Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([NH:41][C@H:42]([CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:43]O)=[O:40])([CH3:37])([CH3:36])[CH3:35].O>C1COCC1.CC#N.C1COCC1>[Si:47]([O:46][CH2:45][CH:42]1[CH2:43][N@@:41]1[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Ph3P (19.65 g, 75 mmol) was dissolved in 9:1 THF/CH3CN (600 mL) and cooled to 0° C., DIAD (14.7 mL, 75 mmol) was added dropwise over 15 min. After stirring for 30 min, a solution of (S)-2-(t-butoxycarbonylamino)-3-(t-butyldimethylsilyloxy)propan-1-ol (15.25 g, 50 mmol) in THF (100 mL) was added dropwise over 15 min, the reaction mixture was allowed to rt and stirred for 24 h. Water (100 mL) was added and volatiles were evaporated. The residue was partitioned between water (100 mL) and EtOAc (2×100 mL). The organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by silica chromatography to provide (S)-tert-butyl 2-(t-butyldimethylsilyloxymethyl)aziridine-1-carboxylate (7.8 g, 54%) as an oil. 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6H), 0.89 (s, 9H), 1.45 (s, 9H), 2.06 (d, J=3.6 Hz 1H), 2.26 (d, J=6 Hz 1H), 2.55 (m, 1H), 3.64 (dd, J=16.4, 4.8 Hz, 1H), 3.82 (dd, J=16.4, 4.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:14])=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:15][CH2:16][C:17](=O)[CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O>C(OCC)(=O)C>[Br:14][C:3]1[C:2]([NH:1][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:13])[N:4]=1
Reactant: CCOC(=O)c1cc(N)c(Br)nc1C
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(NC(CC)CC)c(Br)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of ethyl 5-amino-6-bromo-2-methylnicotinate (1.267 g, 4.89 mmol) in ethyl acetate (30 ml) were added 3-pentanone (0.463 g, 5.38 mmol), sodium triacetoxyborohydride (1.244 g, 5.868 mmol) and trifluoroacetic acid (1.15 g, 9.78 mmol) at room temperature. After stirring overnight at room temperature, another portion of sodium triacetoxyborohydride (0.6 g, 2.83 mmol) was added. The reaction mixture was stirred for another 6 hours. The reaction mixture was quenched with water (20 ml). The organic layer was washed with saturated sodium bicarbonate and brine. After evaporation of solvent, ethyl 6-bromo-2-methyl-5-(pentan-3-ylamino)nicotinate (1.20 g, 74.6% yield) was purified by column chromatography with 7% ethyl acetate/Hexane as eluent. 1H NMR (400 MHz, CDCl3): 7.35 (s, 1H), 4.40 (q, J=6.8 Hz, 2H), 4.10 (br, s, 1H), 3.30 (m, 1H), 2.68 (s, 3H), 1.8-1.5 (m, 4H), 1.42 (t, J=6.8 Hz, 3H), 1.0 (t, J=7.2 Hz, 6H). MS (EI) for C14H21BrN2O2: 329.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCc2cccc(F)c2)c1
Temperature: 0 °C

Procedure:
A solution of 3-nitro-phenol (0.278 g, 2.0 mmol), 1-bromomethyl-3-fluoro-benzene (0.258 ml, 2.1 mmol), potassium carbonate (0.553 g, 4.0 mmol) and tetrabutylammonium iodide (0.001 g) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Afterwards, ice water (10 mL) was added to the solution and the resultant solid was collected by filtration and dried in a vacuum oven to provide the title compound in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH:25]1[C:26]2[CH:14]([CH2:13][O:12][C:10](=[O:11])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=3)[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CO)cc1)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of (4-amino-phenyl)-methanol (500 mg), Fmoc-Cl (1.2 g) and pyridine (1 ml) in THF (15 ml) was stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from dichloromethane. Yield: 470 mg. MS-ESI: [M+H]+=346.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([O:24][C:25]1[C:33]([O:34][CH3:35])=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([N+:36]([O-:38])=[O:37])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C2C(=CC=CC=2)CC1.C(N(CC)CC)C>O1CCCC1>[CH2:17]([O:24][C:25]1[C:33]([O:34][CH3:35])=[CH:32][C:28]([C:29]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH:9]2[C:13]([O:15][CH3:16])=[O:14])=[O:30])=[C:27]([N+:36]([O-:38])=[O:37])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2N1
Reactant: COc1cc(C(=O)Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2N1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 41.4 %

Procedure:
Methyl 6-nitroindoline-2-carboxylate (258a) (0.233 g, 1.048 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml) in a separate flask and cooled to 0° C. an ice bath. In another flask 4-(benzyloxy)-5-methoxy-2-nitrobenzoyl chloride (4) (0.371 g, 1.153 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml) and cooled to 0° C. in an ice bath. To the flask containing the indoline was added triethylamine (0.438 ml, 3.15 mmol) via syringe and the acetyl chloride 4 was added quickly to the reaction mixture via cannula at 0° C. The reaction was stirred for 90 minutes at 0° C. and then at room temperature for an additional 1 hour. The reaction was then quenched with 5% HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using 30% Acetone in hexane to give methyl 1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-6-nitroindoline-2-carboxylate (258b) (0.220 g, 0.434 mmol, 41.4% yield) as a yellowish foam. 1H NMR (400 Hz, CDCl3): δ 3.30 (m, 1H), 3.60 (s, 3H), 3.69 (m, 1H), 3.86 (s, 3H), 4.64 (dd, 1H, J=2.4 Hz, 10.8), 5.23 (s, 2H), 7.31 (m, 1H), 7.46 (m, 6H), 7.99 (dd, 1H, J=2.0, 8.0 Hz), 9.04 (d, 1H, J=2.0 Hz). MS (m/z). found 530.1 ([M]++Na).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:27](OCC)=O>O1CCCC1>[CH3:27][N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (1.5 g), and LiAlH4 (26.6 ml of 1M solution in tetrahydrofuran) were combined in tetrahydrofuran (10 ml) and the reaction mixture stirred at room temperature for 10 min before cooling to 0° C. in an ice/water bath. Ethyl formate (5 ml) was then added dropwise. The reaction was then quenched with 3 N sodium hydroxide solution. The solid precipitate formed was filtered and washed with more tetrahydrofuran. The combined organics were dried over Na2SO4, and evaporated to give the title compound (D18) (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:27]1[CH2:29][CH2:28]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:26])[O:24][CH3:25])[C:14]([CH:17]=[CH2:18])=[N:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([CH:27]1[CH2:28][CH2:29]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:26])[O:24][CH3:25])[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1ncc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc1CCCNC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCc1ncc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc1CCCNC(=O)OC
Reaction time: 2 h
Yield: 74.6 %

Procedure:
to a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-vinylpyridin-3-yl)propyl]carbamate (280 mg) in methanol (10 mL) was added 10% palladium on carbon (140 mg), and the mixture was stirred under hydrogen for 2 hours. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform→chloroform/methanol=4/1) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]-ethyl}-2-ethylpyridin-3-yl)propyl]carbamate [REx(113-7)] (210 mg) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.ClC1N=CC(CC2C=NC(Cl)=CC=2)=C2C=1C=CC=N2.[F:40][C:41]([F:50])([F:49])[C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45].Cl.O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].C(O)C.CCOC(C)=O.O1CCOCC1>[F:40][C:41]([F:49])([F:50])[C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH:45][C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Agent: Cl
Agent: Clc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: Oc1ccc(Cc2cnc(Nc3cccc(C(F)(F)F)c3)c3cccnc23)cn1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
Under a N2 atmosphere, 146 mg (0.5 mmol) of 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contains a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine as an impurity) in 2.0 ml of tbutanol/dioxane 1:5 are mixed with 160 mg (1 mmol) of 3-trifluoromethyl-aniline and 0.12 ml of 4 N HCl/dioxane and stirred for 14 h at 70° C. The cooled reaction mixture is dissolved in diluted Na2CO3 solution and EtOAc whilst adding ethanol. The water phase is separated and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated by evaporation. The resulting oil is separated by reversed phase medium-pressure chromatography (water/acetonftrile/TFA). The fractions are partially concentrated by evaporation, then solid NaHCO3 is added to the aqueous residue. Extraction with 3 portions of EtOAc, drying (Na2SO4) and concentration by evaporation yields 5-(3-trifluoromethyl-anilino)-8-[(6-hydroxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36a (FAB-MS: (M+H)+=397; HPLC(gradient20-100) tRef=8.5); 5-(3-trifluoromethyl-anilino)-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36b (FAB-MS: (M+H)+=411; HPLC(gradient20-100) tRef=10.0) and 5-(3-trifluoromethyl-anilino)-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36c (FAB-MS: (M+H)+=415; HPLC(gradient20-100) tRef=11.5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][N:3]=1.[CH3:15][S-:16].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:9]([NH:8][C:6]1[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][N:3]=[C:2]([S:16][CH3:15])[N:7]=1)([CH3:11])[CH3:10]
Reactant: CC(=O)c1cnc(Cl)nc1NC(C)C
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1ncc(C(C)=O)c(NC(C)C)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1-(2-chloro-4-isopropylamino-pyrimidin-5-yl)-ethanone (11.1 g, 0.052 mol) and sodium thiomethoxide (5.75 g, 0.078 mol) are taken up in 100 mL dioxane and stirred for 16 h at 20° C. The solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and extracted 2× with water. The organic phase is dried, the solvent is eliminated in vacuo and 1-(4-isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (HPLC-MS: tRet.=1.82 min, MS(M+H)+=226; method FECB3) is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[C:12]([Br:14])[CH:13]=1.Cl[CH:17]([C:22](=[O:25])[CH2:23][CH3:24])[C:18](=[O:21])[CH2:19][CH3:20]>CC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([S:15][CH:17]([C:22](=[O:25])[CH2:23][CH3:24])[C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=[C:12]([Br:14])[CH:13]=1
Reactant: CCC(=O)C(Cl)C(=O)CC
Reactant: Sc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)C(Sc1cc(Br)cc(Br)c1)C(=O)CC
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
Potassium carbonate (1.9 g, 14 mmol) was added to a solution of 3,5-dibromobenzenethiol (2.84 g, 10.5 mmol) (Preparation 48) and 4-chloroheptane-3,5-dione (1.7 g, 10.5 mmol) (Preparation 40) in acetone (12 ml) producing a white suspension. The mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (70 ml). The aqueous layer was extracted with further dichloromethane (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a pink oil. The crude product was purified by flash chromatography on silica gel eluting with pentane:dichloromethane (1:1, by volume) to provide the title compound (3 g) as a pink oil.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[C:12](Cl)([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13].O>CCOC(C)=O>[Cl:17][C:16]([Cl:19])([Cl:18])[CH2:15][O:14][C:12](=[O:13])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 2,3-dichloroaniline (0.200 g, 1.23 mmol) in EtOAc (5 mL) was added NaOH (1M, 2 mL, 2 mmol) and Troc-Cl (0.262 g, 1.23 mmol) and the resulting mixture was stirred overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (408 mg, 98%) as a yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J=6.4 Hz, 1H), 7.43 (brs, 1H), 7.25-7.22 (m, 2H), 4.86 (s, 2H); MS (EI) m/z: 335.8 (M+H+).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][N:9]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[C:21]([F:24])([F:23])[F:22])[C:8]2=[O:12])[CH:2]=1
Reactant: Cc1cccc(N2CCNC2=O)c1
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cccc(N2CCN(c3cnccc3C(F)(F)F)C2=O)c1
Yield: 34.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-m-tolyl-imidazolidin-2-one (I-131b: 150 mg, 0.8522 mmol) was reacted with 3-bromo-4-trifluoromethyl-pyridine (160 mg, 0.8522 mmol), 1,4-dioxane (5 mL), copper iodide (16.23 mg, 0.08522 mmol), trans-1,2-diamino cyclohexane (29.27 mg, 0.2552 mmol) and potassium phosphate (542.56 mg, 2.556 mmol) to afford the crude product. Purification by preparative HPLC afforded 94 mg of the product (34.43% yield).
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[NH:4][N:3]=1.[CH3:13]C(C)([O-])C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1
Reactant: CC1(C)CCc2[nH]nc(I)c2C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2c1CCC(C)(C)C2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
In a round-bottomed flask, 3-iodo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole (642 mg, 2.33 mmol) was dissolved in THF (8.5 ml). The solution was cooled to 0° C. and potassium tert-butoxide (365 mg, 3.26 mmol) was added. The reaction mixture was stirred at 0° C. for 40 min then methyl iodide (0.18 ml, 2.88 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1.5 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-15% EtOAc) to provide 497 mg (74%) of 3-iodo-1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.76 (s, 3H), 2.53 (t, J=6.4 Hz, 2H), 2.11 (s, 2H), 1.58 (t, J=6.6 Hz, 2H), 0.99 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)(=[O:38])=[O:37])[C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:17])([F:16])[F:18])[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (5.34 g, 21.86 mmol) in anhydrous dichloromethane (20 mL) was added diisopropylethylamine (10.3 mL, 59.1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes then 3-Methoxy benzene sulfonyl chloride (2.44 g, 11.82 mmol) dissolved in dichloromethane (10 mL) was introduced dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 0.5 hour. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane washed with saturated NaHCO3 (aqueous), dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(3-methoxyphenylsulfonyl)-2-methylpiperazine in quantitative yield (5.10 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:10]1([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: N#Cc1cccnc1Cl
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccnc1C1CC1

Procedure:
2-Chloro-3-cyano-pyridine (9.69 g, 70.0 mmol), cyclopropylboronic acid (7.21 g, 84.0 mmol), Pd(OAc)2 (875 mg, 3.50 mmol), tricyclohexylphosphine (1.96 g, 7.00 mmol), and K3PO4 (44.5 g, 210 mmol) were suspended in toluene (280 ml) and H2O (14 ml) and heated at 100° C. for 5 h. The reaction mixture was dried over MgSO4 and the mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 7/3) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([CH:12]([NH2:19])[C:13]3[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].O.O.Cl.CN(C)C=O>O>[CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(N)C3=CCC=CC3)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)C3=CCC=CC3)[C@H]2SC1
Temperature: 25 °C

Procedure:
50 g of commercially available cephradine hydrate were suspended in a mixture of water and conc. hydrochloric acid (180/7) at 5° to 10° C. with stirring. The pH was brought to 1.6 to 2.0 with hydrochloric acid in order to form a complete solution and 16 g of dimethylformamide were added. The solution was filtered and the residue was washed with 35 ml of water. The combined filtrate was warmed to 35° to 40° and the pH brought to 2.8 with aqueous triethylamine. Stirring was continued for several minutes and the pH was finally adjusted to about 4.9 with aqueous triethylamine. The resulting slurry was cooled to room temperature and filtered. The residue was washed with 80% (v/v) acetone and dried to obtain the heading compound, m.p. 190° to 200° C. (decomp.).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[C:43]1([CH3:52])[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:31][C:27]1[C:26]([CH3:39])=[CH:25][C:24]([C:14]2([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH3:52])[C:15]2=[O:23])=[CH:29][C:28]=1[CH3:30]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1N1C(=O)C(c2cc(C)c(O)c(C)c2)(c2cc(C)c(O)c(C)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.700 g, 1.16 mmol), o-tolylboronic acid (0.316 g, 2.33 mmol), copper (II) acetate (0.211 g, 1.16 mmol), triethylamine (0.325 mL, 2.33 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.256 g, 3.70 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.92 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.086 g (16%) of the title compound: mass spectrum (FAB): m/z=464(M+1); 1H NMR(DMSO-d6): δ8.25 (s, 1H), 8.23 (s, 1H), 7.46-7.33 (m, 7H), 6.76 (s, 2H), 6.75 (s, 2H), 6.41 (d, 1H), 2.08 (s, 6H), 2.06 (s, 6H), 1.98 (s, 3H).