Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][C:8]([NH:10][CH:11]2[CH:16]3[CH2:17][C:18]4(O)[CH2:20][CH:12]2[CH2:13][CH:14]([CH2:19]4)[CH2:15]3)=[O:9])[CH2:5][CH2:4][N:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:2]1.CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[CH2:1]1[N:6]([CH2:7][C:8]([NH:10][CH:11]2[CH:16]3[CH2:17][C:18]4([F:38])[CH2:20][CH:12]2[CH2:13][CH:14]([CH2:19]4)[CH2:15]3)=[O:9])[CH2:5][CH2:4][N:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:2]1
Reactant: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)CC1)NC1C2CC3CC1CC(O)(C3)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)CC1)NC1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C

Procedure:
A solution of N-[(Z)-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamide (66 mg, 0.15 mmoles) from Example 1D in DCM (0.5 mL) was cooled to −78° C., treated with DAST (0.020 mL, 0.16 mmoles) and slowly warmed to room temperature for 6 hours. The mixture was quenched by the addition of aqueous saturated sodium bicarbonate (0.1 mL), filtered through a Celite cartridge and purified (silica gel, 10-15% acetone in hexane) to provide the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.67 (m, 2H), 6.67 (d, J=9.1 Hz, 1H), 3.97 (s, 1H), 3.7 (s, 4H), 3.1 (s, 2H), 2.68 (s, 4H), 2.29-2.24 (m, 3H), 1.91-1.7 (m, 10H); MS(APCI+) m/z 441 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1.C[Al](C)C.[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30](=O)[O:31]C)[N:23]=1.C(O)(=O)C>C(Cl)Cl.Cl>[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30]([NH:14][S:11]([C:10]2[C:4]3[S:3][C:2]([CH3:15])([CH3:1])[S:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[O:31])[N:23]=1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Reactant: CC1(C)Sc2cccc(S(N)(=O)=O)c2S1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SC(C)(C)S3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.6 g 2,2-dimethyl-1,3-benzodithiole-4-sulfonamide prepared in Example 7, in 60 ml methylene chloride at room temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at room temperature, 2.0 g of methyl [4-methoxy-6-methyl-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 5, was added and the reaction mixture was heated at reflux for 72 hours. The reaction mixture was cooled to room temperature and 75 ml ice, 3 ml glacial acetic acid, and 10 drops of hydrochloric acid were sequentially added. The organic phase was separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from an appropriate solvent gave a solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[Cl:17][C:18]1[CH:23]=[C:22]([N:24]=C=O)[CH:21]=[C:20]([Cl:27])[CH:19]=1.[CH2:28]([N:30]1[C:42]2[CH:41]=[CH:40][C:39]([NH2:43])=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:29]>>[Cl:17][C:18]1[CH:23]=[C:22]([NH:24][C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:43][C:39]2[CH:40]=[CH:41][C:42]3[N:30]([CH2:28][CH3:29])[C:31]4[C:36]([C:37]=3[CH:38]=2)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:12])=[O:7])[CH:21]=[C:20]([Cl:27])[CH:19]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 40% purity by LC/MS. MS(ESI+): m/z=507.6.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])C=C.C[N+]1([O-])CC[O:19]CC1.[CH3:23][C:24]([CH3:26])=[O:25]>[Os](=O)(=O)(=O)=O.O>[OH:25][CH:24]([CH2:26][OH:19])[CH2:23][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCOc1cccc(C(=O)OC)c1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COC(=O)c1cccc(OCC(O)CO)c1
Reaction time: 0.25 h

Procedure:
A solution of Example 460A (0.3 g, 1.5 mmol), 4-methylmorpholine N-oxide (0.55 g, 4.5 mmol) and osmium tetroxide (4 wt % solution in water 0.1 mL, 0.015 mmol) in 9:1/acetone:water was stirred at room temperature for 48 h. The reaction was quenched with 10% Na2S2O3 and stirred for 15 minutes, extracted with ethyl acetate, washed with brine, dried (Na2SO4), and concentrated to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])=[CH:13][CH:14]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(-c2ccccc2)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(-c4ccccc4)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-phenylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH:34]1[C:44]2[CH2:43][CH2:42][C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[N:39]([C:49](Cl)=[O:50])[C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH:34]1[C:44]2[CH2:43][CH2:42][C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[N:39]([C:49]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][C@H:13]3[C:17]([OH:19])=[O:18])=[O:50])[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=C(Cl)N1c2ccccc2CCc2ccccc21
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N1c2ccccc2CCc2ccccc21
Yield: 23.4 %

Procedure:
Following the procedure of Example 16, Step B, 811 mg (2.5 mmole) of (S)-4-(benzyloxycarbonyl)-piperazine-2-carboxylic acid (from Example 7, Step A) 680 mg (6.26 mmole) of chlorotrimethylsilane, 1.23 g (9.5 mmole) of N,N-diisopropylethylamine and 665 mg (2.5 mmole ) of 97% of 10,11-dihydro-5H-dibenz[b,f]-azepine-5-carbonyl chloride , gave 284 mg (24%) of (S)-1-(10,11-dihydro-5H-dibenz [b,f]azepine-5-carbonyl)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid, mp 185° C. (softened >90° C.); TLC Rf 0.68 (Antaltech SGF plates developed with isoamyl alcohol:acetone:water [5:2:1]).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][CH:27]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:35])([F:24])[F:36])[N:31]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cccc(C(F)(F)F)n3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364B) and 6-(trifluoromethyl)-2-pyridinecarboxylic acid: MS (ES) m/z 478 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([O:13]CC)=[O:12])[CH:7]=1.[OH-].[Li+:17]>O.CO.C1COCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([O-:13])=[O:12])[CH:7]=1.[Li+:17]
Reactant: CCOC(=O)c1cnn2cc(F)cnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C([O-])c1cnn2cc(F)cnc12
Yield: 108.4 %

Procedure:
A suspension of ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (512 mg, 2.45 mmol) and lithium hydroxide (61.5 mg, 2.57 mmol) in water (1 ml), MeOH (1 ml) and THF (1 ml) was irradiated to 100° C. for 10 min in the microwave. The reaction mixture was concentrated under vacuum, azeotroping with toluene (10 ml) to leave the title compound as a yellow powder (497 mg). This crude material was used directly in the subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([F:34])=[C:12]([NH:11][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)s1
Yield: 32.2 %

Procedure:
In the same manner as in Example 261 and using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (190 mg, 1.2 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2 mmol), N,N-diisopropylethylamine (240 mg, 1.9 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (93 mg, 32%) was obtained as a pale-yellow solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O.O1CCOCC1.O1CCOCC1>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:6]2[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)C1CNCCN1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCNC(C(=O)O)C2)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of piperazine-2-carboxylic acid dihydrochlorid (13.95 g, 68.70 mmol) in water/dioxane 1:1 (280 ml) at 0° C., NaOH 5 N (48 ml) was added to achieve complete dissolution. 4-tert-butylbenzenesulfonylchloride (17.586 g, 75.57 mmol) in dioxane (140 ml) was then added dropwise at 2° C. In 1 h. The reaction mixture was stirred overnight at 2° C. and over the week-end at room temperature. Solvents were removed in vacuo and the residue obtained was crystallized in EtOH to give 17.3 g of crude 4-(4-tert-butylphenyl-sulfonyl)piperazine-2-carboxylic acid. This material was dissolved in DCM (340 ml) and triethylamine (23 ml, 158 mmol) followed by di-tert-butyl-dicarboxylate (11.5 g, 52.7 mmol) were added. The mixture was stirred at mom temperature overnight, washed with HCl 1N, and brine. Organic phase was then dried over magnesium sulfate, filtered and concentrated to give 23.5 g of a white solid. This crude was purified by flash chromatography using DCM/MeOH 95:5 then DCM/MeOH/AcOH 90:10:0.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[S:10][C:11]([C:17]3[C:22]([F:23])=[CH:21][C:20]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:19][C:18]=3[F:28])=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:28][C:18]1[CH:19]=[C:20]([C:24]([OH:27])([CH3:26])[CH3:25])[CH:21]=[C:22]([F:23])[C:17]=1[C:11]1[S:10][C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)=[CH:3][CH:4]=2)=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(Cl)nn3)s2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(-c4ccn[nH]4)nn3)s2)c(F)c1

Procedure:
To a solution of 2-[(6-chloropyridazin-3-yl)amino]-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (64 mg, 0.15 mmol) in THF (3 ml), was added 1H-pyrazol-3-yl boronic acid (34 mg, 0.30 mmol), and sodium bicarbonate (0.38 ml, 0.75 mmol, 2 M). Palladium tetrakis triphenylphosphine (35 mg, 0.03 mmol) was added last and the vial was purged with nitrogen for 5 minutes. The crude product was washed with 3:1 chloroform:isopropanol and water. The resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Purification by column chromatography yielded the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[CH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[CH2:10]([C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:11]
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1ncccc1N
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 0.220 g (1.47 mmol) of 3-nitro-2-vinyl-pyridine dissolved in 1:1 methanol/ethyl acetate was added 0.010 g of Pd/C. The resulting mixture was hydrogenated overnight at 50 psi. Filtration and removal of solvent provided 0.160 g (89% yield) of 2-ethyl-pyridin-3-ylamine.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]([CH3:11])=[CH2:10])=[CH:3][CH:2]=1.C1COCC1.[Br:18]Br>>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7][CH2:8][CH:9]([CH3:11])[CH2:10][Br:18])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: C=C(C)CSc1ccc(C)cc1
Solvent: C1CCOC1
Product: Cc1ccc(SCC(C)CBr)cc1

Procedure:
3-p-Tolylthio-2-methylpropene (15 mmol, 2.67 g) was hydroborated with BH3 -THF (5 mmol) at 0°. The brominations were carried out as described in the general procedure. The product was isolated via chromatography; yield 2.67 g (61%); [90% via Br2 reactions]; m.s. 257 and 259 [M-1] (calcd. 258 and 260); NMR (CDCl3) δ 1.0 (d, 3H, --CH3), 1.6 (m, 1H, --CH--), 2.2 (s,2H, ArCH3), 3.4 (m, 2H, --CH2Br), 3.2 (d, 2H, --SCH2), 7.0 (A'2X'2, 4H, ArH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(Cl)C=CC=2F)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O>C1COCC1>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1F)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-fluorophenyl]benzenesulfonamide (500 mg, 1.56 mmol), triphenylphosphine (859 mg, 3.28 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentanol (682 mg, 3.12 mmol) in THF (7 mL) was added diisopropylazodicarboxylate (0.645 mL, 3.28 mol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22° C. with stirring. Stirring was continued for a period of 12 h followed by the addition of 15 mL of H2O. The mixture was extracted with ether (3×15 mL). The combined organic extracts were washed with NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 495 mg of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)-dimethylsilyl]oxy)butyl]benzenesulfonamide as a yellow oil in 61% yield.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23]([CH2:32][O:33][CH2:34][CH3:35])=[N:22][C:17]=4[CH:18]=[N:19][C:20]=3[CH:21]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:48].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:34]([O:33][CH2:32][C:23]1[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:16]2[C:15]3[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])=[CH:21][C:20]=3[N:19]=[C:18]([NH2:48])[C:17]=2[N:22]=1)[CH3:35]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(C=CS(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(/C=C/S(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Reaction time: 0.5 h

Procedure:
7-(2-Benzenesulfonylvinyl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (0.600 g, 1.22 mmol) was dissolved in chloroform (12 mL). 3-Chloroperoxybenzoic acid (60% purity, 0.351 g, 1.22 mmol) was added. The reaction was stirred for 30 minutes. Ammonium hydroxide (8 mL) was added and the mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride (0.232 g, 1.22 mmol) was added in one portion and the reaction was stirred for an additional 16 hours. The layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using a Horizon HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc.; Charlottesville, Va., USA). The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out with a silica cartridge eluting with a linear gradient of 1-22% CMA in chloroform. The resulting material was subsequently recrystallized from acetonitrile to yield 0.320 g 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-[(E)-2-(phenylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-4-amine as green needles, mp 188.5-190.0° C.
Reaction SMILES: [CH2:1]([C:4]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:27])[C:22]2[S:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(C(OCC)=O)[C:5]([O:7]CC)=[O:6])[CH:2]=[CH2:3].[OH-].[Na+]>>[C:22]1([C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:4]([CH2:1][CH:2]=[CH2:3])[C:5]([OH:7])=[O:6])=[CH:16][CH:17]=2)=[O:27])[S:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 20.3 parts of diethyl 2-allyl-2-[p-(2-thenoyl)phenyl]malonate and 150 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and washed twice with 80 parts of ether. The aqueous phase is separated and acidified with concentrated hydrochloric acid solution till strongly acid: an oil is separated which solidifies. The product is extracted with ether. The extract is washed with water, dried and evaporated. The oily residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from 32 parts of acetonitrile at -20° C, yielding 2-[p-(2-thenoyl)phenyl]-4-pentenoic acid; m.p. 117.1° C; also named p-(2-thenoyl)-α-allyl-phenylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]([CH3:12])=[C:8]([CH2:10][CH3:11])[CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Cl:15][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([CH2:10][CH3:11])=[C:7]([CH3:12])[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Solvent: ClC(Cl)Cl
Product: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of 3-nitro-5-ethyl-6-methylpyridin-2(1H)-one (0.91 g, 5.0 mmol) and phosphorus pentachloride (1.25 g, 6.0 mmol), under a nitrogen atmosphere, was heated at 140° C. for 0.5 hours. The cooled mixture was diluted with chloroform and ice water. The separated chloroform layer was then washed with water, saturated aqueous NaHCO3 and dried (Na2SO4). After filtering through a pad of charcoal, solvent was evaporated to yield 672 mg (67%) of product.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>O1CCCC1>[CH2:25]([NH:27][C:28]([NH:17][CH2:16][CH2:15][CH:13]1[C:14]2[C:5]3[O:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)=[O:29])[CH3:26]
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Reactant: CCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Reaction time: 0.25 h
Yield: 11.4 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (156 mg, 0.617 mmol) and triethylamine (86.1 mL, 0.617 mmol) were dissolved in tetrahydrofuran (6.2 mL), ethyl isocyanate (58.6 μL, 0.741 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (20.2 mg, yield 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12](O)([C:14]([CH3:17])([OH:16])[CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]2[O:16][C:14]([CH3:17])([CH3:15])[C:12]([CH3:13])([CH3:11])[O:8]2)[C:5]([F:10])=[N:4][CH:3]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1cc(Cl)cnc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)OC(c2cc(Cl)cnc2F)OC1(C)C

Procedure:
A flask fitted with a Dean-Stark trap was charged with a solution of 5-chloro-2-fluoronicotinaldehyde, 27, (8.95 g, 56.10 mmol) and 2,3-dimethylbutane-2,3-diol (8.00 g, 67.70 mmol) and p-toluene sulfonic acid mono hydrate (0.54 g, 2.81 mmol) in toluene (250 mL) and heated to vigorous reflux for 3 hr. The mixture was cooled, diluted with EtOAc, washed with NaHCO3 (2×) and brine (1×). The organic phase was dried over Na2SO4, filtered through a silica plug and concentrated in vacuo. A crystalline solid formed on standing (14.47 g): 1H NMR (300.0 MHz, CDCl3) δ 8.12 (s, 1H), 7.97 (dd, J=2.7, 7.8 Hz, 1H), 6.08 (s, 1H), 1.33 (s, 3H) and 1.26 (s, 3H) ppm.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25](=[N:29][O:30][CH3:31])[C:26]([OH:28])=O)[N:24]=1.[CH3:32][C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[C@H:41]([NH2:44])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])=[O:34]>CC(N(C)C)=O.C(Cl)Cl>[C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[CH:41]([NH:44][C:26](=[O:28])[C:25]([C:23]3[N:24]=[C:20]([NH2:19])[S:21][CH:22]=3)=[N:29][O:30][CH3:31])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])(=[O:34])[CH3:32]
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1

Procedure:
The process of claim 1 comprising reacting at low temperature, in dimethylacetamide, in the presence of triethylamine, tosyl chloride and the syn isomer of 2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid and reacting the resulting product with 7-amino-cephalosporanic acid in methylene chloride in the presence of triethylamine to obtain the syn isomer of 3-acetoxymethyl-7[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.