Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].[C:22]([OH:27])(=[O:26])[CH:23]([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[C:22]([O:27][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)CC1(CNC(=O)OC(Cl)C(C)C)CCCCC1
Reactant: CC(C)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
A mixture of (106) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol), and isobutyric acid (442 μL, 4.76 mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μL, 4.76 mmol) was added, and the resulting mixture was stirred for another 24 h. After filtration, the filtrate was concentrated and the resulting residue purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane, to afford 560 mg (63%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 0.94 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 1.15 (d, J=7.2 Hz, 3H), 1.17 (d, J=7.2 Hz, 3H), 1.32–1.58 (m, 10H), 2.01 (m, 1H), 2.19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H), 3.67 (s, 3H), 5.33 (t, 1H), 6.56 (d, J=4.8 Hz, 1H). MS (ESI) m/z 372.38 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCNCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CNCCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-β-alaninate (D78) (287 mg) in tetrahydrofuran (5 mL) and ethanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (60 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and recrystallized from EtOAc to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-β-alanine (E58) (130 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.28 (2H, t), 2.91 (2H, t), 3.68 (3H, s), 4.11 (2H, s), 4.88-4.91 (1H, m), 7.23 (1H, t), 7.45-7.50 (3H, m), 7.96 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d). MS (ES): C24H26ClN4O4 requires 468. found 380.1 (M—NHC2H4COOH+).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:36]#[N:37])[C:22]([N:23]3[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:38])C1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:36]([C:21]1[C:22]([N:23]2[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:38])#[N:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(C#N)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(C#N)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Yield: 42.8 %

Procedure:
Following the procedure of Example 55, (S)-[1-(2-benzyloxy-5-cyano-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)-pyrrolidin-3-yl]-carbamic acid, tert-butyl ester (0.17 g, 0.31 mmol, from Example E2) and 5% Pd/BaSO4 (0.50 g) were reacted, with an additional 0.045 g and 0.030 g of 5% Pd/BaSO4 in methanol (50 mL) being added after 100 hours and 120 hours, respectively, to give 0.056 g of (S)-[1-(5-cyano-2-hydroxy-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)-pyrrolidin-3-yl]-carbamic acid, tert-butyl ester. This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:39].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:39][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COCC#Cc1cc(F)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
4-Chloro-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazoline (201 mg, 0.60 mmol) and 5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (140 mg, 0.63 mmol) in DMF (3 ml) were cooled in an ice-water bath then treated dropwise, under an atmosphere of nitrogen, with a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.25 ml). The resulting mixture was stirred at ice temperature for a further 90 minutes before quenching in dilute aqueous ammonium chloride solution and extracting with dichloromethane (containing a small percentage of methanol). The extract was washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. The residue was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (245 mg, 78%) as a colourless solid; NMR Spectrum: (DMSOd6) 1.97 (quintet, 2), 2.40 (m, 4H), 2.47 (t, 2H), 3.36 (s, 3H), 3.59 (m, 4H), 3.95 (s, 3H), 4.20 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 6.91 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 525.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>ClCCl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[S:16])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cccc(Br)n1
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-bromopyridine (25 g, 144.5 mmol) in dichloromethane (25 mL) cooled to 5° C. was added ethoxycarbonyl isothiocyanate (17.1 mL, 144.5 mmol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temperature at which it was stirred for 16 h. Evaporation in vacuo gave a yellow solid, which was collected by filtration and thoroughly washed with cyclohexane. No further purification was required. Yield: 41.5 g, 94%; LCMS method: 1, RT: 5.66 min, MI: 304-306 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[CH2:4][CH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.C([BH3-])#N.[Na+].O=[CH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CO.C(OCC)C>[CH2:14]([N:13]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:32][CH3:33])[C:28]([F:30])([F:31])[F:29])=[CH:27][CH:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCNCCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Reactant: CCOC(=O)CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecanamine (2.0 g, 4.2 mmol) in methanol (50 ml) was treated with sodium cyanoborohydride (0.55 g, 8.4 mmol) and ethyl 4-oxobutyrate (1.04 g, 8.4 mmol). The resulting mixture was stirred at 22° C. for 16 h, diluted with diethyl ether (350 ml), washed with water (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/AcOEt 9:1 to 6:1) to afford the title compound (1.8 g, 73%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([O:7]C(C)(C)C)=[O:6].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>O.CS(C)=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:12]=[CH:13][C:14]=1[O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=1)[C:5]([OH:7])=[O:6]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
tert-Butyl 3-chloro-2,4-difluorobenzoate (Preparation 154, 0.249 g, 1.00 mmol), 4-chloro-3-(trifluoromethyl)phenol (0.196 g, 1.00 mmol) and potassium carbonate (210 mg, 1.5 mmol) were added to dimethyl sulfoxide (6 mL) and stirred at ambient temperature for 4 hours, then another 18 hours at 70° C. The reaction mixture was diluted with water and extracted three times with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to leave a residue. The residue was purified by silica gel column chromatography eluting with 0-10% ethyl acetate in hexanes. The desired fractions were combined and the solvent removed in vacuo. The residue was dissolved in trifluoroacetic acid (0.50 mL, 6.5 mmol) and stirred for 18 hours. The solvent was removed in vacuo and the residue triturated with dichloromethane. The resulting precipitate was collected by filtration and vacuum dried to afford the title compound as a white solid (140 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH:35]=[CH:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:32][CH:33]=[CH:34][CH2:35][CH2:36]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: C1=CCNCC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC=CCC4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and 1,2,3,6-tetrahydropyridine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 6.05 (m, 1H), 5.79 (m, 2H), 3.4-3.8 (m, 12H), 3.41 (t, J=7.5 Hz, 4H), 2.5 (m, 2H); MS (DCI) m/z 416 (M+H)+;
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:38])[CH2:19][C:20]3[CH:36]=[C:35]([CH3:37])[C:23]4[N:24]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[CH3:34])[O:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C>[CH3:37][C:35]1[C:23]2[N:24]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[O:26][C:22]=2[CH:21]=[C:20]([CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][C:3]([OH:39])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:12][CH:13]=2)=[O:38])[CH:36]=1
Reactant: COC(=O)CC1(c2ccc(NC(=O)Cc3cc(C)c4nc(Nc5ccccc5C)oc4c3)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)Nc3ccc(C4(CC(=O)O)CCOCC4)cc3)cc2o1
Yield: 30 %

Procedure:
A solution of (4-(4-{2-[4-methyl-2-o-tolylamino-benzoxazol-6-yl]-acetylamino}-phenyl)-tetrahydro-pyran-4-yl)-acetic acid methyl ester [0.178 g, Reference Example 17(a)] in degassed ethanol (30 mL) was treated with sodium hydroxide solution (1 mL, 1N) and the mixture was stirred under nitrogen and at reflux temperature for 6 hours. The resulting red solution was evaporated and the residue was subjected to preparative HPLC on a Hypersil Elite C18 column eluting initially with a mixture of acetonitrile, water and trifluoroacetic acid (25:75:0.1, v/v/v) and then 1% acetonitrile/minute gradient to give the title compound (0.052 g) as a solid. LC-MS: RT=3.30 minutes, MS(ES+): 514.06(M+H)+; MS(ES−): 512.08(M−H)−.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]([O:21]CC)=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH:1]1([N:4]([CH2:18][C:19]([OH:21])=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CN(C1CC1)S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(CC(=O)O)C2CC2)c(C)c1
Yield: 83 %

Procedure:
A solution of ethyl 2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)acetate (2.7 mmol, 1 eq.) and LiOH (5 eq.) in THF/H2O (1:1) was stirred at room temperature for 12 h. The solvent was removed completely, in vacuo. The crude product was taken up in water and the mixture was washed with ethyl acetate. The aqueous phase was acidified to pH=4 with 1 M HCl and was then extracted with ethyl acetate. The organic phase was dried over Na2SO4. After the solvent had been distilled off completely, the crude product was obtained, and was employed in the next stage without further purification. Yield: 83%
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:5].[BH4-].[Na+]>CO>[NH2:2][CH2:3][CH:4]([C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[OH:5]
Reactant: CS(=O)(=O)Nc1cc(F)cc(C(=O)CN)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(F)cc(C(O)CN)c1
Yield: 71.7 %

Procedure:
3'-(2-Aminoacetyl)-5'-fluoromethanesulfonanilide hydrochloride (1.7 g) was suspended in 70 ml of methanol, then 114 mg of sodium borohydride was added thereto with stirring at 5°-10° C. and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was made into a free base using ion exchange resin (Dowex 50W X2) followed by recrystallizing from methanol-ethanol to give 1.07 g of (±)-3'-(2-amino-1-hydroxyethyl)-5'-fluoromethanesulfonanilide, m.p. 167°-169° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].[Cl-].[Li+]>CN(C=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:24]=[CH2:25])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Temperature: 90 °C
Yield: 75.2 %

Procedure:
To a solution of 2.48 g (7.05 mmol) of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 2) in 30 mL of DMF was added 2.16 mL (7.40 mmol) of vinyl tributyltin, 0.898 g (21.1 mmol) of lithium chloride and 0.247 g (0.352 mmol) of tetrakis(triphenylphosphine)palladium(0). The reaction was heated to 90° C. for 3 h and then cooled to room temperature. The reaction was diluted with water and extracted with ether. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:25) to provide 1.22 g of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]2([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH2:30]([SH:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]([CH2:11][S:32][CH2:30][CH3:31])([C:12]([F:13])([F:15])[F:14])[OH:10])=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: CCS
Reactant: COc1cc(C(Nc2cccc3nc(C)ccc23)C2(C(F)(F)F)CO2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(F)c(OC)c1)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.25 mmol) {[4-fluoro-3-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-(2-methylquinolin-5-yl)amine (example 11) are reacted with 0.27 ml of the 1 M ethanthiol solution under the presence of 160 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 53 mg of the title compound after preparative thin layer chromatography on silica gel (aceton in hexane 50%).
Reaction SMILES: [CH2:1]([OH:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:21]=1>C(Cl)Cl>[CH:1](=[O:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:21]
Reactant: c1cc[nH+]cc1
Reactant: CCCCCCCCCC/C=C/CO
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CCCCCCCCCCC/C=C/C=O

Procedure:
To dodecyl aldehyde (5.0 g) dissolved in methylene chloride was added (carbomethoxymethylene)-triphenylphosphorane (9.1 g), and the mixture was stirred for 2 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans-2-tetradecenoic acid (5.2 g). To the methyl ester dissolved in tetrahydrofuran was added lithium aluminium hydride (0.9 g) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was distributed into ethyl acetate and water, and the ethyl acetate layer was dried, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give trans-2-tetradecenol (3.2 g). To the solution of the trans-2-tridecenol in methylene chloride were added pyridinium chlorochromate (3.5 g) and Celite (5.0 g), and the mixture was stirred. The reaction mixture was filtered and concentrated to give trans-2-tetradecenal (2.3 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[NH2:15][C@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:15][C@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])=[C:3]([CH3:14])[C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: Cc1c(F)ccc(C#N)c1C(F)(F)F
Reactant: CC(C)(O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Temperature: 85 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile (763 mg, 3.76 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (500 mg, 3.76 mmol) in DMSO (25 mL). K2CO3 (1.56 g, 11.28 mmol) was added to the reaction mixture and the reaction mixture stirred at 85° C. for 18 h. The reaction mixture was allowed to cool to room temperature, quenched with H2O (25 mL) and extracted with EtOAc (2×30 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×80 mL). The later organic extracts were combined, washed with H2O (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a yellow solid (1.15 g, 97%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.63 (d, J=9 Hz, 1H), 6.97 (d, J=9 Hz, 1H), 5.62 (d, J=9 Hz, 1H), 4.20 (d, J=9 Hz, 1H), 2.33 (s, 3H), 1.43 (s, 3H) and 1.42 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH:29]([NH:32][S:33]([C:36]1[S:37][C:38]([Cl:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])[CH2:30][OH:31]>>[Cl:42][C:38]1[S:37][C:36]([S:33](=[O:35])(=[O:34])[NH:32][CH:29]([CH2:28][OH:27])[CH2:30][OH:31])=[CH:40][C:39]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according to general procedure II. Yellow solid. MS (ISP) 642.2 [(M−H)−]; mp 225° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][O:12][CH2:11]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Ic1ccncc1NCC1CCCOC1
Product: COc1cc(F)ccc1-c1ccncc1NCC1CCCOC1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((tetrahydro-2H-pyran-3-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 5 hours at reflux. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) followed by EtOAc:MeOH (100:0 to 90:10). Yellow oil (106%). MS (ESI): m/z=317.166 [M+H]+.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=2)[N:18]=1.[K][S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][K]>>[CH3:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][C:26]1=[N:25]2
Reactant: Cc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: N#CC(C#N)=C(S[K])S[K]
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: Cc1ccc2nc3c(nc2c1)SC(=C(C#N)C#N)S3
Yield: 73 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 3.0 g of 2,3-dichloro-6-methylquinoxaline and 3.84 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a yellow powder weighing 2.9 g with a calculated overall yield of 73 percent and has a melting point of 265° to 267° C.