Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]#N)(=[O:4])=[O:3].[CH3:8]I.[H-].[Na+].O.C[N:14]([CH3:17])C=O>>[CH3:8][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[C:17]#[N:14]
Reactant: CI
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methylsulfonylacetonitrile (25 g) and methyl iodide (27.4 mL) in N,N-dimethylformamide (300 mL) was added sodium hydride (20 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (18 g, yield 58%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C)C=O.O>[CH3:19][C:17]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)([CH3:18])[CH2:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (3.4 g, 0.024 mol), K2CO3 (6.6 g, 48 mmol) and 4-(tert-octyl)phenol (5.0 g, 0.024 mol) in dimethylformamide (50 mL) was heated at reflux for 24 hours. The mixture was allowed to cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (250 mL). The organic phase was washed with water (5×100 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the desired product as a yellow solid (7.8 g, 100%): 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, 9.2 Hz, 2 H), 7.48 (d, 8.8 Hz, 2 H), 7.09-7.05 (m, 4H), 1.72 (s, 2 H), 1.34 (s, 6 H), 0.69 (s, 9 H); MS (FAB) m/z 328 (MH+); Rf =0.92 (15:85 ethyl acetate/hexane).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[O:26]1CCOCC1.O>[N+]([O-])([O-])=O.[Ag+].C(Cl)Cl>[CH3:23][N:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:17](=[O:18])[N:12]([C:9]2[CH:10]=[CH:11][C:6]3[S:5][N:4]=[C:3]([CH:2]=[O:26])[C:7]=3[CH:8]=2)[C:13]1=[O:24]
Reactant: C1COCCO1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.500 g, 0.00100 mol) in a dioxane/water mixture (5:2) is treated with silver nitrate (0.340 g, 0.00200 mol), refluxed for 90 minutes, cooled to and stirred at room temperature overnight, refluxed for three hours, cooled, and filtered through a pad of diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain an aqueous mixture. The aqueous mixture is extracted with methylene chloride. The organic extract is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel and methylene chloride gives the title product as a solid (0.240 g, mp 193-194.5° C.).
Reaction SMILES: [OH:1][C@H:2]([C@@H:11](O)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][C@@H:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1.CCOCC>[Br:36][C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:2]([OH:1])[CH2:3][C@@H:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)C[C@H](O)[C@@H](O)C[C@H](C(=O)O)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)C[C@@H](Br)[C@@H](O)C[C@H](C(=O)O)C(C)C
Reaction time: 0.5 h

Procedure:
A stirred solution of the γ-lactone of (2S,4S,5S)-4,5-dihydroxy-2-isopropyl-7-methyloctanoic acid from Preparation IIIA (0.214 g., 1 mmol) and triphenylphosphine (0.289 g., 1.1 mmol) in benzene (3 ml) is cooled in an ice bath and treated during 5-10 minutes with N-bromosuccinimide (0.196 g., 1.1 mmol). The mixture is kept cold for an additional 30 minutes and then at ambient temperature for 4 hours. It is diluted with Et2O and filtered. The filtrate is con-centrated and the residue chromatographed on silica gel (100 g.) with 7.5% EtOAc-hexane. The product, the γ-lactone of (2S,4S,5R)-5-bromo-4-hydroxy-2-isopropyl-7-methyloctanoic acid, thus obtained was crystallized from cold pentane to give 0.061 g., m.p. 62.5°-63.5° C. and 0.054 g., m.p. 60°-62.5° C.
Reaction SMILES: N1C=CN=C1.[CH2:6]1[CH2:18][O:17][C:8]([CH3:16])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][OH:14])[O:7]1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[O:14]([CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]1([O:7][CH2:6][CH2:18][O:17]1)[CH3:16])[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(CO)CCCC1(C)OCCO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CCCC1(C)OCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Imidazole (26.5 g) is added to a solution of 6,6-ethylenedioxy-2-methyl-heptanol (33.35 g) in dimethylformamide (50 ml). A solution of t-butyldiphenylsilyl chloride (52.2 g) in dimethylformamide (200 ml) is added dropwise to the reaction mixture and allowed to stir for 3 hours at room temperature. The reaction mixture is extracted with hexane (3×300 ml) and the combined extract is washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give 1-t-butyldiphenylsiloxy-6,6-ethylenedioxy-2-methyl-heptane (75.35 g, 99.6%); nmr (CDCl3,δ), 0.91 (d, 3H, CH3CH), 1.03 [s, (CH3)3C], ##STR43## 3.47 (d, CHCH2O), 3.88 (s, OCH2CH2O), 7.2-7.8 (m, 10 H, 2φ).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18](=O)[C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]1[N:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]2=[N:16][N:17]=1
Reactant: O=C(NNc1ccc(F)cn1)c1c(Cl)cccc1Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(-c3c(Cl)cccc3Cl)n2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
Hexachloroethane (2.60 g, 11.0 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 26b (1.65 g, 5.50 mmol), triphenylphosphine (2.88 g, 11.0 mmol), and triethylamine (3.06 mL, 22.0 mmol) in THF (50 mL). The reaction mixture was stirred at RT for 18 h and then allowed to stand at RT for 72 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo and purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH, and the product was eluted with 2M NH3 in MeOH to give the title compound (1.44 g, 93%) as a beige solid. LCMS (Method 3): Rt 3.08 min, m/z 282, 284 [MH+].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:9]1=[O:22])=[O:7])(C)(C)C.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].[CH3:33]C([O-])=O.[Na+]>CC(OC(C)=O)=O>[C:6]([N:8]1[C:9](=[O:22])[N:10]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:11](=[O:13])/[C:12]/1=[CH:29]\[C:28]1[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1)(=[O:7])[CH3:33]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Yield: 109.9 %

Procedure:
A mixture of 3-(3,5-dichlorophenyl)-2,4-dioxoimidazolidine-1-carboxylic acid tert-butyl ester (3.45 g, 10 mmol) (Preparation 11), 4-cyanobenzaldehyde (1.31 g, 10 mmol) and NaOAc (0.82 g, 10 mmol) was refluxed for 3 h in Ac2O (50 ml). The solid obtained after concentration was taken into a mixture of ice/water and DCM. The organic layer was dried and concentrated to yield a solid (4.4 g) which was chromatographed over silica gel (eluent: DCM) to yield 4-[3-acetyl-1-(3,5-dichlorophenyl)-2,5-dioxoimidazolidin-4-ylidenemethyl]-benzonitrile as a white solid (1.25 g). mp=212° C. 1H NMR (CDCl3): 8.52 (1H, s), 7.6-7.75 (4H, m), 7.43 (1H, m), 7.37 (2H, m), 2.78 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)[C:27](OC)=[O:28].COC1C=C(S)C=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:28][CH3:27])[CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: COc1cccc(S)c1
Product: COC(=O)c1c(CSc2cccc(OC)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-methoxythiophenol.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][NH2:20].S1(CCCC1)(=O)=O>CO>[CH3:19][NH:20][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: CNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
11 g of 4-chloro-3-nitro-benzophenone, 20 g of methylamine, 153.4 g of methanol and 27.5 g of sulpholane are warmed to 125° for 15 hours in a closed vessel. The reaction solution is evaporated to dryness, the residue is boiled thoroughly with 400 ml of 2 N hydrochloric acid for 20 minutes and the precipitate is filtered off, washed with water and dissolved in methylene chloride. After drying over sodium sulphate and evaporating, 4-methylamino-3-nitro-benzophenone with a melting point of 198°-201° is obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:13]=2[C:14](/[N:16]=[C:17]2/[N:18]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[N:19]([CH3:26])[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21]/2)=[O:15])[CH2:7]1.C(N(CC)CC)C>C1COCC1>[C:22]([C:20]1[N:19]([CH3:26])[N:18]([CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][O:29]2)/[C:17](=[N:16]/[C:14](=[O:15])[C:13]2[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:12]=2[O:11][CH2:10][CH:8]2[CH2:9][N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]2)/[CH:21]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCC2CNC2)n1C[C@H]1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCC2CN(S(C)(=O)=O)C2)n1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
Methanesulfonyl chloride (0.05 g, 0.4 mmol) was added to a solution of Example 54B (0.21 g, 0.4 mmol) in THF (5.0 mL) followed by triethylamine (0.17 mL, 1.2 mmol). The mixture was stirred for 1 hour at ambient temperature, then partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, solvent A—hexane:EtOAc:Et3N (1:3:0.2), solvent B—hexane:EtOAc:MeOH:Et3N (1:3:1:0.2) 100% solvent A to 100% solvent B over 450 mL then isocratic for 180 mL) to afford the title compound (0.12 g, 0.21 mmol, 49% yield). 1H NMR (500 MHz, pyridine-d5) δ ppm 1.21 (s, 9H), 1.54-1.62 (m, 2H), 1.64-1.71 (m, 1H), 1.75-1.85 (m, 1H), 3.01-3.09 (m, 1H), 3.31 (s, 3H), 3.54-3.63 (m, 1H), 3.69-3.76 (m, 1H), 3.85 (s, 3H), 4.05 (t, J=8.1 Hz, 2H), 4.09 (d, J=4.3 Hz, 2H), 4.22-4.28 (m, 1H), 4.36-4.46 (m, 3H), 4.62 (dd, J=15.1, 3.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.65 (dd, J=8.7, 2.3 Hz, 1H), 8.48 (d, J=2.4 Hz, 1H); MS (ESI+) m/z 573.2 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O.O1CCCC1>>[CH:12]1([CH:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[CH2:8][C:9]([OH:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(CC(=O)O)C1CCCCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Methyl chloroformate (54 uL, 0.70 mmol) was added to a mixture of 3-amino-3-cyclohexylpropanoic acid (100.0 mg, 0.5840 mmol) (Key Organics/Bionet, Cat. #7T-0112) and potassium carbonate (160 mg, 1.2 mmol) in water (2.0 mL, 110 mmol) and tetrahydrofuran (2.0 mL, 25 mmol). After stirring at r.t. for 10 min, the mixture was extracted with ether to remove impurity. The aqueous layer was adjusted to pH=2 with HCl, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (130 mg, 97%). Analytic LCMS (M+H)+: m/z=230.1.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[CH3:9][C:10]1([CH3:24])[O:11][C:12](=[O:23])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:2]3[O:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=3)=[CH:16][C:15]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1ccc(Br)o1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)o3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile was prepared, according to the procedure of Example 5 from 2-bromo-5-cyanofuran (1.0 g, 5.6 mmol) (J. Med. Chem. (1997), 40(23), 3804-3819) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8 g, 8.18 mmol), as a white solid (0.39 g, 1.45 mmol, 17%): mp 257-260° C.; 1H-NMR (DMSO-d6) δ 10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H, J=3.8 Hz), 6.98 (d, 1H, J=8.9 Hz), 1.66 (s, 6H); MS ((+)-APCI) m/z=269 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17][N:16]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.[Br:29][Si](CC)(CC)CC>C1COCC1>[Br:29][CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17][N:16]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1)[OH:1]
Reactant: CC[Si](Br)(CC)CC
Reactant: CCCc1c(-c2nc(-c3ccc(C4CO4)cc3)no2)noc1-c1ccccc1
Solvent: C1CCOC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazole (205 mg, 0.549 mmol) in THF (5 mL) at −78° C. was slowly added bromotriethylsilane (100 μL, 0.582 mmol). The reaction mixture was stirred for 1 hour at −78° C. LC/MS was employed to determine extent of reaction. An aliquot was removed and concentrated in vacuo. Crude NMR indicated mostly desired regioisomer. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated. The solids were purified on a silica cartridge using an EtOAc/hexanes gradient to yield 130 mg of Preparation 1C as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16-8.24 (2H, m), 7.72-7.81 (2H, m), 7.61 (2H, m, J=8.13 Hz), 7.49-7.58 (3H, m), 5.12 (1H, dd, J=7.47, 5.93 Hz), 4.09-4.17 (1H, m), 4.01-4.08 (1H, m), 2.97-3.05 (2H, m), 1.70-1.83 (2H, m), 1.06 (3H, t=7.36 Hz).
Reaction SMILES: C([O:4][C@@H:5]([CH3:28])[C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(OCC)C>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:28])=[C:10]([C:19]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=3)=[O:20])[NH:11]2)=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: C[C@H](O)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reaction time: 30 h
Yield: 74.7 %

Procedure:
To a suspension of 3-[(S)-2-acetoxypropionylamino]-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 362, 316.7 mg, 0.7536 mmol) in DMSO (10 ml) was added potassium carbonate (104.2 mg, 0.7536 mmol) in water (1 ml) at room temperature. After stirring for 30 h, the mixture was diluted with diethyl ether (200 ml), and then washed with water (50 ml×3), brine (50 ml), and dried (MgSO4). Removal of solvent gave a crystalline residue, which was recrystallized from ethyl acetate to afford 213.0 mg (74.7%) of the title compound. m.p.: 244-246° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3483, 3288, 1690, 1570, 1553, 1533, 1481, 1348, 1240, 1186, 737 cm−1. 1H-NMR (DMSO-d6) δ: 12.07 (1 H, br s), 11.43 (1 H, br s), 8.82 (1 H, dd, J=5.3 and 0.5 Hz), 8.26 (1 H, d, J=9.1 Hz), 8.20 (1 H, dd, J=2.1, 0.5 Hz), 7.91 (1 H, dd, J=5.4, 2.1 Hz), 7.67 (1 H, dd, J=2.0, 0.5 Hz), 7.07 (1 H, dd, J=8.9, 2.0 Hz), 6.18 (1H, d, J=4.9 Hz), 4.23 (1 H,dd, J=6.8, 4.9 Hz), 134 (3 H, d, J=6.8 Hz).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1=[N:6][C:7](=[O:17])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34].O>CS(C)=O>[CH3:3][NH:4][C:5]1=[N:6][C:7](=[O:17])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][N:14]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[C:33]([F:34])([F:36])[F:35])[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNC1=NC(=O)S/C1=C\C1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To a solution of (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (100 mg) in dimethyl sulfoxide (2 mL) were added cesium carbonate (327 mg) and 4-fluoro-3-(trifluoromethyl)benzonitrile (76 mg), and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (14.5 mg).
Reaction SMILES: C1(C)C=CC=CC=1[C:7]1[CH:8]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3C=CC=CC=3C)[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.O(C1C=C(C=CC=1)C[Br:39])C1C=CC=CC=1.C1(C)C(C)=CC=CC=1.O.[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[Br-:39].[O:13]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][N+:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1-c1cccc(Oc2cccc(-c3ccccc3C)c2)c1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: [Br-]
Product: c1ccc(Oc2cccc(C[n+]3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
52.6 g of the brominated product of m-tolylphenyl ether containing 26.3 g of 3-phenoxybenzyl bromide was added to a mixed solution of 100 ml of xylene and 50 ml of water, and then 11.9 g of pyridine was added thereto. The mixture was heated to 70° to 75°C, kept at the same temperature for 3 hours while stirring and then cooled to room temperature (about 20° - 30°C). The lower aqueous layer which separated was removed, washed with a small amount of xylene, evaporated and then dried under a reduced pressure to obtain 34.5 g of colorless, crystalline 3-phenoxybenzyl pyridinium bromide (m.p. 120° - 121°C).
Reaction SMILES: C([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:16]=1OC)([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)[C:4]([O:6]CC)=[O:5])#N.[C:31](O)(=O)C>I>[CH2:9]([CH:3]1[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:16]=2[O:6][C:4]1=[O:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:31]
Reactant: CCCCCCC(C#N)(C(=O)OCC)c1cccc(Sc2ccccc2C)c1OC
Reactant: CC(=O)O
Agent: I
Product: CCCCCCC1C(=O)Oc2c(Sc3ccccc3C)cccc21

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]octanoate (5 g) in hydriodic acid (58%, 20 ml) and acetic acid (40 ml) was refluxed under heating for 24 hours. The reaction mixture was treated in a similar manner to that of Example 31-(7) to give oily 3-n-hexyl-7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one (1.7 g).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20].[Cu][C:25]#[N:26]>CN1CCCC1=O.O.N.C(OCC)(=O)C>[F:20][C:19]([F:22])([F:21])[C:18]([N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[CH2:11][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[C:25]#[N:26])=[O:23]
Reactant: O=C(N1CCCCC1Cc1oc2ccccc2c1Br)C(F)(F)F
Reactant: N#C[Cu]
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1c(CC2CCCCN2C(=O)C(F)(F)F)oc2ccccc12

Procedure:
To a solution of (RS)-1-(2-3-bromo-benzofuran-2-ylmethyl-piperidin-1-yl)-2,2,2-trifluoro-ethanone, D41 (840 mg, 2.1 mmol) in N-methylpyrrolidinone (15 ml) was added copper(I)cyanide (387 mg, 4.2 mmol) and the mixture refluxed for 4.5 h. The reaction mixture was cooled sand diluted with water (100 ml), 0.880 ammonia (3 ml) and ethyl acetate (3×). The combined extracts were dried (Na2SO4) and the solvent removed in vacuo. The residual oil was redissolved in ethyl acetate (75 ml) and washed with water (4×), brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel) afforded the title compound as a solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:24])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][C:15]([Cl:23])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])=[CH:5][CH:6]=1.C([O-:28])(C)C.C([O-])(C)C>O>[CH2:13]1[CH:12]2[CH:11]([NH:10][C:8]([C@H:7]([NH2:24])[C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[O:9])[C:18](=[O:19])[N:17]2[C:16]([C:20]([OH:22])=[O:21])=[C:15]([Cl:23])[CH2:14]1.[OH2:28]
Reactant: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Reactant: CC(C)[O-]
Solvent: O
Product: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Temperature: 75 °C

Procedure:
A sample of loracarbef isopropanolate is charged to the 300 mm. Allihn condenser. Deionized water (200 g) is charged to a 1 L., 1-neck, round bottom flask. The flask is placed in the Kugelrohr oven and connected to the condenser. The system's pressure is pulled down to approximately 300 mbar. The jacket on the condenser is heated to 75° C. with a constant temperature bath. The Kugelrohr oven is heated to 65° C. The system's pressure is further reduced to 250 mbar and the isopropanolate is subjected to a relative humidity of 100% with agitation for approximately 6 to 8 hours. The oven and condenser are cooled to 20°-25° C. The system is vented to atmospheric pressure. The hydrated product is removed and placed in a vacuum oven at 40°-45° C. The product is dried overnight under full vacuum with a slight nitrogen sweep.