Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:34])([CH3:33])[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[CH:17]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:34][C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:35])([CH3:36])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:33])[C:24]([N:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)=[O:25]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(C(=O)C(C)(C)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 0.5 %

Procedure:
A mixture of 2-{3-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.895 g, 1.8 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (5 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (4 mg, 0.4%) as a white solid: LC/MS m/e calcd for C27H36N4O3 (M+H)+: 465.61, observed: 465.2.
Reaction SMILES: [F:1][C:2]1([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][NH:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:21]([O:30]N1C(=O)CCC1=O)([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=O>CC#N>[C:16]([O:15][C:14]([NH:13][C@@H:9]([CH2:8][C:2]1([F:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:10][N:11]([CH3:12])[C:21](=[O:30])[O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])=[O:20])([CH3:19])([CH3:17])[CH3:18]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC[C@H](CC1(F)CCCCC1)NC(=O)OC(C)(C)C
Solvent: CC#N
Product: CN(C[C@H](CC1(F)CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
Crude (S)-tert-butyl 1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate and TeocOSu (137 mg, 0.5 mmol) were dissolved in 1:1 CH3CN/10% aqueous K2CO3 (20 mL). The mixture was stirred for 2 h. After this time all of the free amine was consumed. The CH3CN was removed in vacuo and the aqueous residue extracted with EtOAc (3×10 mL). The combine organic extracts washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography on silica, eluting with 0-27% EtOAc in hexanes, afforded (S)-2-(trimethylsilyl)ethyl 2-(t-butoxycarbonylamino)-3-(1-fluorocyclohexyl)propyl(methyl)carbamate (70 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.Cl.[CH3:20][N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.C(OC(O)C)C>N1C=CC=CC=1>[CH3:20][N:21]([CH3:29])[C:22]1[CH:23]=[C:24]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Reactant: CN(C)c1cccc(N)c1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(OC)c2c(Nc3cccc(N(C)C)c3)c(C#N)cnc12
Yield: 77.2 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.146 g of N,N-dimethyl-1,3-phenylenediamine dihydrochloride, 0.2 ml of pyridine, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. Then the mixture was partitioned between ethyl acetate and saturated sodium chloride solution. The organic layer was dried and concentrated in vacuo. The residue thus obtained was chromatographed on silica gel eluting with ethyl acetate. Solvent was removed from product fractions giving 0.160 g of 4-(3-dimethylamino-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 103-105° C.; mass spectrum (EI, m/e): M 348.1588.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#C)=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.I(O)(=O)(=O)=[O:20].[OH2:24]>[Cl-].[Cl-].[Cl-].[Cl-].C.O.[Ru](Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:20])=[O:24])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O
Reactant: C#Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Cl-]
Solvent: CC#N
Product: CC(C)(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
4-tert-Butyl-1-ethynyl-2-nitro-benzene (1.662 g, 8.176 mmol) was dissolved in 20 mL carban tetrachloride, 20 mL acetonitrile, and 40 mL water. Periodic acid (9.322 g, 40.89 mmol) was added followed by ruthenium(III)chloride hydrate (85 mg, 0.41 mmol). After stirring of 90 minutes, the resulting mixture was diluted with water and extracted with three portions of dichloromethane. The combined dichloromethane layers wee dried over anhydrous MgSO4, and concentrated in vacuo to yield 4-tert-Butyl-2-nitro-benzoic acid (1.924 g, 86.19 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:29])[C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH:19]([F:29])[F:18])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(C(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-difluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=397.3 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[O:33]>C1COCC1.CCCCCC>[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([OH:33])[C:14]1([CH3:13])[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24]
Reactant: COC(=O)CCCCC=O
Reactant: CC1CCc2ccccc2C1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCCCC(O)C1(C)CCc2ccccc2C1=O
Reaction time: 0.17 h
Yield: 25.8 %

Procedure:
To 1.55 mL diisopropylamine in 40 mL THF is added a solution of 4.36 mL n-butyllithium (2.5M) in hexane at −78° C. After 10 min, 1.63 g 2-methyl-1-tetralone in 5 mL THF is added, and the solution is stirred for 50 min. Then, 1.60 g 6-oxo-hexanoic acid methyl ester in 5 mL THF is added dropwise, and stirring is continued for 15 min. After that, the cooling bath is removed and the mixture allowed to reach rt. Conc. ammoniachloride sol is added, and extracted with ethylacetate. After evaporation the residue is purified by column chromatography yielding 0.8 g 6-hydroxy-6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hexanoic acid methyl ester (7a). 2.5 g of this alcohol 8a is dissolved in 50 mL dichloromethane and 2.27 mL triethylamine is added. After cooling to 0° C., 2.86 g methanesulfonic acid anhydride in 20 mL dichloromethane is added dropwise. After complete addition, the cooling bath is removed and stirring continued over night. The solution is washed with 2N HCl and water, separated, dried and evaporated. The crude product and 1.6 g 1,8-diazabicyclo[5.4.0]undecen-7-en (DBU) is dissolved in 60 mL toluene an heated to reflux for 24 h. The mixture is poured on 2N HCl and extracted with dichloromethane. After evaporaton and column chromatography 0.6 g 6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hex-5-enoic acid methyl ester (7b) is obtained. 7b is converted to 7c in an analogous manner to that described for the conversion of 1c to 1d in example 1. 7c was obtained as an oil, MS (APCI): 286.1 (M−1).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:17][C@H:18]2[O:20][CH2:19]2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
p-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature and (S)-Glycidyl nosylate (1.71 g, 6.6 mmol) was added. The system was stirred for an additional 24 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent system to give (S)-Glycidyl p-nitrophenyl ether (99.6% ee, based on chiral HPLC with Chiralcel OD, m.p 78-9° C.) as a yellowish solid (1.21 g, 93% yield). The NMR values are the same as the literature values for the racemic mixture: 1H-NMR (CDCl3) δ 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H), 4.38 (dd, 1H), 6.99 (dd, 2H), 8.2 (dd, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1.[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17](=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][CH:21]=2)[N:16]=1)([CH3:13])([CH3:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17]([N:16]=1)=[C:18]([C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1)[CH:19]=[CH:20][CH:21]=2)([CH3:13])([CH3:12])[CH3:11]
Reactant: NC(=O)c1cc(Br)c[nH]1
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3c[nH]c(C(N)=O)c3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 16.5 h
Yield: 50.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrole-2-carboxamide (100 mg, 0.529 mmol), N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b; 311 mg, 0.529 mmol), K3PO4 (337 mg, 1.587 mmol), XPhos (Strem Chemicals, Inc.; 25.2 mg, 0.053 mmol), and (Aldrich; 24.22 mg, 0.026 mmol) in a mixture of dioxane (4.0 mL) and water (1.0 mL) was stirred under argon at 100° C. for 16.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-2-carboxamide (86.7 mg, 0.268 mmol, 51% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.), 7.78 (1H, dd, J=2.6, 1.5 Hz), 7.61 (1H, dd, J=7.3, 1.3 Hz), 7.54 (1H, dd, J=8.1, 1.5 Hz), 7.44 (1H, br. s.), 7.31 (1H, t, J=7.7 Hz), 7.22-7.26 (1H, m), 6.94 (1H, br. s.), 5.78 (1H, s), 2.53 (3H, s), 1.53 (9H, s). m/z (ESI, +ve) 324.0 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C([O+:10]([CH2:13][CH3:14])[CH2:11][CH3:12])C.O=[C:16]1[NH:21]CC[N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>>[CH2:13]([O:10][C:11]1[CH2:12][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16][N:21]=1)[CH3:14]
Reactant: CC[O+](CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethyloxonium hexafluorophosphate (3.20 g, 28.0 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.54 g, 12.7 mmol) in CH2CL2 (31.7 mL) at 0° C., and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated NaHCO3, dried (Na2SO4), and concentrated to give tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate as an oil. LCMS (APCI+) M+H−t−Bu: 173 (40%); rt=3.14 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][O:34][CH3:35])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][O:34][CH3:35])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(C)S(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: COCCN(C)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(2-methoxy-ethyl)-4,N-dimethyl-benzenesulfonamide (Intermediate 141), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].S(Cl)([Cl:14])=O>>[CH2:1]([C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6])[CH3:2]
Reactant: CCc1cnccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCc1cnccc1C(=O)Cl
Temperature: 25 °C

Procedure:
A mixture of 0.62 g of 3-ethyl isonicotinic acid 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give 3-ethyl isonicotinic acid chloride. A mixture of the resultant 3-ethyl isonicotinic acid chloride and 3 ml of DMF was added dropwise to a mixture of 0.87 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.83 g of triethylamine and 3 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for two hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]-3-ethyl isonicotinamide.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[CH2:8][CH2:9][NH:10][CH3:11])(C)(C)C.Cl[C:24]1[S:28][N:27]=[C:26]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[N:25]=1.O>CS(C)=O.CCOC(C)=O>[O:17]1[C:16]2[CH:20]=[CH:21][C:13]([CH2:12][NH:7][CH2:8][CH2:9][N:10]([C:24]3[S:28][N:27]=[C:26]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:25]=3)[CH3:11])=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: CNCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Reactant: Clc1nc(-n2ccnc2)ns1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (200 mg, 649 μmol), 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (121 mg, 649 μmol) and TEA (181 μL, 1.30 mmol) in DMSO (6 mL) was stirred at r.t. for 21 h. Water (50 mL) was added and the solution was extracted with ethyl acetate (2×25 mL), washed with brine, dried over Na2SO4, filtered and concentrated to a clear oil. The crude residue was dissolved in TFA/DCM (1:1, 4 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford an orange oil. The crude product was diluted with EtOAc (50 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an oil. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 21.3 mg (9%) of N′-benzo[1,3]dioxol-5-ylmethyl-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-methyl-ethane-1,2-diamine as a white solid. [M+H]+ 358.92; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.64 (s, 1H), 7.07 (s, 1H), 6.81 (s, 1H), 6.73 (m, 2H), 5.92 (s, 2H), 3.76 (s, 3H), 3.65 (br s, 1H), 3.14 (m, 4H), 2.95 (t, 2H).
Reaction SMILES: CS(C)=O.Br[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:26][CH:25]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C#N)cc2)CC1
Reaction time: 26 h
Yield: 97.7 %

Procedure:
To a dimethylsulfoxide (130 mL) solution of 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate were added 5.13 g of 4-cyanophenol and 11.9 g of potassium carbonate at room temperature, which was then stirred at the same temperature for 26 hours. The reaction mixture was added to a mixture of toluene and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to provide 14.5 g of tert-butyl 4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate as white solid form.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:23](=[O:24])[NH:22][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
12.3 g. of 4-fluoro-4'-hydroxy-α-ethyl-benzhydrol, 4.68 g. of n-propyl-isocyanate and 0.7 g. of anhydrous, powdered potassium carbonate in 61 ml. of acetonitrile containing 15 μlit. of a 50% aqueous ethanol solution are refluxed under stirring. When the reaction is complete, the reaction mixture is cooled to room temperature, potassium carbonate is filtered off and acetonitrile is distilled off under reduced pressure. The residue is dissolved in benzene, the benzene solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and benzene is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 13.6 g. of the desired compound, melting at 107° to 108° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[N:6][OH:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=2)[N:33]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:8]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)=[CH:11][CH:10]=1)=[N:6][OH:7])[CH3:2]
Reactant: CCOC(=O)C(=NO)C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a solution in dry DMF (20 mL) of bis(4-hydroxyphenyl)methyloximinoacetic acid ethyl ester (0.64 g, 2 mmol), prepared as in step 1, was added cesium carbonate (1.6 g, 5 mmol), the mixture was stirred for 10 mutes, and 2-bromomethyl-7-chloroquinoline (1 g, 4 mmol) was added. After stirring for 18 hours, the mixture was poured into water and the precipitated solid was collected by filtration, washed with water, and dried in vacuo. Chromatography on silica gel (hexane/EtOAC 3:1) afforded bis(4-(7-chloro-2-quinolylmethoxy)phenyl)-methyloximinoacetic acid ethyl ester (1.1 g).
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:20]([S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1ccccc1C(O)Cn1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Reaction time: 2.7 h

Procedure:
8.3 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 578 mg of methyl 4-mercaptobenzoate and 500 mg of 1-[2-hydroxy-2-(2-methoxyphenyl)ethyl]imidazole, and the mixture was stirred at a temperature between 0° and 5° C. for 2.7 hours, and then at room temperature for 2.5 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.[CH2:23]([Mg]Cl)[CH:24]([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:8]=[C:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:10]=[C:11]([Cl:13])[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC(C)C[Mg]Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,6-dichloro-isonicotinic acid tert.-butyl ester (1.74 g, 7.0 mmol), Fe(acac)3 (706 mg, 2.0 mmol) and NMP (1.0 g, 10 mmol) in THF (250 mL), a solution of isobutylmagnesium chloride (1.15 g, 9.8 mmol) in THF is slowly added at −77° C. The brown solution turns turbid and black. Stirring is continued for 1 h at −72° C. before it is warmed to rt. The mixture is again cooled to −40° C. and then stirred for 16 h. The reaction is carefully quenched with 0.5 N aq. HCl (100 mL) and diluted with ether. The org. layer is separated and the aq. phase is extracted five more times with ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-chloro-6-isobutylisonicotinic acid tert.-butyl ester as a pale yellow oil (1.70 g) which contains 2,6-di-isobutylisonicotinic acid tert.-butyl ester as an impurity; LC-MS: tR=1.12 min, [M+1]+=270.07.