Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[CH:10]=2)=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1)CCC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:30]3[S:31][CH:32]=[C:33]([CH3:35])[N:34]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nc(C)cs3)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of compound 274 (1 g, 1 eq.) and 2-(tributylstannyl)-4-methylthiazole (1.28 g, 1.2 eq.) in DMF (14 mL) were added PdCl2(PPh3)2 (193 mg, 10%) and potassium carbonate (455 mg, 1.2 eq.) and the resulting mixture was stirred at 90° C. overnight. DMF was concentrated under vacuum and water and dichloromethane were added. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on a silica gel to yield compound 275 as a white solid in 65% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.57 (s, 3H), 3.86 (s, 3H), 4.06 (s, 3H), 5.33 (s, 2H), 6.98 (d, J=8.64 Hz, 2H), 7.08 (s, 1H), 7.25 (d, J=9.25 Hz, 1H), 7.46 (d, J=8.64 Hz, 2H), 7.74 (s, 1H), 8.12 (d, J=9.25 Hz, 1H); MS (ESI, EI+): m/z=427.1 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1>C(#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:17][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CSCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (Aldrich, 1.0 mL, 9.1 mmol) in acetonitrile (10.0 mL) were added K2CO3 (2.76 g, 20.0 mmol) and 1-(bromomethyl)-4-fluorobenzene (2.27 g, 12.0 mmol). The mixture was stirred at room temperature for 12 h. After filtration and concentration, the residue was purified by flash column chromatography on SiO2 to give ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 91% yield). MS(ESI+): m/z 251.08 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1CCc2ccc(OCc3ccccc3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C1\CCc2ccc(OCc3ccccc3)cc21
Temperature: -78 °C
Yield: 38 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (4 mL, 26 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (4 g, 26 mmol) in THF (20 mL). The reaction mixture was maintained at −78° C. for 22 minutes. 1.2 (3.5 g, 15 mmol) in THF (20 mL) was then added slowly to the mixture. The mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (300 mL). The organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing solvent by rotary evaporation, the residue was purified by column chromatography (1:4 EtOAc/hexane). The Product 1.3 was obtained in 38% yield as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([NH2:13])=[O:12].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([NH2:13])=[O:12]
Reactant: Oc1cccc(F)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1cccc(F)c1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A mixture of 3-fluorophenol (11.2 g, 100 mmol), 2-bromoacetamide (13.8 g, 100 mmol), K2CO3 (13.82 g, 100 mmol) and Cs2CO3 (32.58 g, 100 mmol) in acetone (150 mL) was refluxed overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (5.06 g, 30%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH3:14])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH:15]2[CH2:16][CH2:17][CH2:18]2)[CH3:14])[N:12]=1
Reactant: CN(c1cncc(Cl)n1)C1CCC1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reaction time: 0.33 h
Yield: 66 %

Procedure:
Phosphoryl chloride (4.3 mL) was added dropwise to DMF (20 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 6-chloro-N-cyclobutyl-N-methylpyrazin-2-amine (4.61 g) in DMF (5 mL), and the mixture was stirred at 50° C. for 15 hr. Water was added to the reaction mixture and the mixture was stirred for 2 hr and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) and recrystallized from hexane-diisopropyl ether to give the title compound (3.46 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[C:8](=[N:10]O)[CH3:9].[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9]
Reactant: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(F)cc32)cc1
Temperature: 60 °C
Yield: 69.4 %

Procedure:
A mixture of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime (0.75 mg, 2.16 mmol), zinc powder (7.06 g, 108 mmol), and NH4Cl (2.31 g, 43.2 mmol) in MeOH (30 mL) and HOAc (6 mL) was heated at 60° C. for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was suspended in ammonia solution (50 mL) and extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude was purified by SiO2 chromatography eluting with DCM/MeOH/Et3N to afford 0.5 g (97.7%) of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine as a yellow solid. MS (ESI): m/z=334.3 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:21]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2,2,2-trifluoroethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 10.4 mg of 254. MS (Q1) 462.7 (M)+.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:20][C:3]1[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1C
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
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1C
Yield: 86.8 %

Procedure:
Methyl 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.1 g), phenylboronic acid (487 mg), sodium carbonate (488 mg) and tetrakis(triphenylphosphine)palladium (355 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), and the mixture was reacted in a microwave reactor (Emrys Optimizer, Personal Chemistry, 140° C., 4 min). The reaction mixture was filtered through celite, water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 947 mg, 87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)C)=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(C2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-[4-(1-methyl(4-piperidyl))-2-nitrophenyl]acetamide (1 equivalent) was dissolved in methanol and 30% KOH (2.5 equivalents) was added dropwise with vigorous stirring. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water (2×) and brine (1×). The organic solution was dried (Na2SO4) and evaporated to obtain the desired product as an orange brown solid. MH+=236.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9]C#N)=[CH:5][CH:4]=1.Cl.O.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][C:16]([OH:17])=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCCC#N)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OCCC(=O)O)cc1
Temperature: 100 °C
Yield: 86.04 %

Procedure:
A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile (1)) was charged to a 22 L round bottom flask equipped with an overhead stirrer under N2. To the stirred solids, 4 L of concentrated HCl was slowly added, followed by 2 L of H2O. The reaction mixture was heated to 100° C. for 3.5 h, at which point the reaction was complete by HPLC analysis. The reaction was cooled to 10° C. by the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 2. The crude material was dissolved in 5 L of 6 wt. % sodium carbonate (such that pH=9), and 2 L of DCM (dichloromethane) was added to the reaction vessel. After stirring thoroughly, the organic layer was separated and discarded via a separatory funnel, and the aqueous layer charged back into the 22 L flask. The pH of the aqueous layer was carefully adjusted to 4.0, by slow addition of 6 M HCl. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 2 as a white solid (Yield: 86.04%). 1H NMR (450 MHz, CDCl3); δ=2.78 (t, 2H; CH2COOH); 3.70 (s, 3H; OCH3); 4.18 (t, 2H; OCH2); 6.78 (m, 4H; Ar—H); 13C NMR (112.5 MHz, CDCl3): δ=34.703 (CH2COOH); 55.925 (OCH3); 64.088 (OCH2); 114.855 (CH3OCCH); 115.984 (CH2OCCH); 152.723 (CH3OC); 154.302 (CH2OC); 177.386 (COOH).
Reaction SMILES: [C:1](=[O:10])(OC1C=CC=CC=1)[NH2:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC#N.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:1]([NH2:2])=[O:10])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: NC(=O)Oc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CN1CCN(C(N)=O)CC1
Temperature: 80 °C
Yield: 67.9 %

Procedure:
To a solution of phenyl carbamate (20.0 g, 146 mmol) in MeCN (200 mL) was added N-methylpiperazine (20.00 g, 200 mmol) followed by catalytic amount of ytterbium triflate (0.500 g, 1.061 mmol) and the resulting mixture was heated at 80° C. for 1 h. The solvent from the reaction mixture was completely evaporated and the residue was crystallized from MTBE to provide 4-methylpiperazine-1-carboxamide (14.2 g, 68% yield) as white solid 1H NMR (400 MHz, DMSO-d6): δ 5.92 (s, 2H), 3.42 (t, J=4.9 Hz, 4H), 2.19 (t, J=4.9 Hz, 4H), 2.14 (s, 3H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 105.3 %

Procedure:
As described in Example 3, 8.92 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate, 3,45 g of p-tert.-butylphenol and 9.17 g of 60% sodium hydride-oil dispersion are reacted in 75 ml of tetrahydrofuran containing 1 ml of hexamethylphosphoramide and worked-up to give 11 g of product as an oil. Chromatography over silica gel with dichloromethane as eluent gives 7.1 g of gum which is crystallized from methanol to give 4.9 g of white crystals. Recrystallization gives white crystals, mp 64°-65° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([NH2:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[S:4]1[CH:5]=[CH:6][C:2]([NH:15][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3]1
Reactant: Brc1ccsc1
Reactant: NC(=O)c1ccccc1
Product: O=C(Nc1ccsc1)c1ccccc1
Yield: 98 %

Procedure:
Using general procedure C, 3-bromothiophene was coupled with benzamide with the reaction time of 21 h. Chromatography gave 198.9 mg (98%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.34 (br s, 1H), 7.85 (dd, 2H, J=1.2, 8.1 Hz), 7.72 (dd, 1H, J=1.2, 3.0 Hz), 7.55−7.41 (m, 3H), 7.26 (dd, 1H, J=3.3, 4.8 Hz), 7.14 (dd, 1H, J=1.5, 5.4 Hz).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:3][C:4]([CH3:7])=[CH:5][CH:6]=3)=[C:18]([F:25])[CH:17]=2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: Cc1ccc(Br)s1
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: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3ccc(C)s3)c(F)c2)cc1

Procedure:
A mixture of 5.0 g (28.2 mmol) of 2-bromo-5-methylthiophene, 7.70 g (28.3 mmol) of 4′-ethyl-3-fluoro-4-biphenylboronic acid, 1.70 g (1.47 mmol) of tetrakis(triphenylphosphine)palladium(0) and 30 ml of 2 N sodium carbonate solution in 90 ml of toluene/ethanol (1:2) is refluxed for 3 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=97:3). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(4′-ethyl-3-fluorobiphenyl-4-yl)-5-methylthiophene as a colourless solid (m.p. 102° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([O:32][CH2:33][CH2:34][CH2:35][NH:36][CH3:37])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:36]([CH3:37])[CH2:35][CH2:34][CH2:33][O:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCOc1ccc(OC)c(OC)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1ccc(OCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-1-chloropropane, N-[3-(3,4-dimethoxyphenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(OCC)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: CC(=O)c1ccccc1F
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 1-(2-fluorophenyl)ethanone (5.00 g, 36.2 mmol) in diethyl ether (100 ml) was slowly added dropwise bromine (5.78 g, 36.2 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure to give the desired product (5.89 g, 74.9%) as an oil.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[C:30]2[C:25](=[C:26]([O:31]C)[N:27]=[CH:28][CH:29]=2)[N:24]([CH3:33])[CH:23]=1>O1CCCC1>[CH:1]1([CH2:6][CH2:7][O:8][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[C:22]2[C:30]3[CH:29]=[CH:28][NH:27][C:26](=[O:31])[C:25]=3[N:24]([CH3:33])[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Reactant: OCCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCCC2CCCC2)c2cc[nH]c(=O)c21
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 40.5 %

Procedure:
2-cyclopentylethanol (0.137 g, 1.196 mmol) in tetrahydrofuran (5 mL) was treated with NaH (0.029 g, 1.196 mmol) at ambient temperature, stirred for 5 minutes and treated with the product from Example 17C (0.1 g, 0.299 mmol). The reaction mixture was heated at 60° C. for 12 hours and partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. The resulting residue (0.15 g) was treated with 4 M HCl in dioxane (15 mL), heated at 70° C. for 12 hours, cooled, concentrated and the residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) to give the title compound (0.05 g, 0.121 mmol, 34.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.79 (dd, J=8.7, 2.4 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 6.94-6.86 (m, 1H), 6.42 (d, J=6.5 Hz, 1H), 4.31-3.99 (m, 5H), 3.20 (s, 3H), 1.85 (dd, J=14.6, 7.3 Hz, 1H), 1.79-1.63 (m, 4H), 1.62-1.39 (m, 4H), 1.11 (dd, J=12.0, 7.9 Hz, 2H). MS (ESI+) m/z 415.1 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1([CH2:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:21][C:22]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:23])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)CC1CCC1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(CC1CCC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-cyclobutylacetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO) δ 11.61-11.40 (m, 1H), 8.46-8.38 (m, 1H), 8.17-8.09 (m, 1H), 8.09-7.98 (m, 2H), 2.73-2.61 (m, 1H), 2.46 (d, J=7.5, 2H), 2.15-2.01 (m, 2H), 1.93-1.70 (m, 4H); MS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:35])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:35][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH2:25][CH2:24]1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc3c(c2)OCO3)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 18.4 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.40 g), tetrahydrofuran (2 ml) and magnesium (30 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(3,4-methylene-dioxyphenyl)cyclopropane (Example 22) (0.32 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 5:95) to afford 1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (82 mg, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([O:23][C:17](=[O:22])[CH:18]=[C:19]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Br:15])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:21])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(Br)c(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCOC(=O)C=C(C)Nc1ccc(Br)c(OCc2ccccc2)c1
Yield: 106.2 %

Procedure:
To a mixture of 3-benzyloxy-4-bromo-phenylamine (55.7 g, 0.168 mol) and ethyl acetoacetate (23.4 mL, 0.185 mol) in cyclohexane was added toluene-4-sulfonic acid monohydrate (0.320 g, 1.68 mmol) The reaction mixture was refluxed during 6 h and the water was azeotropically removed. The reaction mixture was then partitioned between ethyl acetate and an aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 69.6 g of the title compound were obtained. Black oil, ISP-MS m/e=392.2 ([M+H]+).