Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccccc1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccccc2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
A mixture of ethyl 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetate (syn isomer, 35 g.), 1 N aqueous sodium hydroxide (172 ml.), methanol (150 ml.) and tetrahydrofuran (150 ml.) was stirred at 35° to 40° C. for 9 hours and at room temperature for 12 hours. After adjusted the resultant solution to pH 6.5 with conc. hydrochloric acid, the solution was concentrated to about 2/3 volume of the initial. The concentrate was adjusted to pH 3.5 with conc. hydrochloric acid under ice cooling, and the precipitates were collected by filtration, washed with water and acetone in turn and then dried over phosphorus pentoxide under reduced pressure to give 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetic acid (syn isomer, 11.5 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]2[CH2:25][OH:26])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)c1nc(CO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In ethyl acetate was dissolved 800 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (103a), and platinum sulfided carbon was added. After replacement with hydrogen atmosphere, the mixture was catalytically hydrogenated under atmospheric pressure at room temperature. After 1 hour, the mixture was filtered through Celite, the filtrate was distilled off under reduced pressure, and to the residue, diethyl ether was added. The precipitated crystals were filtered, and 579 mg of 1-(p-aminobenzyl)-5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1H-imidazole (104a) was obtained (yield 78%). mp 130° C. (decomp.).
Reaction SMILES: Br[CH:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4]([CH3:10])([CH3:9])[C:3]1=O.[NH2:12][C:13]([NH2:15])=[S:14].C(N(CC)CC)C>C(O)C>[CH3:7][C:6]1([CH3:8])[C:2]2[N:12]=[C:13]([NH2:15])[S:14][C:3]=2[C:4]([CH3:10])([CH3:9])[O:5]1
Reactant: NC(N)=S
Reactant: CC1(C)OC(C)(C)C(Br)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)OC(C)(C)c2sc(N)nc21

Procedure:
To a solution of Example 248A (10.0 g, 0.045 mol) in ethanol (100 mL) were added thiourea (3.8 g, 0.05 mol) and triethylamine (6.3 mL, 0.045 mol). The reaction mixture was heated at reflux overnight, then cooled, and concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-5% methanol in CH2Cl2) to afford the title compound MS (ESI+) m/z 199 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[C:17]([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccnc1Cl
Yield: 40 %

Procedure:
A solution of 2-chloronicotinic acid (1.61 g, 10.2 mmol) and sulfuric acid (0.5 mL) in methanol (30 mL) was stirred at reflux overnight. The solution was poured into water (100 mL) and neutralised with NaHCO3 (s) before being extracted with 1:1 hexane/ethyl acetate (3×40 mL). The solvents were dried (MgSO4) and evaporated and the residue was purified by flash column chromatography (SiO2, 25% ethyl acetate/hexane eluent) to afford the ester as a colourless oil (700 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(F)cc1Cl
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1ccc(F)cc1Cl
Yield: 101.4 %

Procedure:
A mixture of 2-chloro-4-fluorocinnamic acid (22.9 g, 0.11 mol) and platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (140 ml) was placed on a Parr hydrogenation apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the mixture was concentrated in vacuo to give 22.6 g (98%) of 3-(2-chloro-4-fluorophenyl)propanoic acid as a purple solid. This material was used without further purification.
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].Cl.C[O:7][C:8]1[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2>C1(C)C=CC=CC=1>[ClH:2].[OH:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC1CCc2c(ccc(O)c2O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41.4 g of dry AlCl3 (310.4 moles), 230 ml of toluene and 20.0 g of 5,6-dimethoxy-2-methylaminotetralin HCl (77.6 moles) are placed into a 4-necked round-bottomed flask, with stirring, under a slight stream of dry nitrogen. Temperature is brought to 80° C. to obtain a stirrable brown mixture, left at 80° C. for 4 hours, then cooled to room temperature and poured into ice-water (about 1000 ml total). The aqueous phase is separated and evaporated under vacuum (T about 80° C.). The whitish solid is triturated at room temperature in 750 ml of absolute ethanol, then dried at 60° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 6-chloro-2-(bromoacetamido)benzoic acid from Example 42 (7 g, 0.024 mol), aniline (5.6 g, 6 mL, 250 mol %) and DMF (40 mL) was heated at 100° C. for 5 h. The reaction mixture was cooled to rt, poured onto ice and the resulting crystalline product was solubilized by adding 5% KOH (70 mL, pH=9). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL), and the aqueous layer was acidified to pH=3 with 5% HBr and extracted with EtOAc (4×100 mL). Combined EtOAc washings were dried and concentrated. Recrystallization of the resulting solid from EtOAc/Hex, afforded 6 g (82%) of the title compound as white crystals, 176-178.2° C.; 1H NMR (DMSO-d6) δ 9.93 (s, 1H, COOH), 7.97 (d, 1H, J=8), 7.42 (t, 1H, J=8), 7.30 (d, 1H, J=7.6), 7.12 (t, 2H, J=7.2), 6.65 (t, 3H, J=7.2), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 170.19, 166.30, 148.15, 136.56, 131.12, 130.53, 128.98, 125.51, 121.39, 117.23, 112.71, 48.13; MS (EI, m/z) 304 (M+)
Reaction SMILES: [Cl:1][C:2](=[CH:7][CH:8](Cl)[CH:9]([CH3:11])[CH3:10])[C:3]([F:6])([F:5])[F:4].[Cl-].[Li+].O>CN(C)C=O>[Cl:1][C:2](=[CH:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]([F:4])([F:5])[F:6]
Reactant: CC(C)C(Cl)C=C(Cl)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CC=C(Cl)C(F)(F)F
Temperature: 160 °C
Yield: 76 %

Procedure:
2,4-Dichloro-5-methyl-1,1,1-trifluorohex-2-ene (22.1 g) in dimethylformamide (100 ml) containing lithium chloride (5.0 g) is heated under a nitrogen atmosphere in an oil bath at 160° C. for 1.5 hours. The cooled mixture is added to water (1.5 l), extracted with dichloromethane and the extracts dried over anhydrous sodium sulphate and distilled to afford 2-chloro-5-methyl-1,1,1-trifluorohexa-2,4-diene (76%). The identity of the product was proved by comparison to 'Hnmr and infra-red spectra with those of authentic material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([F:24])=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.C[Si](C)(C)[C:38]([F:41])([F:40])[F:39].[F-].[Cs+]>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:35][CH:34]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[C:38]([F:41])([F:40])[F:39])[CH:19]=[N:18][C:17]=3[F:24])[N:10]=2)=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3F)n2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108 %

Procedure:
To a stirred solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoronicotinaldehyde (3.7810 g, 7.99 mmol; Example 143, Step 1-2) in THF (50.00 mL) was added trimethyl(trifluoromethyl)silane (TCI America, Inc.; 1.703 g, 11.98 mmol) followed by CsF (0.243 g, 1.597 mmol) at 0° C. and the mixture was stirred at the same temperature for 10 min before warming to room temperature and stirring for 3.5 h. The reaction was quenched with 1 N HCl and stirred for another 30 min, and then EtOAc (10 mL) was added. The separated aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a brown foam residue as the desired product 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2,2,2-trifluoroethanol (4.69 g, 8.63 mmol, 108% yield) which was used directly for the next step.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH3:23])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (52 mg, 0.17 mmol) in DMF (2 mL) was added Cs2CO3 (65 mg, 0.2 mmol) and the mixture was stirred at RT for 10 minutes. A solution of methyl iodide in DMF (0.2 mL, 0.2 mmol, 1 M) was added and the reaction solution was stirred at RT for 2 h. The reaction was quenched with EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated in vacuo to give the title compound (35 mg, 65%) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:13]O>Cl[Ti](Cl)(Cl)Cl>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([OH:11])=[C:9]([I:12])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)c1cc(I)c(O)c(I)c1
Yield: 76 %

Procedure:
To a stirring solution of 3,5-diiodo-4-hydroxybenzoic acid (10.00 g, 25.65 mmol) in dry methanol (250 mL) was added TiCl4 (1.41 mL, 12.82 mmol) in one lot. The reaction was stirred at reflux for 6 h and was then stirred at room temperature for 24 h. The mixture was concentrated down and the residue was taken up in diethyl ether and filtered through a plug of silica gel. The filtrate was concentrated down and the residue was recrystallized from hot methanol to give 7.84 g (76%) of the ester as white crystalline needles. 1H NMR (DMSO-d6) δ 10.41 (br s, 1H), 8.22 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](N)=[C:8]([C:20]#[N:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)=[O:4].[I:23]CI.N(OCCC(C)C)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:23])=[C:8]([C:20]#[N:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)=[O:4]
Reactant: COC(=O)c1sc(N)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)c1sc(I)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Combine 5-amino-3-(4-tert-butyl-phenyl)-4-cyano-thiophene-2-carboxylic acid methyl ester (0.29 mmol) in acetonitrile and add diiodomethane (1.02 mmol) and iso-amyl nitrite (0.73 mmol) and heat to 100° C. After 15 minutes, cool the reaction slowly to room temperature and stir an additional 1 hour. Concentrate the reaction to a dark oil which is purified by radial chromatography on a 2000 micron silica plate eluting with 50/50 methylene chloride/hexane and then 100% methylene chloride. Concentrate desired fractions were to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 4H), 3.78 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C)nc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.05 g) in methylene chloride (100 mL) was added m-chloroperbenzoic acid (77%, 13.5 g). The reaction mixture was stirred at room temperature for 2 h and then diluted with chloroform (100 mL). The mixture was washed successively with aqueous sodium sulfite, saturated sodium bicarbonate, and brine. The organic later was then dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 6.21 g of methyl 6-methylnicotinate 1-oxide. A solution of methyl 6-methylnicotinate 1-oxide (4.35 g) in acetic anhydride (50 mL) was heated at 120° C. for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1:2 to 3:5 ethyl acetate/hexanes) provided 3.3 g of the title compound: 3H NMR (300 MHz, CDCl3) δ 9.18, 8.31, 7.44, 5.29, 3.96, 2.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:15][CH3:16])[C:12]#[C:13][CH3:14].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:15][CH3:16])[C:12]#[C:13][CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CC#CC1(OC)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC#CC1(OC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 15 %

Procedure:
5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) were stirred at room temperature in dimethoxyethane (22 cm3). After 15 min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodium carbonate (1.06 g, 10 mmol) in water (11 cm3) were added and the mixture heated under reflux. After 16 h, the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were washed with sodium hydroxide (1N, ×2), brine, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, EtOAc:hexane, gradient elution) and the product triturated with hexane to afford the title compound (0.095 g, 0.30 mmol, 15%) as a solid: mp. >190° C. (decomp.); (CDCl3) δ 1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s, 1H), 6.91 (d, 1H, J=8.1 Hz), 7.29-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.54-7.57 (m, 2H), 7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M+).
Reaction SMILES: Br.[C:2]1([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[N:13]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc3ccccc23)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc4ccccc34)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A mixture of 10 g of 4-(1-naphthyl)-thiazol-2-ylamine hydrobromide with 7.4 g of 4-methoxy-benzenesulfonyl chloride was stirred for 16 hours with 40 ml of pyridine. The resulting, red colored suspension was poured into 400 ml of 1N hydrochloric acid and the extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and free from solvent. The residue was dissolved in a mixture of 500 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 10 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated, the residue was taken up with ethyl acetate, dried with magnesium sulphate and concentrated. Crystallization from ethyl acetate/hexane yielded 10.2 g of 4-methoxy-N-(4-naphthalen-1-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals, which were recrystallized once from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[Br:53][C:54]1[CH:55]=[C:56]([CH2:61][NH2:62])[CH:57]=[CH:58][C:59]=1[F:60]>C(Cl)(Cl)Cl>[Br:53][C:54]1[CH:55]=[C:56]([CH2:61][NH:62][C:18]([C:17]2[CH:16]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:57]=[CH:58][C:59]=1[F:60]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To solution of the commercially available 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (200 mg, 0.63 mmol) in CHCl3 (5 mL) was added HOBt (90 mg, 0.67 mmol), EDCI (180 mg, 0.94 mmol), and triethylamine (0.2 ml, 1.4 mmol), followed by [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (151 mg, 0.62 mmol). The resulting mixture was allowed to stir at room temperature for 2 hours then quenched with saturated aq. NaHCO3 (1 mL) was added. The organic layer was separated, dried over Na2SO4 and evaporated to give a residue which was purified by Combiflash® chromatography eluting with hexane/ethyl acetate (95/5 to 70/30 over 15 min.) to give the title compound as white solid (265 mg, 80%). LC/MS: m/z, 505 (M+H), 2.81 min.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Se](=O)=[O:22].O1CCOCC1>O>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:19]=[O:22])=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=[Se]=O
Reactant: CCCCCCCCCCOc1ccc(C(C)=O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCOc1ccc(C(=O)C=O)cc1

Procedure:
A mixture of 11.56 g. of 4'-(decyloxy)acetophenone, 4.6 g. of selenium dioxide, 150 ml. of dioxane and 4 ml. of water was refluxed overnight, filtered through diatomaceous earth, washed with dioxane and the filtrate evaporated to dryness. The residue was triturated with water, dried and crystallized from 150 ml. of hot acetone giving the desired product as an off-white solid, m.p. 81°-83° C.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:5]1[CH2:6][CH2:7][N:2]([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:3][CH2:4]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added DIEA (158 μL, 0.91 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with MsCl (26 μL, 0.33 mmol) and the resulting solution was stirred (rt, 2 h). The reaction mixture was partitioned with EtOAc and brine (20 mL each) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a white solid (42 mg, 31%). MS (ESI): mass calcd. for C20H20N4O4S2, 444.54; m/z found, 445.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.74 (d, J=8.5, 1H), 7.62-7.56 (m, 2H), 7.30 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=8.0, 4.8, 1H), 3.69 (d, J=0.5, 2H), 3.32-3.21 (m, 4H), 2.79 (s, 3H), 2.67-2.54 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:10]1[CH:9]=[CH:8][C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=1
Reactant: CCOC(=O)Cn1cc(C)ccc1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(=O)n(CC(=O)NN)c1
Yield: 92 %

Procedure:
As described for example 112a, (5-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 92%). MS: m/e=204.1 [M+Na]+.