Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13](OC)=[O:14])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:17][C:11]=3[C:12]=2[CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(OC)cc3)S(C)(=O)=O)c(OC(C)C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(CO)c3cc2OC(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyl 2-(4-fluorophenyl)-5-isopropoxy-6-(N-(4-methoxybenzyl)methylsulfonamido)benzofuran-3-carboxylate (0.8 g, 1.48 mmol) was dissolved in tetrahydrofuran cooled in an ice bath and treated with lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.48 mL). The resulting solution was stirred at room temperature for 45 minutes. The reaction was quenched with 0.3 mL water, 0.3 mL 15% aqueous NaOH and 0.6 mL water, stirred 15 minutes, and decanted. The solid was washed with ethyl acetate, diluted with 100 mL ethyl acetate, and washed with 1 N aqueous H3PO, 10% aqueous sodium bicarbonate, and 10% aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate(s), filtered and the solvent was removed in vacuo leaving an oily residue, 0.68 g, 90%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Reaction time: 18 h

Procedure:
To a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylic acid methyl ester (0.041 g, 0.1 mmol) in methanol (1 mL) is added 10% Pd/C (0.1 g). The resulting mixture is placed under one atmosphere of hydrogen and: stirred for 18 h. The mixture is filtered and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol in dichloromethane) to yield the desired product as a pale yellow solid, 0.035 g (85%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH:18]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:18]
Reactant: CSc1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of 4.6 g (0.0191 mole) of 4-(4-(methylthio)phenoxy)benzonitrile dissolved in 50 ml of glacial acetic acid was added dropwise 2.38 g (0.0210 mole) of 30% aqueous hydrogen peroxide. The mixture was heated at 50° C. for 1 hr and most of the solvent removed in vacuo. The crude product was dissolved in CH2Cl2 and washed with 2 N aqueous NaOH and water. The organic layer was dried (Na2SO4) and solvent removed in vacuo leaving 4.7 g (95.9% yield) of 4-(4-(methylsulfinyl)phenoxy)benzonitrile as an oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(Cn2ccnc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cn1ccnc1
Yield: 85 %

Procedure:
Prepared analogously to Example 19b from methyl 4-(imidazol-1-ylmethyl)-3-methoxybenzoate and sodium hydroxide solution in methanol. Yield: 85%; C12H12N2O3 (232.24); mass spectrum: (M+H)+=233.
Reaction SMILES: [CH:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([CH:12]([CH3:14])[CH3:13])[C:5]=1[NH:15][C:16](=[O:28])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]1)([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:41][C:42]1[CH:43]=[C:44]([CH:53]([CH3:55])[CH3:54])[C:45]2[O:49][C:48]([SH:50])=[N:47][C:46]=2[C:51]=1[CH3:52].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.CN(C)C1C=CN=CC=1.O>[Cl:41][C:42]1[CH:43]=[C:44]([CH:53]([CH3:55])[CH3:54])[C:45]2[O:49][C:48]([S:50][CH2:26][CH2:25][CH2:24][N:21]3[CH2:20][CH2:19][N:18]([CH2:17][C:16]([NH:15][C:5]4[C:6]([CH:12]([CH3:13])[CH3:14])=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=4[CH:1]([CH3:2])[CH3:3])=[O:28])[CH2:23][CH2:22]3)=[N:47][C:46]=2[C:51]=1[CH3:52]
Reactant: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c1C(C)C
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c1C(C)C
Yield: 38.9 %

Procedure:
To a solution of the alcohol (150 mg, 0.38 mmol) in THF (3 ml) were added triethylamine (50 mg, 0.50 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol), then methanesulfonyl chloride (53 mg, 0.46 mmol) was dropped thereinto with ice cooling and stirring, the mixture was stirred for 30 minutes. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was dissolved in DMF (5 ml), then 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole (93 mg, 0.38 mmol), potassium carbonate (64 mg, 0.46 mmol) and 18-crown-6 (10 mg, 0.04 mmol) were added thereto and the mixture was stirred at 80° C. for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=50:1) and the resulting crystals were recrystallized from ethyl acetate-hexane to provide 91 mg (yield 39%) of the desired compound as colorless powdery crystals.
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.[CH3:21][Si:22]([CH3:26])([CH3:25])OCl>O>[CH3:10][C:2]([O:1][Si:22]([CH3:26])([CH3:25])[CH3:21])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)OCl
Reactant: C#CCC(C)(O)CCC=C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C)(CCC=C)O[Si](C)(C)C

Procedure:
To a mixture of 50 g. of 4-hydroxy-4-methyl-oct-1-yn-7-ene and 61.3 g. of imidazole in 100 ml. of dimethylformamide at 0° C., is added, with stirring, 49.1 g. of trimethylsilyloxy chloride. The mixture is stirred at room temperature overnight and poured into petroleum ether and water. The organic layer is washed with water and saturated sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed and the residue distilled (74°-78° C., 1.5 mm.) to give the product as a colorless liquid.
Reaction SMILES: [F:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)=O>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:13][C:2]2([F:1])[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:3]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=C(F)CN(CC=O)C(=O)OCC
Agent: O=C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(Cc3ccccc3)CCC2(F)C1

Procedure:
20.8 g (0.11 mol) of ethyl N-(2-fluoroallyl)-N -(2-oxoethyl)-carbamate are heated under reflux with 19 g (0.115 mol) of N-benzylglycine in 300 ml of toluene until evolution of CO2 is complete. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:20][C:18]2[N:19]=[C:12]3[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:16][CH:15]=[CH:14][N:13]3[N:17]=2)=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)cc1

Procedure:
(4-Methanesulfonyl-phenyl)-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-bromo-4-methanesulfonyl-benzene (75.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as tan solid (0.063 g, 55%). MP=280-282° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.56 (d, J=5.7 Hz, 1H), 8.22 (d, J=8.0 Hz, 2H), 8.10 (d, J=7.6 Hz, 2H), 7.92 (d, J=7.8 Hz, 2H), 7.77 (d, J=7.3 Hz, 2H), 7.72 (d, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.14-7.09 (m, 1H), 3.11 (s, 3H), 3.06 (s, 3H). MS=443 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:13](OCC)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.CCCCCCC>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc(C(F)(F)F)c(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A dry vessel under nitrogen at room temperature was charged with 5-bromo-4-(trifluoromethyl)pyridin-2-amine B1 (200 g, 830 mmol) and ethyl acetate (200 ml). The reaction mixture was cooled to 0° C. To the solution was added N,N-dimethylpyridin-4-amine (1.01 g, 8.29 mmol). Heptane (400 ml) was added and the mixture was cooled to 0° C. Acetic anhydride (109.6 ml, 1162 mmol) was added over a period of 60 min. The reaction mixture was warmed to 50° C. within 60 min. The reaction mixture was stirred at 50° C. for 18 h. Solvent (330 g) was removed by distillation (540-250 mbar, 50° C.) until a residue of ˜300 ml was obtained. The reaction mixture was allowed to cool to 20° C. Heptane (800 ml) was added and the mixture was stirred for 30 min. The precipitate was collected by filtration. The filter cake was washed with heptane (100 ml). The product was dried in a tray dryer for 16 h at 40° C., <20 mbar to yield 212 g (90%) B2 as sligthly brown solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Br:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Br:26][C:10]1[C:11]2[C:16](=[CH:15][C:14]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Sc3ccccc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Br)c2ccc(Sc3ccccc3)cc2c1O

Procedure:
216 mg of 1-bromo-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) from Example D-2a) were reacted with glycine and sodium methylate analogously to Example D-1 g). 194 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.17 (t, 1H), 8.12 (d, 1H), 7.51 to 7.78 (m, 7H), 4.00 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:23])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[N:10]2[CH2:18][C:19]([O:21]C)=[O:20])[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si](C)(C)[O-].[K+:29]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:23])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][C:19]([O-:21])=[O:20])[CH:5]=[C:6]([F:8])[CH:7]=1.[K+:29]
Reactant: COC(=O)CN1C(=O)C(C)(C)CC[C@@]1(C)c1cc(F)cc(F)c1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)[O-])C1=O
Reaction time: 24 h

Procedure:
To a solution of methyl [(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetate from Step D (298 mg, 0.916 mmol) in THF (9 mL) at ambient temperature was added potassium trimethylsilanolate (147 mg, 1.14 mmol). The reaction was stirred for 24 hours and found to be incomplete by LCMS analysis. Additional quantities of potassium trimethylsilanolate were added as needed. The reaction was concentrated in vacuo to give a residue that required no further purification. MS: m/z=312 (M+1 for parent acid).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:22][C:11]3=[N:12][C:13]([NH2:21])=[C:14]([C:16]([O:18]CC)=[O:17])[CH:15]=[C:10]3[C:9](=[O:23])[C:8]=2[CH:24]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:22][C:11]3=[N:12][C:13]([NH2:21])=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9](=[O:23])[C:8]=2[CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C(C)=O)ccc3oc2nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc2oc3nc(N)c(C(=O)O)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
In ethanol (3 l) was suspended ethyl 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (46 g). To the suspension were added water (460 ml) and 1N sodium hydroxide (462 ml). The mixture was stirred at room temperature for 1.5 hour, then at 50°-55° C. for 2 hours. The precipitating crystals were collected by filtration, and washed with ethanol. The crystals thus obtained were suspended in warm water (about 2 l). To the suspension was added concentrated hydrochloric acid (20 ml), and the mixture was stirred for 20 minutes. Insoluble matter was collected by filtration, washed with water, followed by recrystallization from dimethylformamide-water to give 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid as colorless crystals (39.3 g). Melting point: >300° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([O:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:24][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH:14]([CH3:16])[CH3:15])[N:23]=2)[CH:7]=1
Reactant: CC(C)Oc1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OC(C)C)n1
Temperature: 130 °C
Yield: 13.3 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (1.63 g, 7.36 mmol) in acetonitrile (25 mL) was added 6-isopropoxypyridin-2-amine (1.12 g, 7.36 mmol) and the mixture heated at 130° C. in a sealed tube for 60 h. Upon completion, the mixture was concentrated on to silica gel and purified by chromatography (20% to 66% EtOAc in hexanes) to give ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate (330 mg, 13%). MS (EI/CI) m/z: 337.1 [M+H].
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:10]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[CH:34](Br)[CH:35]=O)[CH:29]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:28]2=[O:46])=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C.N1C=CC=CC=1>[CH:10]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[C:34]1[S:8][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:35]=1)[CH:29]([NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[C:28]2=[O:46])=[O:25])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=S)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4cccnc4)s3)CSC12
Temperature: 50 °C
Reaction time: 1.33 h

Procedure:
Thionicotinamide (28.2 g) and pyridine (16.5 cc) are added to a solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the diastereoisomers) (120 g) in tetrahydrofuran (1,200 cc). The reaction mixture is stirred at 50° C. for 80 minutes. After cooling to +5° C., methanesulphonyl chloride (15.8 cc) and triethylamine (57.3 cc) are added successively in the course of 5 minutes. The reaction mixture is kept for 30 minutes at +5° C. and then reheated to 20° C. and poured into a mixture of ethyl acetate (1 liter) and a 5% strength solution of sodium bicarbonate (2 liters). The organic phase is washed with a 5% strength solution of sodium bicarbonate (2 liters) and then with a semi-saturated solution of sodium chloride (2 liters). After drying over magnesium sulphate and evaporation of the solvent to dryness under reduced pressure (4 kPa) at 30° C., the residue obtained is chromatographed on a column of diameter 9 cm containing silica gel (0.06-0.2 mm) (3.4 liters), 1 liter. fractions being collected. Elution is carried out successively with: methylene chloride (11 liters) and then the following mixtures (proportions by volume) of methylene chloride and ethyl acetate: 94/6 (16 liters), 88/12 (4 liters), 75/25 (12 liters) and 70/30 (10 liters). Fractions 32 to 52 are combined and concentrated to dryness and the residue is solidified with isopropyl ether to give 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-3-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (37.1 g) in the form of a beige solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:15].[C:16](OC(=O)C)(=[O:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1CCNC1=O>>[C:16]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5]1=[O:15])(=[O:18])[CH3:17]
Reactant: O=C1NC(c2ccccc2)CN1CCO
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1NCCN1
Product: CC(=O)OCCN1CC(c2ccccc2)NC1=O

Procedure:
Approximately 9.2 g of 1-(2-hydroxyethyl-4-phenyl-2-imidazolidone is stirred with acetic anhydride (25 ml.) and p-toluenesulfonic acid (200 mg.) for four hours, during which time the imidazolidone completely dissolves. The solution (100 ml.) from which a white solid precipitates. The solid is extracted with methylene chloride (3×100 ml.). The organic layer is separated, dried and the solvent removed to give a pale yellow solid. Recrystallization from ether gives the title compound as a white crystalline solid; m.p. 88°-90° C.
Reaction SMILES: [CH:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=O)([CH2:3][CH3:4])[CH3:2].[CH:16]([NH:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:18])[CH3:17].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([N:19]([CH:16]([CH3:18])[CH3:17])[NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CCC(C)c1ccccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)c1ccccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 36.4 %

Procedure:
A solution of (2-sec-butyl-phenoxy)-acetic acid (193 mg, 0.93 mmol), and benzoic acid N′-isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (113 mg, 33%). MS m/e 369.32 (M+H+)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:25]1[C:20]([N:8]2[CH2:9][CH2:10][C:11]([OH:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C1(O)CCN(Cc2ccccc2)CC1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(O)CCN(c2ncccc2Cl)CC1
Temperature: 90 °C

Procedure:
Methyl 1-benzyl-4-hydroxy-4-piperidinecarboxylate (15.0 g, 77 mmol), 2,3-dichloropyridine (12.0 g, 81 mmol), and potassium carbonate (15.0 g, 108.7 mmol) were combined in DMF (200 mL) and heated at 90° C. for 2 days. The mixture was allowed to cool to room temperature, concentrated, and standard work-up provided a residue that was purified via chromatography (SiO2, ethyl acetate:hexanes, 1:6) to provide the title compound MS (EI, M+H)+ 271.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[Cl:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(C)cc(Cl)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(C)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A dry CS2 solution (30 mL) containing N-(3-chloro-5-methyl-phenyl)acetamide (5.0 g, 27 mmol) and acetyl chloride (2.9 ml, 40.8 mmol) was slowly added with aluminum chloride (9.1 g, 68 mmol). The reaction mixture was heated at reflux for 30 min, cooled to room temperature, and stand for 4.0 h. The CS2 was decanted and the remaining syrup was poured into icy HCl. The resultant solids were collected, re-dissolved in EtOH, and decolorized by charcoal. The solution was filtered and the filtrate was concentrated under vacuum to give N-(4-acetyl-3-chloro-5-methylphenyl)acetamide (5.2 g) as light yellow solids in 85% yield: 1H NMR (500 MHz, CDCl3) δ 7.48 (s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 2.52 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]([CH3:22])[CH2:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1.[CH3:23][Mg]I.CCOCC>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[N:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1
Reactant: C[Mg]I
Reactant: CCOC(=O)c1cc(CC(C)=O)n(COCC[Si](C)(C)C)n1
Solvent: CCOCC
Product: CCOC(=O)c1cc(CC(C)(C)O)n(COCC[Si](C)(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 2(d) starting from ethyl 5-(2-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (5.24 mmol, 1.7 g) and 3 M solution of MeMgI in ether (6.78 mmol, 2.2 ml). Yield 301 mg. 1H-NMR (400 MHz; CDCl3): δ −0.05 (s, 9H), 0.89 (t, 2H), 1.24 (s, 6H), 1.38 (t, 3H), 2.76 (s, 2H), 3.57 (t, 2H), 4.34 (q, 2H), 5.81 (s, 2H), 6.76 (s, 1H).