Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(-c2ccccc2)cn1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
5-Bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide (example 30A66, step 1) (80 mg, 0.155 mmol) and phenylboronic acid (27 mg, 0.22 mmol) were dissolved under argon in 0.4 ml 2M sodium carbonate and 1.6 ml 1,2-dimethoxyethane. Triphenylphosphine (16 mg, 0.062 mmol) and Pd(II)acetate (7 mg, 0.03 mmol) were added and the mixture stirred at 85° C. for 16 hrs. The reaction mixture was extracted with water and two times dichloromethane. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired compound was obtained as a brown solid (36 mg, 45%), MS: m/e=514.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:25]#[C:26][NH2:27]>O1CCOCC1>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:26]([NH2:27])=[NH:25])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1)=[O:24])([OH:23])=[O:22]
Reactant: Nc1cccc(-c2cccc(NC(=O)CCCCC(=O)O)c2)c1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2cccc(NC(=O)CCCCC(=O)O)c2)c1

Procedure:
Prepared by refluxing 3-amino-3'-[(5-carboxyvaleryl)amino]biphenyl hydrochloride with cyanamide in dioxane for 3 hours.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C(N(CC)CC)C>C(O)C>[NH2:15][C:14]1[CH:16]=[CH:17][N:10]=[C:11]([S:12][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:13]=1
Reactant: CCOC(=O)CCCBr
Reactant: Nc1cc[nH]c(=S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCSc1nccc(N)n1

Procedure:
In a nitrogen atmosphere, 28.6 ml (200 mmol) of ethyl 4-bromobutyrate was added to a solution of 25.44 g (200 mmol) of 2-thiocytosine and 30.7 ml (220 mmol) of triethylamine in 400 ml of ethanol at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→1/9) to yield 46.31 g (96.0%, white crystal) of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: BrCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCCCCBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (3.04 g of a 50% oil dispersion, 127 mmol) is suspended in dimethylformamide (300 ml) and the suspension is cooled to 0° C. t-Butyl methyl malonate (20.08 g, 115 mmol) is added dropwise slowly and the reaction mixture is warmed to room temperature. 1,7-Dibromoheptane (29.75 g, 115 mmol) is added dropwise and the mixture is stirred for 3 hours. The mixture is partitioned between diethyl ether (500 ml) and water (1000 ml). The organic layer is washed with water (3×500 ml), brine (1×500 ml), dried (MgSO4) and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give t-butyl methyl 7-bromoheptylmalonate as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>ClCCl>[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:13][CH2:12]1
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)c(F)c2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)CC1
Yield: 92.3 %

Procedure:
The title compound (83 mg, 92%) was prepared as a white solid from 4-({[3-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (80 mg, 0.20 mmol), diisopropylethylamine (0.11 mL, 0.60 mmol), isopropyl chloroformate (1.0M in toluene, 0.22 mL, 0.22 mmol) and dichloromethane (6 mL) in a manner similar to Example 66, Step 2. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 7.40-7.25 (m, 2H), 7.10-7.00 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.22 (bs, 2H), 3.92 (d, 2H, J=6.4 Hz), 3.08 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.95-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 450 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[H][H]>CO.[Pt]=O>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][NH:13][CH2:14]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: c1ccc(-c2ccc3ccncc3c2)cc1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: c1ccc(-c2ccc3c(c2)CNCC3)cc1

Procedure:
To a solution of 7-phenylisoquinoline (1.25 g, 6.1 mmol)in methanol (50 ml) was added conc HCl (2 ml) and platinum oxide (100 mg). The reaction mixture was hydrogenated at 50 psi until no further uptake of hydrogen was observed. The catalyst was filtered off, washed with methanol. The filtrate was evaporated under reduced pressure to give a solid. The solid was partitioned between ethyl acetate and sodium carbonate solution. The aqueous solution was extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, washed with brine (2×100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil, which crystallised on standing. The solid was a mixture of the title compound and 7-phenyl-decahydroisoquinoline; Rf 0.66 (EtOAc/MeOH/NH3 5:1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
p-Methoxyaniline (0.078 g, 0.639 mmol), triethylamine (0.066 g, 0.639 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.108 g, 0.639 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.135 g, 0.318 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0756 mmol, 24%).
Reaction SMILES: IC.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][C:5]([C:14](=[O:16])[CH3:15])=[C:4]([NH:3][CH3:17])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Iodomethane (14 ml) was added to a stirred mixture of 2'-amino-4',5'-dimethoxyacetophenone (40 g), potassium carbonate (31.2 g) and dry dimethylformamide (200 ml) and the mixture stirred at ambient temperature for 40 hours. The solvent was evaporated under reduced pressure and the residue triturated with dichloromethane (250 ml). The mixture was filtered and the filter bed washed with dichloromethane (50 ml). The combined filtrate and washing were evaporated and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:industrial methylated spirit (99:1then 49:1) followed by trituration with diethyl ether (400 ml then 100 ml) to give the novel compound 4',5'-dimethoxy-2'-(methylamino)acetophenone, m.p. 121°-123.5°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5](I)=[C:6]([O:8][CH3:9])[CH:7]=1.C([Mg]Cl)(C)C.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:5]2[CH:4]=[C:3]([F:11])[C:2]([Cl:1])=[CH:7][C:6]=2[O:8][CH3:9])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1
Reactant: COc1cc(Cl)c(F)cc1I
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)c(Cl)cc2OC)c(N)n1

Procedure:
To a solution of 5-chloro-4-fluoro-2-iodoanisole (1.0 g, Example 375) was added isopropylmagnesium chloride (1.92 mL, 2M in tetrahydrofuran, Aldrich) and the reaction was stirred at −40 to −35° C. for 40 minutes before 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (170 mg, Example 1) in tetrahydrofuran (4 mL) was added. The resulting reaction was quenched with aqueous ammonium chloride. Work-up and purification as in Exam pie 47 gave (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 342.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:11][C:10]2=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:27])[N:11]([CH3:29])[N:12]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NN(Cc2cccnc2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(=O)c(-c2ccc(Cl)c(Cl)c2)c(-c2ccncc2)n1Cc1cccnc1
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 70 mg 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-1-pyridin-3-ylmethyl-pyrazolidin-3-one and 10 mL THF, stirred at 0° C. under nitrogen. 0.26 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min. 0.017 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hour, quenched with 20 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The crude MS showed the desired 4-(3,4-Dichloro-phenyl)-2-methyl-5-pyridin-4-yl-1-pyridin-3-ylmethyl-pyrazolidin-3-one was there, MS (ES+): 413 (M+H)+. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, the 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-1-pyridin-3-ylmethyl-pyrazolidin-3-one was oxidized on column and obtained the 4-(3,4-Dichloro-phenyl)-2-methyl-5-pyridin-4-yl-1-pyridin-3-ylmethyl-1,2-dihydro-pyrazol-3-one 12 mg as light yellow solid. MS (ES+): 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.C(N(CC)CC)C>CC#N>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Cl)N1CCc2cc(F)ccc21
Temperature: 23 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
2-Chloronicotinoyl chloride (200 mg, 1.14 mmol) was dissolved in CH3CN (5.6 mL). 5-Fluoroindoline (171 mg, 1.25 mmol) was added followed by triethylamine (0.24 mL, 1.71 mmol) and the reaction mixture was stirred at 23° C. for 16 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 (10 mL) and sat. aq. NaHCO3 solution (10 mL). The organic phase was removed and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography (40 g SiO2, 2% CH3OH—CH2Cl2) afforded the desired product as an off-white solid (247.8 mg, 79%). 1H NMR (DMSO-d6) δ 3.14 (t, 2H, J=8.39 Hz), 3.82 (t, 2H, J=8.39 Hz), 7.09 (dt, 1H, J=9.03, 2.80 Hz,), 7.20 (dd, 1H, J=8.39, 2.80 Hz), 7.60 (dd, 1H, J=7.38, 4.83 Hz), 8.10 (dd, 1H, J=7.63, 2.03 Hz), 8.15 (dd, 1H, J=8.90, 4.83 Hz), 8.55 (dd, 1H, J=4.83, 1.78 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>CC(=O)CC>[C:9]([C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:3][CH2:2][O:1][C:29](=[O:30])[CH2:28][CH2:27][Cl:26])=[CH:6][CH:7]=1)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCl
Reactant: O=C(c1ccccc1)c1ccc(OCCO)cc1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCl)OCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
3.6 g (15 mmol) 4-(2-hydroxyethoxy)benzophenone and 1.8 g (18 mmol) triethyl amine were dissolved in 40 ml 2-butanone. The mixture was cooled to −10° C. and 2.3 g (18 mmol) 3-chloro-propionyl chloride was added drop wise while the temperature was kept below −5° C. The reaction was allowed to continue first at 0° C. for 30 minutes, followed by 16 hours at room temperature. The precipitated salts were removed by filtration and the solvent was removed under reduced pressure. The crude 3-chloro-propionic acid 2-(4-benzoylphenoxy)ethyl ester was purified by preparative column chromatography on a Prochrom LC80 column, using n.-hexane/ethyl acetate 70/30 as eluent at a flow rate of 50 ml/min and Kromasil 60A 10 micron as silica. 1.9 g (32%) of 3-chloro-propionic acid 2-(4-benzoylphenoxy)ethyl ester was isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:17])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:27])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methoxyphenyl)2-phenylethan-1-one (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-phenylpropane-1,3-dione.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11]1([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH:5]([C:21](=[O:22])[NH:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])[C:4](=[O:9])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C(=O)NS(=O)(=O)c2ccccc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5,5-dimethyl-1,3-cyclohexanedione with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5,5-DIMETHYL-2-(N-BENZENESULFONYLCARBAMOYL)1,3-CYCLOHEXANEDIONE, m.p. 101°-103° C. (corr.).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: Cc1cccc(CBr)c1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC#N)c1Br
Temperature: 90 °C
Reaction time: 20 h
Yield: 44.1 %

Procedure:
A mixture of 2-brom-3-methylbenzylbromide (25 g, 0.095 mol) and potassium cyanide (16 g, 0.25 mol) in dimethylformamide (100 ml) was stirred at 90° C. for 20 h. The solvent was evaporated under reduced pressure and to the residue were added toluene and water. The organic layer was separated washed with water, separated and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 8.8 g (44%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:22][C@@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].OCC[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.B(F)(F)F.CCOCC.CCN(CC)CC>C(C#N)(C)=O>[C:8]([O:7][C@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:21]([CH3:23])[O:22][C@H:5]1[O:4][CH2:1][CH2:2][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:10])[CH3:9]
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(=O)OC1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCNC(=O)OCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,2,3,4-tetra-O-acetyl-L-fucopyranose (200 g, 601.86 mmol) in AcCN (100 mL) and benzyl (2-hydroxyethyl)carbamate (140.96 g, 722.08 mmol) at 0° C. was added BF3.Et2O (427.7 g, 3.01 mol) dropwise over 2 hr. After stirring at rt for 16 hr, the reaction mixture was cooled to 0° C. and followed by the addition of Et3N (130 mL). The resulting mixture was concentrated and the residual was dissolved in CH2Cl2 (2.0 L), which was subsequently washed with sat. NaHCO3 (2×500 mL), water (2×500 mL) and brine (500 mL). The organic phase was separated, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/petroleum ether (1:3) to give the title compound. 1H NMR (CDCl3) δ 7.33-7.37(5H, m), 5.12-5.32(5H, m), 4.99-5.04(1H, m), 4.42-4.45 (1H, d), 3.87-3.94 (1H, m), 3.78-3.84 (1H, m), 3.66-3.70(1H, m), 3.42-3.44 (2H, m), 2.19 (3H, s), 2.05-2.12(6H, m), 1.25-1.30 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:50]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54]2)[CH:51]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:58][C:55]1[CH:56]=[CH:57][N:53]([CH2:52][C:50]2[CH:51]=[C:46]([Cl:45])[CH:47]=[CH:48][C:49]=2[O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[N:54]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Nc1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1)c1c(F)cccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-chloro-6-fluorobenzoic acid (18 mg, 0.1 mmol, Aldrich) in DMF (0.1 ml) was added a solution of HATU (38 mg, 0.1 mmol) in DMF (0.2 ml). After 5 min, DIPEA (0.050 ml, 0.27 mmol) was added to the mixture. To the mixture was added a solution of 1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-amine (for a preparation see Intermediate 55)(0.1 mmol) in DMF (0.1 ml). After shaking for 10 min, the resulting solution was allowed to stand for 16 h at ambient temperature. The solvent was removed using a genevac. The sample was dissolved in 1:1 MeOH:DMSO (0.6 ml) and purified by MDAP on a C18 column using Acetonitrile-Water with a TFA modifier (Method D). The solvent was evaporated in vacuo using the Genevac to give the title compound; LCMS (System 3) MH+=470/472, tRET=1.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([I:14])[CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18]2)=[C:4]([I:14])[CH:3]=1
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1ccc(Cl)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Cl)cc2I)CCC1
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
Ethyl 2-(4-chloro-2-iodophenyl)acetate (3.95 g, 12 mmol) was mixed in DMF (80 mL) in a round bottom flask. NaH (60% dispersion in mineral oil (0.54 g, 13 mmol)) was added, and the reaction mixture was stirred for 15 minutes under a nitrogen atmosphere. 1,3-dibromopropane (1.4 mL, 13 mmol, 1.1 eq) was added via syringe, and the reaction mixture was stirred for 2 hours. An additional 1.10 eq NaH (60% dispersion in mineral oil (0.54 g, 13 mmol)) was added, and the reaction was stirred for 3 hours. The reaction mixture was quenched with water and diluted with EtOAc. The organic layer was separated, washed with water and brine, dried (MgSO4), and concentrated in vacuo to give an orange oil. The crude product was purified by silica flash chromatography (0-30% DCM/hexane) to give the desired compound as a light yellow oil (2.01 g). MS (m/e)=365.1 (M+H)+.