Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5]OC(C)(C)C)(C)(C)C.[Se](=O)=O.[C:14]([CH:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH3:35])[CH:29]=[C:28]3[C:36]([F:39])([F:38])[F:37])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH:35]=[O:5])[CH:29]=[C:28]3[C:36]([F:39])([F:37])[F:38])[CH2:20][CH2:19]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1cc(C(F)(F)F)c2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(C(F)(F)F)c3c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Di-tert-butyl peroxide (0.186 mL, 1.01 mmol) was added to a suspension of Selenium dioxide (0.252 g, 2.27 mmol) in 1,4-Dioxane (6.0 mL). The mixture was stirred for 30 minutes, then 6-(4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline (0.366 g, 1.00 mmol) was added as a solution in 1,4-Dioxane (2.0 mL). The mixture was sealed and was heated at 50° C. for 20 h. The reaction was filtered through Celite and washed with dioxane. The solvent was evaporated and the residue was purified on silica gel column using 0-20% ethyl acetate in hexanes as eluent. Isolated was (Rf=0.70 in 3:1 hexanes/ethyl acetate) the product (212 mg, 56%). ESI-MS (M+H+): 380.20.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][NH2:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:25][C:26](=O)[CH2:27][C:28](=O)[CH3:29]>CC(O)=O>[CH3:25][C:26]1[CH:27]=[C:28]([CH3:29])[N:22]([C:20]2[S:21][C:17]([C:13]3[N:8]4[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]4=[N:15][C:14]=3[CH3:16])=[C:18]([CH3:24])[N:19]=2)[N:23]=1
Reactant: CC(=O)CC(C)=O
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NN)nc3C)c(C)nc12
Solvent: CC(=O)O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-n4nc(C)cc4C)nc3C)c(C)nc12
Temperature: 100 °C
Yield: 70.4 %

Procedure:
28 mg of {5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-hydrazine (0.08 mmol) and 80 mg of 2,4-pentanedione (0.8 mmol) are dissolved in 1.0 ml of AcOH and heated at 100° C. for 2 h. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to give 23 mg of the title compound. Yield 70%: mass spectrum (m/e): 409 (M+1). 6.72 (s, 1H), 6.03 (s, 1H), 3.36 (m, J=7.1, 14.1 Hz, 1H), 2.75 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 1.87 (m, 4H), 0.91 (t, J=7.5 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14](=O)[CH3:15])[C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:21][NH:22][CH3:23])[CH2:20][CH2:19][CH2:18]1.C([O-])(=O)C.[Na+]>CCOC(C)=O.O>[CH:17]1([N:21]2[C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:14]([CH3:15])[N:22]2[CH3:23])[CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)=O
Reactant: CNNC1CCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)OC(C)(C)C)c(=O)n(C2CCC2)n1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-oxobutanoate (400 mg, 1.730 mmol) in EtOAc (6.407 mL) was treated with 1-cyclobutyl-2-methylhydrazine (284 mg, 2.076 mmol) followed by sodium acetate (213 mg, 2.59 mmol). The suspension was stirred at room temperature for 30 minutes and at 80° C. for 4 hours. The resulting mixture was diluted with water (10 mL) and EtOAc was added. The layers were separated and aqueous extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was dissolved in EtOAc and iso-hexane was added. The resulting suspension was filtered and the solid rinsed with iso-hexane. The filtrate was concentrated under reduced pressure. The crude material was then adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[C:14](=[O:19])[CH2:15][CH:16]([OH:18])[CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:18][CH:16]1[CH2:15][C:14](=[O:19])[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17]1)(=[O:28])[CH3:27]
Reactant: COc1cc(C2=CC(O)CC2=O)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2=CC(OC(C)=O)CC2=O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(3,4,5-trimethoxyphenyl)-4-hydroxy-cyclopent-2-en-1-one (3 gm, 11.36 mmol) in dichloromethane (30 ml) was cooled to 0° C. using ice-salt bath. To the cold solution dry pyridine (1.70 gm, 1.73 ml; 26.0 mmol) was added and stirred at 0° C. for 10 min. To the stirred solution, acetic anhydride (1.63 gm, 1.50 ml, 16.0 mmol) was added dropwise while maintaining the temperature below 0° C. The reaction mixture was stirred at room temperature for 15 h (monitored by TLC) then quenched by adding cold, dilute hydrochloric acid. The organic layer was washed three times with water, 10% sodium bicarbonate solution and finally brine. The organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure using a rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether: acetone as eluent) to collect the pure 4-acetoxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-en-1-one (2.56 gm, 73.47%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH3:10])=[CH:4][CH:3]=1.[Si](C#C)([C:20](C)(C)[CH3:21])(C)C.CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.C(Cl)Cl.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>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH3:10])=[CH:4][CH:3]=1)#[CH:21]
Reactant: CC(Cc1ccc(I)cc1)NC(=O)C1CC1
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#Cc1ccc(CC(C)NC(=O)C2CC2)cc1
Temperature: 25 °C

Procedure:
To 900 mg (2.73 mmol) N-(1-(4-iodophenyl)propan-2-yl)cyclopropanecarboxamide (I52.3) and 0.56 mL (3.01 mmol) (tert-butyldimethylsilyl)acetylene in 5 mL THF at 0° C. are added 0.77 mL (5.48 mmol) DIPEA, 96.1 mg (0.14 mmol) bis(triphenyl-phosphine)dichloropalladium and 53.1 mg (0.28 mmol) CuI, and the reaction mixture is stirred at r.t. over night. The mixture is diluted with water and extracted with DCM (2×). The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, DCM/MeOH 98/2) to yield the silylated compound. To this substance in DCM are added 949 mg (3.01 mmol) TBAF*3H2O and the mixture is stirred at r.t. for 3 h. The mixture is diluted with water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][C:4]3[CH:18]=[CH:19][S:20][C:3]=3[C:2](=[O:1])[C:8]=2[CH:9]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2cc(CCCCO)ccc2OCc2ccsc21
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A chilled stirring solution of 9.5 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol in 200 ml of sieve dried pyridine was treated dropwise with 3.80 g of methanesulfonyl chloride and the addition funnel was rinsed with a few ml of methylene chloride. The stirring solution was allowed to equilibrate to room temperature overnight with the bath in place. The resulting solution was poured into 750 ml of water and was allowed to stand for 15 min. The solids were collected by filtration, and dried in vacuo overnight at 42°0 C. Concentration of the mother liquor produced additional solids which were combined with the first crop and dried to give a total of 9.09 g of crude material. A 2.0 g portion of the product was recrystallized from hexane/ethyl acetate to give 1.3 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, m.p. 97°-98° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])[N:16]=[C:15]2[CH2:26][CH2:27][S:28][CH2:29][C:14]=12.CCOCC.CCCCC>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])[N:16]=[C:15]2[CH2:26][CH2:27][S:28](=[O:9])[CH2:29][C:14]=12
Reactant: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CSCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCCCC
Product: O=S1CCc2nn(-c3ccc(Cl)cc3F)c(Cl)c2C1
Reaction time: 16 h

Procedure:
1.6 parts of 85% m-chloroperbenzoic acid dissolved in 110 parts of chloroform were added dropwise for 1 hour to a stirred solution of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole dissolved in 75 parts of chloroform. The resulting solution was stirred 16 hours, washed 4 times with 40 parts of saturated aqueous NaHCO3, 2 times with water, dried with anhydrous magnesium sulfate, and solvent evaporated under a reduced pressure of 50 to 300 mm Hg. to give a pale yellow oil. The oil, when contacted with a mixture of ether and pentane, gave 1.2 parts of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-5-oxide as a pale caramel-colored solid, m.p. 119°-122° C. This solid can be recrystallized from a mixture of methylene chloride, ether, and pentane to give m.p. 1221/2°-125° C.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9](OC)=[O:10])=[CH:5][CH:4]=1)#[N:2].O.[NH2:16][NH2:17]>>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([NH:16][NH2:17])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: COC(=O)COc1ccc(C#N)cc1
Solvent: O
Product: N#Cc1ccc(OCC(=O)NN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of methyl (4-cyanophenoxy)acetate (3.52 g, 18.4 mmol) in MEOH (100 mL) was added hydrazine hydrate (8.9 mL). After stirring for 1 h at rt, a solid precipitated out. Filtration, washing with MeOH (5 mL) and water (4×10 mL) and drying under vacuo at 50° C. overnight gave the title compound (2.63 g, 75%) as a white solid in 98.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[N:8][C:7]([Br:11])=[CH:6][N:5]=1.[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24](Cl)(=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC>[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24]([NH:3][C:4]1[C:9]([CH3:10])=[N:8][C:7]([Br:11])=[CH:6][N:5]=1)(=[O:26])=[O:25]
Reactant: Cc1nc(Br)cnc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 18 h
Yield: 32.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.1 g) was added portionwise to a stirred solution of 2-amino-5-bromo-3-methylpyrazine (0.188 g) in 1,2-dimethoxyethane (DHE; 4 ml). After 5 minutes 5-dimethylamino-1-naphthalenesulphonyl chloride (0.3 g) was added, in a single portion, and the reaction was allowed to a stir for 18 hours. 2M Aqueous citric acid solution (10 ml) was added and the reaction was extracted with dichloromethane (3×25 ml). The combined extracts were dried (MgSO4) and evaporated to give a brown oil. The oil was purified by chromatography on silica gel, eluting with dichloromethane/diethyl ether (1:1) to give 5-dimethylamino-N-(5-bromo-3-methyl-2-pyrazinyl)-1-naphthalenesulphonamide as a cream solid (0.138 g, 33%), m.p. 171°-172° C.; mass spectrum (+ve FAB, DMSO/methanol/NBA): 421 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](=[N:19]O)[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1.[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[CH3:1][C:2]1[C:3]([CH:17]([NH2:19])[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: CC(=NO)c1cc2ncn(C3CCCCO3)c2cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2c(cc1C(C)N)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A mixture of 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone oxime (1.1 g, 4.0 mmol), zinc (2.6 g, 40.0 mmol) and NH4Cl (2.2 g, 40.0 mmol) in MeOH (20 mL) and HOAc (4 mL) was stirred at 80° C. for 4 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. Aqueous ammonia solution (50 mL) was added to the residue, and the mixture was extracted with DCM (50 mL×3), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (10:1:0.2) to afford 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanamine (101) as a yellow solid (840 mg, 80%). MS (ESI): m/z=260.2 [M+1]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[N:9]=[C:10]([NH:17][CH2:18][CH:19]([F:21])[F:20])[C:11]2[O:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH3:34])([CH3:33])[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][CH:19]([F:21])[CH2:18][NH:17][C:10]1[C:11]2[O:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH3:34])([CH3:33])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[N:9]=1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: FC(F)CNc1nc(Cl)nc2ccoc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: CC1(C)C(=O)Nc2cc(Nc3nc(NCC(F)F)c4occc4n3)ccc21
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
To a vial was added Pd2dba3 (0.235 g, 0.257 mmol), Cs2CO3 (2.37 g, 7.28 mmol) and Ru-Phos (0.240 g, 0.514 mmol) in t-AmOH (8.00 mL). The mixture was evacuated and purged with N2. The mixture was stirred at about 65° C. for about 20 min. 2-Chloro-N-(2,2-difluoroethyl)furo[3,2-d]pyrimidin-4-amine (1.00 g, 4.28 mmol) and 6-amino-3,3-dimethylindolin-2-one (0.754 g, 4.28 mmol, Astatech) were added in one portion. Additional t-AmOH (12.00 mL) was added. The mixture was evacuated and purged with N2. The mixture was stirred at about 70° C. for about 5 h, stirred at about 60° C. for about 15 h and then stirred at about 75° C. for about 2 h. The mixture was cooled to rt and filtered. The precipitate was washed with DCM (20 mL) and MeOH (20 mL). The combined filtrate was concentrated and purified by column chromatography eluting with 25-65% EtOAc/heptane (40 g silica gel) to give a crude material. The material was suspended in Et2O (about 15 mL) and sonicated. The suspension was filtered and washed with Et2O (50 mL), then with DCM (about 30 mL). The precipitate was dissolved in DCM (50 mL), combined with filtrate, concentrated under reduced pressure, dissolved in MeOH (40 mL), and adsorbed onto silica gel (Mesh#200-400, 60A°; 3 g). The material was purified by column chromatography eluting with 0 to 28% of 10% MeOH/DCM and DCM (40 g silica gel) to give a solid. The solid was purified by mass-triggered HPLC (Table 2, Method x) purification to give 6-(4-(2,2-difluoroethylamino)furo[3,2-d]pyrimidin-2-ylamino)-3,3-dimethylindolin-2-one (0.397 g, 25%): LC/MS (Table 2, Method c) Rt=1.75 min.; MS m/z: 374 (M+H)+. Syk IC50=A
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccsc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccsc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and thiophene-3 carbaldehyde. MS (ESI) m/z 475.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[N:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(Nc2ccc(S(N)(=O)=O)cc2)nc1N

Procedure:
A solution of (4-amino-2-chloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (120 mg, 0.40 mmol, Example 289) and 4-amino-benzenesulfonamide (260 mg, 1.51 mmol, Aldrich) in isopropyl alcohol (30 mL) was stirred for 2 hours at 150° C. in a sealed pressure bottle. The reaction was cooled and poured into water (˜60 mL) and the resulting precipitate was filtered and air dried. This residue was purified by silica gel chromatography (2% triethylamine/ethyl acetate) to give 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-benzenesulfonamide as a white solid. MS: M+H; 436
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[N:27]=[C:26](Cl)[N:25]=2)[CH2:11]1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.[Pd]>[Si:16]([O:15][C@H:14]1[CH2:13][C@H:12]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[N:27]=[CH:26][N:25]=2)[CH2:11][C@H:10]1[CH2:9][OH:8])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(N[C@@H]2C[C@@H](COCc3ccccc3)[C@@H](O[Si](C)(C)C(C)(C)C)C2)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(N[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)n1
Reaction time: 48 h
Yield: 57.2 %

Procedure:
A suspension of N-((1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentyl)-6-chloro-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazine-2,4-diamine (250 mg, 0.00041 mol) and 10% Pd/C (44 mg, 0.000041 mol) in methanol (1.61 mL) was stirred under an atmosphere of hydrogen for 2 days. The reaction was purged with nitrogen and filtered through celite with EtOAc. The filtrate was concentrated to obtain a yellow oil. The oil was taken up in CH2Cl2 and saturated NaHCO3. The layers were separated and the aqueous was extracted with CH2Cl2 (1×). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to obtain 114 mg (57%) of the title compound. LC/MS: Rt=1.68 min, ES+ 486 (FA standard).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:29](=[CH:30][CH:31]=1)[O:28][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:32].O.O.Cl[Sn]Cl.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(=O)(O)[O-].[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:29](=[CH:30][CH:31]=1)[O:28][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:32]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)O2
Agent: Cl[Sn]Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(N)cc3)CC1)O2
Temperature: 25 °C
Yield: 64.2 %

Procedure:
(E)-3-{1′-[2-(4-Nitro-phenyl-)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (377 mg, 0.833 mmol) was dissolved in AcOEt. SnCl2.2H2O (753 mg, 3.35 mmol) was added and the mixture heated under reflux for 12 h. After cooling down to room temperature the solution was treated with an aqueous solution of sodium potassium tartrate and sodium bicarbonate, and the organic phase was separated, dried and evaporated. The crude product was purified by column chromatography (eluent:DCM/MeOH 99:1 to 97:3) to give (E)-3-{1′-[2-(4-amino-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (225 mg) as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].Cl.C([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29]([NH2:37])=[O:30])=[CH:28][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
2-(4-Benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxylic acid (700 mg) obtained in Example 12 was dissolved in dimethylformamide (10 ml), and ammonium chloride (108 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (390 mg), 1-hydroxybenzotriazole (275 mg) and triethylamine (0.3 ml) were added. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the residue for crystallization and the crystals were collected by filtration to give the title compound (571 mg, yield 81%).