Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][N:38]2[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:41]3[CH:40]=[N:39][N:38]([CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH:42]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.06 g, 25% yield). LCMS: 561.35 (M+1)+; HPLC % 96.87 (@254 nm) (Rt; 4.209; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.15 (s, 1H), 8.06 (t, 1H), 7.81 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 4.21 (t, 2H, J=6 Hz), 3.54 (m, 4H), 2.72 (t, 2H, J=6.8 Hz), 2.61 (s, 3H), 2.40 (m, 4H), 2.20 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.70 (m, 4H), 1.53-1.56 (m, 3H), 1.10-1.23 (m, 4H).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C[Zn]C.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17](Cl)([CH3:19])[CH3:18])=[CH:15][CH:14]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:11][C:12]([F:24])([F:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([CH3:1])([CH3:19])[CH3:18])=[CH:15][CH:14]=1
Reactant: CC(C)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Zn]C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: -40 °C

Procedure:
To a toluene solution of dimethylzinc (150 mL, 2.0M, 0.30 mol) at -78° C. is added a CH2Cl2 solution of titanium tetrachloride (150 mL, 1.0 M, 0.15 mol) and after stirring for 30 min 4-trifluoromethyl-α,α-dimethylbenzyl chloride (83.3 g, 0.373 mol) in CH2Cl2 (100 mL) is added dropwise over 20 min. After the addition is complete the reaction is allowed to warm to -40° C. over 1.5 h. After an additional 2 h at -40° C. the brown reaction mixture is carefully poured onto crushed ice, extracted with CH2 Cl2 (2×500 mL), the combined extracts dried over MgSO4 and concentrated to give 4-trifluoromethyl-t-butylbenzene; yield: 60.3 g (80%). Anal. Calcd. for C11H13F3 : C, 65.32; H, 6.48. Found: C, 65.11; H, 6.38.
Reaction SMILES: [O:1]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13]I.[Cl-].[NH4+].O>C(COC)OC.[Cl-].[Na+].O>[O:1]=[C:2]([C:9]([F:10])([F:11])[F:12])[CH:3]([CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CI
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (7.05 g of a 50% oil dispersion, 0.15 mol) was washed 3 times with 25 ml of dimethoxyethane to remove the oil and then suspended in 220 ml of dimethoxyethane, under an argon atmosphere and cooled in an ice bath. A solution of ethyl 3-keto-4,4,4-trifluorobutanoate (25.77 g, 0.14 mol) in 25 ml of dimethoxyethane was added dropwise from an addition funnel to the stirred suspension. After the addition was completed, the cooling bath was removed and the reaction mixture stirred for 30 minutes past the cessation of hydrogen gas evolution. Methyl iodide (43.0 ml, 0.70 mole) was added by syringe and the reaction mixture refluxed overnight. The reaction was cooled to room temperature and poured into a separatory funnel containing a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with 100 ml ether. The combined organic phase and ether extract was washed with brine, dried over magnesium sulfate and filtered. The solvents were removed by distillation at atmospheric pressure using a Vigreaux column leaving ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate as the pot residue. Rf: (EtAc/hexane - 20:80)
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:20](Cl)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CCOCC>C1C=CC=CC=1.O>[C:20]([O:12][C:10]1[CH:9]=[C:8]([CH3:13])[C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=1)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1cc(O)cc(C(C)(C)C)c1O
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1cc(C)c(O)c(C(C)(C)C)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
6.5 G OF 2-T-BUTYL-6-METHYLHYDROQUINONE ARE DISSOLVED IN 65 ML OF BENZENE UNDER NITROGEN AND 2.85 G OF PYRIDINE ARE ADDED. The solution is warmed to 45°C and 10.9 g of stearoyl chloride added. The reaction mixture is maintained at 45°-50°C while stirring for about 3 hours and then cooled to room temperature. 25 ml of benzene, 30 ml of ether and 50 ml of water are added and the mixture shaken in a separatory funnel. The benzene ether layer is then washed twice wth 30 ml portions of water and then dried over magnesium sulfate, filtered and the benzene-ether stripped in vacuo. The residue of 15.6 g was recrystallized twice from methanol and yielding 11.4 g of an off-white crystalline solid having a melting point of 64°-65.5°C.
Reaction SMILES: II.[N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[C:4]=[O:5]>ClC1C=CC=CC=1Cl>[CH3:14][C:11]1[CH:10]=[C:9]2[C:8]([CH:7]=[CH:6][NH:3][C:4]2=[O:5])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C=CN=C=O)cc1
Agent: II
Solvent: Clc1ccccc1Cl
Product: Cc1ccc2cc[nH]c(=O)c2c1
Temperature: 180 °C
Yield: 31.1 %

Procedure:
Iodine (0.63 g, 2.51 mmol) is added to a solution of 1-(2-isocyanato-vinyl)-4-methyl-benzene (ca. 20 g, 125.6 mmol) in o-dichlorobenzene (125 mL), then is heated to reflux (180° C.) overnight. The mixture is cooled to room temperature then concentrated to dryness. The residue is purified by column chromatography eluting with 40% EtOAc/hexanes. The product (6.23 g, 39.1 mmol) is obtained as a tan solid.
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].Cl.N[OH:13]>COCCO>[CH3:1][N:2]1[C:9]([NH:10][OH:13])=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: NO
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: Cl
Solvent: COCCO
Product: Cn1c(NO)cc(=O)[nH]c1=O
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A mixture of 2 g of 1-methyl-6-aminouracil, 2 g of hydroxylamine hydrochloride and 30 ml of methyl-cellosolve is boiled for 2 hours, after which the insolubles are filtered off. The filtrate is concentrated to dryness and tritulated with water. The resultant crystals are recovered by filtration and recrystallized from ethanol. By the above procedure is obtained 1.5 g of the captioned compound as pale-yellow crystals, melting point: 247°-250° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH2:1]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:14][CH:15]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CCCCCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid hexylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (35% yield). 1H NMR (300 MHz, CDCl3) δ8.02, 7.85, 7.72, 7.56, 7.34, 6.97, 4.00, 3.90-3.64, 3.48-3.28, 1.58, 1.29, 0.85. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.5, 134.3, 132.8, 129.5, 127.6, 127.2, 126.9, 125.4, 46.4, 44.6, 44.4, 41.3, 39.4, 31.5, 29.5, 26.6, 22.6, 14.0. MS (ES+) m/z (%) 464 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1NN(CC2CCCCC2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccc(Cl)c(Cl)c2)C(c2ccncc2)N1CC1CCCCC1
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.4 g 1-Cyclohexylmethyl-4-(3,4-dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one and 20 mL THF, stirred at 0° C. under nitrogen. 1.32 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min. 0.11 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hour, quenched with 50 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 0.4 g as light solid. MS (ES+): 418 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][CH2:20][C:15]3=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][CH2:20][C:15]3=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCC3
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Yield: 65.4 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.40 mL, 3.6 mmol) was added to a stirred solution of chloride 196 (270 mg, 1.2 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 197 (216 mg, 65%) as a yellow solid: mp (MeOH/EtOAc) 153-157° C.; 1H NMR δ 7.50 (s, 1H, H-9), 7.40 (t, J=1.4 Hz, 1H, H-5), 5.73 (br s, 1H, NH), 4.67 (t, J=8.3 Hz, 2H, H-7), 3.48-3.53 (m, 2H, CH2N), 3.53 (dt, J=8.3, 1.4 Hz, 2H, H-6), 2.55 (dd, J=6.1, 5.9 Hz, 2H, CH2N), 2.28 [s, 6H, N(CH3)2]; 13C NMR δ 158.3, 158.2, 146.1, 140.6, 130.6, 121.8, 96.6, 71.9, 57.7, 45.1 (2), 38.8, 29.7. Anal. calcd for C13H17N5O2.¼CH3OH: C, 56.2; H, 6.4; N, 24.7. Found: C, 56.1; H, 6.2; N, 25.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:29][C:30]([NH:32][CH:33]([CH:40]([CH3:42])[CH3:41])[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[O:31])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C(C)(C)C)[CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:29][C:30]([NH:32][CH:33]([CH:40]([CH3:41])[CH3:42])[C:34](=[O:39])[C:35]([F:38])([F:36])[F:37])=[O:31])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccc(OC(C)(C)C)c2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2cccc(O)c2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a solution of 2-[3-benzyloxycarbonylamino-6-(3-tert-butoxyphenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (78 mg) in dry dichloromethane (3 mL) was added trifluoroacetic acid (57 mg). After 5 h the reaction was incomplete, and additional trifluoroacetic acid (57 mg) was added. After 18 h the reaction mixture was diluted with dichloromethane (50 mL), washed with water and brine, dried, and evaporated to a crude oil which was purified by chromatography, eluting with ethanol:ethyl acetate:dichloromethane (0.5:5:94.5), to give the title compound as a white solid (60 mg); TLC: Rf =0.15, ethanol:ethyl acetate:dichloromethane (0.5:5:94.5); HPLC: tR =6.04, FR=2.0, column A, water:acetonitrile (55:45); MS: m/z=546(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:8][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: Oc1ncc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc(Br)cnc1OCC1CC1
Temperature: 70 °C

Procedure:
To a solution of 5-bromo-3-fluoropyridin-2-ol (1.00 g) in DMF (10 mL) were added potassium carbonate (1.44 g) and (bromomethyl)cyclopropane (0.758 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer 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 (hexane/ethyl acetate) to give the title compound (491 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[F:8][C:9]1[C:14](O)=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[F:8][C:9]1[C:14]([O:5][C:4](=[O:6])[CH2:3][N:2]([CH3:7])[CH3:1])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CN(C)CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 0.40 M solution of N,N-dimethylglycine (82.0 mg, 0.800 mmol) in EtOAc (2.00 mL, filtered through activated alumina) were added pentafluorophenol (162 mg, 0.880 mmol) and 1,3-dicyclohexylcarbodiimide (182 mg, 0.88 mmol). The reaction mixture was stirred for 12 h at rt at which time it was filtered (washing with EtOAc) and concentrated. Ester 18 was used immediately without further purification.
Reaction SMILES: OC1ON=[C:4]([CH3:7])[C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.C(O)(=[O:16])C.CO.Cl>[Fe].O>[CH2:3]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[C:4]([CH3:7])=[O:16]
Reactant: CC(=O)O
Reactant: Cc1cc(-c2c(C)noc2O)on1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)Cc1cc(C)no1
Temperature: 60 °C

Procedure:
9.70 g of 5-hydroxy-3-methyl-4-(3-methylisooxazol-5-yl)isoxazole was added to 18 ml of acetic acid and 30 ml of methanol, and was heated to 60° C. to dissolve. To the resulting solution was added 3.20 g of electrolytic iron powder to stir for an hour at 60° C. 20 ml of 3N hydrochloric acid was further added to the reaction solution to stir for 20 minutes at 60° C. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt water, dried over anhydrous magnesium sulfate and concentrated to give 6.00 g of the title compound as a reddish brown liquid.
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([O:18][CH3:19])[CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C>C1COCC1>[CH3:19][O:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:25]([OH:28])[OH:26])[CH:3]=1
Reactant: COB(OC)OC
Reactant: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
[2-(4-Bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane (2.6 g, 7.5 mmol) was stirred in dry THF (10 mL) at −78° C. under argon. n-Butyllithium (3.75 mL, 2.5 M in hexanes, 9.36 mmol) was added dropwise, and the reaction stirred for 30 min before it was transferred via cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15 mL), which was also stirring at −78° C. under argon. After addition was complete, the reaction stirred 30 min at −78° C. and then 30 min while warming to 0° C. It was then quenched with H2O (20 mL), acidified with 0.1 N HCl, and extracted with ethyl acetate (2×25 mL). Organics were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% to 50% ethyl acetate/hexanes) gave 1.11 g (47%) of 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid as a white solid. 1NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.10 (s, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.83 (t, 2H, J=8.4 Hz), 2.79 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C14H25BO5Si—H2O) C, H. Calculated: C, 57.15; H, 7.88. Found: C, 56.89; H, 7.87.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccc(CC2(O)CCCCC2)nc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc(Cc2ccccc2)nc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of 5-hydroxy-2-[(1-hydroxycyclohexyl)methyl]pyridine (1 g) in acetic acid (15 ml) containing sulfuric acid (5 ml) was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured on an ice, basified with 10% aqueous sodium hydrogen carbonate, and extracted with ether. The combined ether extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The residue was washed with isopropylalcohol to give 2-benzyl-5-hydroxypyridine (409 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:15])[N:21]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C=O)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 112.4 %

Procedure:
In 15 ml of dichloroethane, 315 mg of 4-t-butoxycarbonylaminopiperidine, 320 mg of 6-methyl-2-pyridinecarbaldehyde and 100 mg of acetic acid were dissolved. To the solution 575 mg of sodium triacetoxyborohydride was added at room temperature, followed by an hour's stirring at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1 to 50/1), to give 540 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+]([O-])=O)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:14]1(OC)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccccc1Cl

Procedure:
Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acid chloride with anisole in the presence of aluminum trichloride to produce a chlorobenzophenone compound; the chlorobenzophenone compound was reduced in the presence of trifluoromethanesulfonic acid and triethylsilane to produce a chlorodiphenylmethane compound; the chlorodiphenylmethane compound was treated with lithium sulfide and 2,2-dibutyl-3-(methanesulfonato)propanal to produce 1-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene (40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29. The first step of that method of preparing compound 29 requires the use of a corrosive and reactive carboxylic acid chloride that was prepared by the reaction of the corresponding carboxylic acid with phosphorus pentachloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][C:26]([CH3:41])([C:28]([O:30]CC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[CH3:27])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1.[Na+:42].[H][H].C(=O)([O-])O.[Na+]>O.O1CCCC1.[Pd]>[Na+:42].[Na+:42].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][C:26]([CH3:41])([C:28]([OH:30])=[O:29])[CH3:27])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1.[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][C:26]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:41])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]

Procedure:
In a mixture of 25 ml of water and 25 ml of tetrahydrofuran is dissolved 500 mg of sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer), followed by addition of 500 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for one hour. After addition of 25 ml of an aqueous solution of sodium hydrogen carbonate (62 mg), the catalyst is filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn-isomer).