Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([CH:8]=1)[NH2:7].[C:16]([Cl:19])(=O)[CH3:17]>C1(C)C=CC=CC=1>[ClH:19].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:16]([CH3:17])=[N:7][C:6]=2[CH:8]=1
Reactant: Nc1cc(Br)ccc1NC1CCOCC1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2cc(Br)ccc2n1C1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A 2-neck flask was charged with 5-bromo-2-(tetrahydropyran-4-yl)aminoaniline (see Synthesis Example 18-2) (2.72 g, 10.0 mmol) and anhydrous toluene (20 mL) and this was refluxed. To this was added dropwise over approx. 15 m acetyl chloride (1.57 g, 20.0 mmol) in toluene solution (approx. 2.5 mL), and this was stirred under these conditions for 2 hours. After being allowed to cool to room temperature, this was concentrated under reduced pressure and the residue was reslurried in hexane (20 mL). The precipitated crystals were filtered off and washed with hexane. The crystals obtained were dried at reduced pressure with heating to yield the title compound (3.14 g, 94.7% yield) as a light purple solid.
Reaction SMILES: C(O)(=O)C.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N+]([O-])=O)=[CH:8][C:7]=1[C:19]([NH:21]CCCOC1C=CC(C(CC)(C)C)=CC=1C(CC)(C)C)=[O:20]>[Fe].O>[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1ccc2ccccc2c1

Procedure:
In 500 ml of a 90% acetic acid aqueous solution, 50 g of 1-hydroxy-4-nitro-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide was reduced with 50 g of iron as a reducing agent. The reaction mixture was added to water and then was extracted with ethyl acetate. After evaporating off the ethyl acetate, the crystals were recrystallized from ligroin to provide 40 g of 1-hydroxy-4-amino-N-[γ-2,4-di-tert-amylphenoxy)propyl]-2-naphthamide having a melting point of 132° to 133° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].[CH:20]([O-])=[O:21].[Na+].C(OC(=O)C)(=O)C.C(O)C>C(O)=O>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][CH:20]=[O:21])[CH3:3]
Reactant: O=C[O-]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride 1 (Luxen, A., Perlmutter M., Bida, G. T., Van Moffaert, G., Cook, J. S., Satyamurthy, N., Phelps, M. E. and Barrio, J. R. (1990) Remote, semiautomated production of 6-[18F]fluoro-L-dopa for human studies with PET. Appl. Radiat. Isot. 41, 275) (5.3 g, 18.3 mmol) and sodium formate (1.44 g, 21.2 mmol) in formic acid (52 mL) cooled in an ice bath was added acetic anhydride (20 mL) and stirred at room temperature for 3 h. After addition of ethanol (40 mL) the mixture was stirred at room temperature for an additional 3 h and evaporated. The residue was dissolved in ethyl acetate, filtered and the insoluble material was washed with ethyl acetate. The combined filtrates were washed successively with aqueous 10% HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to a yellow syrup. Crystallization of the syrup from ethyl acetate-petroleum ether give a white solid 2 (3.1 g, 61%); m.p. 102°-103° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1Cl)#[N:2].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].CC([O-])(C)C.[K+].C1COCC1>CN(C=O)C>[NH2:2][C:1]1[C:3]2[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: N#Cc1c(Cl)ccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1sc2ccnc(Cl)c2c1N
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To 3-cyano-2,4dichloropyridine (653 mg) and methyl thioglycolate (340 μL) in DMF (12 mL) at 5° C. was added a solution of 1.0M KOtBu/THF (4.5 mL). The reaction was stirred 20 min at 5° then 1 h at RT, then quenched in sat'd NH4Cl, the solid precipitate collected, washed with water and sucked dry to give 800 mg (88%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(Cl)c1
Product: Nc1cc2ncnc(Nc3cccc(Cl)c3)c2cn1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (208 mg, 1.08 mmol) and 3-chloroaniline (1.21 g, 9.48 mmol) is stirred at 150° C. for 20 min. The resulting product is chromatographed over alumina (5-10% MeOH/CH2Cl2) to give 7-amino-4-(3-chloroanilino)pyrido[4,3-d]pyrimidine (177 mg, 60%) as a white solid. 1H NMR (DMSO) δ 9.92 (1H,brs), 9.35 (1H, s), 8.45 (1H, s), 8.08 (1H, brs), 7.79 (1H, brd, J=8.0 Hz), 7.40 (1H, t, J=8.1 Hz), 7.16 (1H, dd, J=7.9, 1.3 Hz), 6.68 (2H, brs), 6.46 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].[Al]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(=O)cc(-c2cccc(I)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (9.98 g, 20.0 mMol) was suspended in diethylamine (300 mL). To this solution was added 50 mL of anhydrous N,N-dimethylformamide (DMF), (trimethylsilyl)acetylene (8.5 mL) and bis(triphenylphosphine)-palladium(II) chloride (1.40 g, 2.00 mMol). The flask was covered with aluminum foil and then copper(I) iodide (780 mg, 4.09 mMol) was added causing the reaction mixture to exotherm. After stirring overnight under an atmosphere of dry N2 at ambient temperature, the reaction mixture was concentrated under vacuum and the residue was chromatographed on flash silica gel eluting with a gradient of DCM to MeOH/DCM (2:98) to give 8.55 g of the titled product as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]([C:5](Cl)=[O:6])[C:3]1([CH3:9])[CH3:8].[NH2:11][CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15]>[OH-].[Na+].ClCCl>[CH3:1][C:2]1([CH3:10])[C:3]([CH3:9])([CH3:8])[CH:4]1[C:5]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])=[O:6]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: NCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)C(C(=O)NCCS(=O)(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,2,3,3-tetramethylcyclopropanecarbonyl taurine (TMC-taurine) is synthesized by adding tetramethylcyclopropanecarbonyl chloride (TMC-chloride) to taurine dissolved in a sodium hydroxide solution, preferably 5–15% NaOH aqueous solution, more preferably 10% NaOH aqueous solution. The reaction mixture is stirred for 3–10 hrs, preferably for 5 hr at room temperature (20–25° C.). The water is evaporated and the product is extracted by boiling ethanol. The insoluble salts are filtered off and TMC-taurine is crystallized using ethanol:diethyl ether solution. TMC-taurine is chlorinated in dry dichloromethane using thionyl chloride and the suitable amides (compound XXVII in reaction scheme II) are synthesized by slowly adding of the TMC-taurine chloride in dichloromethane to an aqueous solution of the corresponding amine (compound XXVI in reaction scheme II). After the addition, the reaction mixture is stirred for 2–5 hr, preferably for 2 hr at room temperature (20–25° C.), the organic solvent is evaporated, water is added and the products are extracted with a suitable organic medium such as chloroform. The organic fraction is dried using a drying agent such as Na2SO4 or MgSO4, filtered, evaporated and the products are crystallized using chloroform:hexane mixtures to get the desirable product. The chemical structures are identified by elemental analysis and spectroscopic methods.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:29](=[O:30])[CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
In a two neck round bottom flask, 1-(naphthalene-2-yl-sulfonyl)piperazine hydrochloride (compound 4, 0.639 moles, 0.200 g) and 2-phenoxyacetylchloride (0.639 moles, 0.109 g) were charged in DCM (20 mL). TEA (2.557 moles, 0.258 g) was added slowly to the reaction flask. The resulting mixture was stirred for 3 h at room temperature. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 4:6, Ethyl acetate/Hexane) to obtain the title compound (0.200 g, 76.33%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]1([CH3:30])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[O:19]1>CN(C=O)C>[CH3:17][C:18]1([CH3:30])[C:22]([CH3:23])([CH3:24])[O:21][B:20]([C:25]2[CH:29]=[N:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:26]=2)[O:19]1
Reactant: ClCCCN1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCCN3CCOCC3)c2)OC1(C)C
Temperature: 25 °C

Procedure:
A solution of 4-(3-Chloro-propyl)-morpholine (702 mg, 4.2 mmol), Cs2CO3 (753 mg, 2.31 mmol) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (832 mg, 4.2 mmol) in 5 ml dry DMF are heated at 80° C. under argon for 24 h and then allowed to cool to RT. DMF is removed under HV and the residue is re-taken in EtOAc and washed with de-ionized water. The aqueous phase is re-extracted with EtOAc and the combined organic extracts are washed with saturated brine, dried over Na2SO4, filtered and concentrated under vacuum to dryness. After drying under HV, the title compound is obtained as a pale orange oil, Rt=0.728 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 322 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)CC1(N)CCCCC1
Product: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1

Procedure:
2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide was prepared from 2-(1-Amino-cyclohexyl)-acetamide (2.0 g, 0.013 mol) (Suzuki, T.; Imanishi, N. Itahana, H.; Watauki, S.; Ohta, M.; Mase, T., Synthetic Communications, 1988, 28(4), 701-712) and 2,4,5-Trichloro-pyrimidine (1.5 mL, 0.013 mol) in an analogous manner to Example 1d. Product isolated as a white solid (2.28 g, 59%). MP: 124-128° C. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 8.19 (s, 1H), 7.51 (br s, 1H), 7.34 (br s, 1H), 7.04 (br s, 1H), 2.62 (s, 2H), 2.58-2.52 (m, 2H), 1.55-1.30 (m, 8H). MS: 303.00 (MH)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[CH:8]1.[Li]CCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>C1COCC1.C1CCCCC1>[CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2n1COCC[Si](C)(C)C
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a solution of 1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 0.0020129 mol) in THF (5 mL) at −10° C. was added a 2.0 M of n-BuLi in cyclohexane (1.2 mL). After 10 min at −10° C., the mixture was cooled to −20° C. and tributyltin chloride (0.65 mL, 0.0024 mol) was added. The mixture was stirred at rt for 1 h, the poured into a 5% aqueous ammonium chloride (20 mL), extracted with EtOAc (3×20 mL) and the combined extracts dried over anhydrous MgSO4 and concentrated in vacuo. The material thus obtained was chromatographed over silica gel eluting with 1:9 EtOAc:hexane to afford 0.7 g of the title compound. 1H NMR (400 MHz DMSO-d6) δ 0.01 (s, 9H), 0.10 (s, 2H), 0.92-0.94 (m, 9H), 1.14-1.27 (m, 6H), 1.37-1.46 (m, 6H), 1.60-1.72 (m, 6H), 3.48-3.52 (m, 2H), 5.71 (s, 2H), 6.74 (s, 1H), 7.16-7.19 (m, 1H), 8.02 (dd, J=1.6, 7.6 Hz, 1H) and 8.31 (dd, J=1.6, 4.4 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[C:8]([O:11][CH2:12][CH:13]([NH:19][C:20]([C:22]1[C:27]([I:28])=[C:26]([NH2:29])[C:25]([I:30])=[C:24]([C:31]([NH:33][CH:34]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:35][O:36][C:37](=[O:39])[CH3:38])=[O:32])[C:23]=1[I:45])=[O:21])[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:10])[CH3:9]>CC(N(C)C)=O>[C:37]([O:36][CH2:35][CH:34]([NH:33][C:31]([C:24]1[C:25]([I:30])=[C:26]([NH:29][C:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:27]([I:28])=[C:22]([C:20]([NH:19][CH:13]([CH2:12][O:11][C:8](=[O:10])[CH3:9])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:21])[C:23]=1[I:45])=[O:32])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:39])[CH3:38]
Reactant: C=CCCC(=O)Cl
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Solvent: CC(=O)N(C)C
Product: C=CCCC(=O)Nc1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reaction time: 16 h
Yield: 89 %

Procedure:
4-Pentenoyl chloride (11.9 g, 100 mmol) was added to a stirred solution of N,N'-bis-[2-(acetyloxy)-1-[(acetyloxy)-methyl]ethyl]-5-amino-2,4,6 -triiodo-1,3-benzenedicarboxamide (47.75 g, 50 mmol) in dimethylacetamide (400 mL) at room temperature and the mixture was stirred for 16 hours. Dimethylacetamide was removed in vacuo and the residue dissolved in ethyl acetate (600 ml). The solution was washed with aqueous sodium bicarbonate (10%, 2×150 mL) and with water (2×100 mL) and brine (150 mL). The organic layer was dried and the solvent removed to obtain the crude product as an off-white solid. Further purification by crystallization from a mixture of acetone (250 mL) and hexane (75 mL) afforded the title A compound (42.5 g), m.p. 162°-64°. TLC: Rf 0.55 in ethyl acetate. Mass Spectrum: m/z 956 (M+H)+, 830, 653.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:43]N)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1.C[N:46](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:43][N:20]([CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:32][CH3:33])[C:21]([C:23]2[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH2:46])=[O:28])[CH:24]=2)=[O:22])[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1
Reactant: COc1cc(Br)cc(CN)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1cc(Br)cc(OC)c1)C(=O)c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (762 mg, 1.69 mmol), {[3-bromo-5-(methyloxy)phenyl]methyl}amine (529 mg, 1.86 mmol), HBTU (769 mg, 2.03 mmol) and Et3N (0.47 mL, 3.38 mmol) in DCM was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified using CombiFlash chromatography eluting with 0 to 10% methanol in DCM to obtain N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.05 g, 96%). LC-MS m/z 649 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[C:22]([C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34])[C:23]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[O:29])=[O:24].[Cl-:42].[NH4+]>C1COCC1>[ClH:42].[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[C:22]([C:23]([C:25]1[CH:32]=[CH:31][CH:30]=[C:27]([CH:28]([OH:29])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:26]=1)=[O:24])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34]
Reactant: [Cl-]
Reactant: Brc1ccccn1
Reactant: O=Cc1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(C(C(=O)c1cccc(C(O)c2ccccn2)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
0.33 ml portion of 2-bromopyridine was dissolved in 3 ml of THF, and the solution was cooled to −78° C., mixed with 2.2 ml of n-butyl lithium and then stirred at the same temperature for 30 minutes. This solution was poured at −78° C. into a solution prepared by dissolving 3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzaldehyde in 10 ml of THF. This was slowly risen to room temperature and mixed with 50 ml of saturated ammonium chloride aqueous solution. This was extracted with ethyl acetate, dried with sodium sulfate and then concentrated, and the thus formed residue was purified by a silica gel column chromatography (chloroform:methanol=from 100:0 to 90:10). By subjecting the thus obtained reddish brown solid to salt formation with 4N HCl/EtOAC (0.2 ml), 151 mg (42%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-{3-[hydroxy(pyridin-2-yl)methyl]phenyl}propane-1,3-dione hydrochloride (Example 11-1) was obtained. FA: 466
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([S:8][C:9]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:11](=[O:13])[C:10]3[C:9](=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[CH:14]=3)[S:8][C:6]=2[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Reaction time: 8 h

Procedure:
The requisite 1-chloro-7-methoxy-4-nitrothioxanthone was prepared as follows: A mixture of 118.5 g (0.35 mole) of 2-(5-chloro-2-nitrophenylthio)-5-methoxybenzoic acid and 131 ml of thionyl chloride in 600 ml of toluene was heated under reflux for 1.5 hours. The mixture was concentrated in vacuo, and the resulting solid was dissolved in 950 ml of nitrobenzene with heating and then cooled to 0° in an ice bath. Aluminum chloride (44.2 g) was added in portions over 0.5 hour with cooling, and the mixture was then allowed to come to room temperature and stirred overnight. The mixture was poured into 5 l of cold water. As much of the water layer as possible was decanted. The residue was triturated twice with 1 l portions of methanol and then twice with 2 l portions of methanol. The oil was triturated with 4 l of methanol and a solid resulted. This was washed with methanol and dried in vacuo at 75° to give 72.7 g of the product as a brownish-yellow solid, mp 235°-240°.
Reaction SMILES: [F:1][C:2]1([CH2:26]O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:34])CC>COCCOCCOC>[F:1][C:2]1([CH2:26][F:34])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CO)CC3)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: COCCOCCOC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CF)CC3)c(F)c2)C(=O)O1
Yield: 24 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-fluoro-4-hydroxymethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with DAST (1.25 mmol) in diglyme (10 ml) at a temperature 0° C. for two hours and by purifying the compound by silica gel column chromatography in 24% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([Li])[CH2:9][CH2:10]C.[Cl:13][C:14]1[N:19]=[C:18](S(C)(=O)=O)[N:17]=[C:16]([NH:24]C(C)C)[C:15]=1[C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35].Cl>O1CCCC1>[Cl:13][C:14]1[N:19]([CH:9]([CH3:10])[CH3:8])[CH:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]=[C:16]([NH2:24])[C:15]=1[C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35]
Reactant: Nc1ccccc1
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cccc1Cl
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)N1C(Cl)=C(c2c(F)cccc2Cl)C(N)=NC1Nc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
At −70° C., 0.62 g (6.6 mmol) of aniline was added to a suspension of 2.9 g of butyllithium (15% solution in hexane) in 15 ml of tetrahydrofuran [THF], and the mixture was then stirred at −70° C. for 1 hour. 1.0 g (2.64 mmol) of [6-chloro-5-(2-chloro-6-fluorophenyl)-2-methanesulfonylpyrimidin-4-yl]isopropylamine (abbr. sulfone 3) was added, and the mixture was then warmed to 20-25° C. The reaction mixture was poured into ice-water and acidified with hydrochloric acid. The mixture was extracted with 2×40 ml of MTBE, and the combined organic phases gave, after drying and distillative removal of the solvent, 1.0 g of the title compound.