-benzisoxazol-5-yl)methanol (Intermediate 334, 0.7 g, 3.51 mmol) and manganese dioxide (6.11 g, 70.30 mmol) in CH2Cl2 (70 ml) was stirred at room temperature for 3 days. TLC shows conversion to a higher Rf spot with starting material. Additional MnO2 (5 g) was added and the mixture was heated to reflux for 24 hours. The mixture was filtered through celite and rinsed well with CH2Cl2. Solvent was removed from the filtrate to give 640 mg of product as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:28]O)[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[C:30]1(=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:40]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:28][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:6]2[N:7]([C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCc1c(CN2C(=O)c3ccccc3C2=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A mixture of ethyl 5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100 mg), 1H-isoindole-1,3(2H)dione (44.6 mg) diisopropyl azodicarboxylate (76.7 mg) and triphenylphosphine (995 mg) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 1 hour. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1–1:1) to give ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (107 mg).