Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][NH:4][C:5]([NH2:7])=[NH:6].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]=[C:26]=[O:27]>O1CCCC1>[ClH:1].[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[C:19]=1[NH:25][C:26]([NH:6][C:5](=[NH:7])[NH:4][O:3][CH3:2])=[O:27]
Reactant: CONC(=N)N
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CONC(=N)NC(=O)Nc1c(C)cccc1C
Reaction time: 1 h

Procedure:
To a suspension of 12.0 g. (0.11 mole) of methoxyguanidine hydrochloride in tetrahydrofuran (100 ml.) is added 8.8 g. (0.11 mole) of fifty percent (w/w) aqueous sodium hydroxide. After one hour of stirring, 5.0 g. of anhydrous sodium sulfate is added and the mixture is stirred for an additional hour. A solution of 14.7 g. (0.1 mole) of 2,6-dimethylphenylisocyanate in tetrahydrofuran (30 ml.) is added dropwise after which the mixture is stirred at room temperature overnight. The tetrahydrofuran is removed under vacuum and the residue partitioned between water and chloroform. The layers are separated and the aqueous layer extracted with chloroform (4×100 ml.). The combined organic extracts are washed with water (1×50 ml.), dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified with ethereal HCl and the solvents removed in vacuo to give a brown oil which is crystallized from acetonitrile to give 1-(2,6-dimethylphenyl)-3-methoxyamidinourea hydrochloride, m.p. 170°-1° C.
Reaction SMILES: Br[C:2]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[CH:6][N:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1.C[C:26]([N:28](C)C)=O>CS(C)=O.[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:26]([C:2]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[CH:6][N:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1)#[N:28]
Reactant: O=C(O)CNC(=O)c1ncc2c(cc(Br)n2-c2ccccc2)c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Product: N#Cc1cc2c(O)c(C(=O)NCC(=O)O)ncc2n1-c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of [(2-bromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (50 mg), Zn(CN)2 (9.0 mg), Zn dust (1.0 mg), Pd2(dba)3 (5.9 mg), dppf (7.1 mg) in DMA (1 mL) was heated to 120° C. for 60 min; then the mixture was cooled, diluted with DMSO and purified by C18 reverse phase chromatography to give the desired title compound (33 mg). The title compound, ESI MS (m/z): 337 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>C1COCC1>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Phenol (2.00 g, 12.3 mmol) was dissolved in THF (40 mL), 55% sodium hydride (1.02 g, 23.4 mmol) was added thereto at 0° C., followed by stirring at 0° C. for 30 minutes. A solution (10 mL) of 2-methylbenzoyl chloride (4.16 mL) in THF was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to afford phenyl 2-methylbenzoate (2.88 g, 64%).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]=2)[CH:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN1CCCC1=O>[NH:31]([C:7]1[NH:8][C:3](=[O:2])[CH:4]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:6]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2c[nH]c3ncccc23)nc(Nc2ccccc2)[nH]1

Procedure:
A mixture of EXAMPLE 1B (0.089 g, 0.20 mmol), and aniline (0.2 mL) in N-methylpyrrolidone (3 mL) was heated in a microwave at 235° C. for 1.5 hours. The mixture was concentrated and purified by reverse phase HPLC to provide the title compound. MS (ESI) m/e 304 (M+H)+; 1H NMR (DMSO-d6) δ 6.33 (s, 1H), 7.06-7.18 (m, 2H), 7.34-7.45 (m, 2H), 7.68 (d, J=7.67 Hz, 2H), 8.23 (s, 1H), 8.26-8.31 (m, 1H), 8.56 (d, J=7.67 Hz, 1H), 8.84 (s, 1H), 12.22 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[N+:15]([O-])([O-:17])=[O:16].[K+].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1ccccc1NCCN(C)C
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc([N+](=O)[O-])cc1NCCN(C)C
Temperature: 0 °C
Yield: 48.8 %

Procedure:
N,N-dimethyl-N'-(2-methoxyphenyl)ethylenediamine (D18, 1.5 g, 0.0077 mole) was dissolved in 5N sulphuric acid (0.86 ml) and the water was removed in vacuo. Conc. H2SO4 (6.5 ml) was added and the mixture stirred until homogeneous, then cooled to 0° C. Potassium nitrate (1.01 g, 0.01 mole) was added portionwise, maintaining the temperature below 10° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured onto ice (150 ml) and made slightly alkaline by addition of sodium carbonate. This solution was extracted into EtOAc, dried (Na2SO4) and evaporated in vacuo, to leave an orange oil. This was purified by flash column chromatography to afford the title compound as an orange oil (0.90 g, 49%)
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(O[CH2:17][C:18]([F:32])([F:31])[C:19]([F:30])([F:29])[CH2:20][O:21]S(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:29][C:19]1([F:30])[CH2:20][O:21][C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:17][C:18]1([F:32])[F:31]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCC(F)(F)C(F)(F)CO2
Temperature: 50 °C

Procedure:
A mixture of 2 g of 3,5-dihydroxybenzaldehyde, 10 g of 2,2,3,3-tetrafluorobutane-1,4-diyl bis(trifluoromethanesulfonate) and 12 g of cesium carbonate in 100 mL of anhydrous acetonitrile was heated under nitrogen to 50° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 250 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-35% ethyl acetate in hexanes) gave the product as crystalline solid. MS (m+1)=265.1; 1H NMR (400 MHz, CDCl3) 9.85 (s, 1H), 7.6 (m, 2H), 7.2 (d, 1H), 4.64 (t, 2H), 4.45 (t, 2H).
Reaction SMILES: N1(C(OC2C=CC(Cl)=CC=2C(=O)NC2C=CC([N+]([O-])=O)=CC=2Cl)=O)CCCC1C([O-])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C(N(C(C)C)CC)(C)C.[Cl:53][C:54]([O:57]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.ClC1C=CC(O)=C(C=1)C(NC1C=CC([N+]([O-])=O)=CC=1Cl)=O>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:53][C:54]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:57]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CN(C)c1ccncc1
Agent: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1O
Agent: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1OC(=O)N1CCCC1C(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-tert-butyl 1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl pyrrolidine-1,2-dicarboxylate (Compound 26). (S)-tert-butyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was prepared following the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenlee et al with minor modification. A solution of 1.06 g (6.19 mmol) (S)-2-tert-butyl pyrrolidine-2-carboxylate and diisopropylethylamine (3.2 mL, 18.57 mmol) in dichloromethane (5.0 mL) was introduced dropwise into a solution of 1.84 g (6.19 mmol) bis(trichloromethyl)carbonate in dichloromethane (5.0 mL) at ice-bath temperature. The mixture was allowed to warm to room temperature and was stirred for one hour. The reaction mixture was washed with 1N aqueous HCl, dried over magnesium sulfate, and concentrated to an oil. The residue was dissolved in chloroform (5.0 mL) and added dropwise to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (1.82 g, 5.57 mmol) in pyridine (25 mL) containing 20 mg 4-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 72 hours, then partitioned between ethyl acetate and 1N aqueous HCl, dried over magnesium sulfate, and concentrated to a solid. The product was isolated using silica gel chromatography with 3 ethyl acetate: 7 hexanes as elution solvent. The product was recrystallized from ethyl acetate/hexanes. 1H NMR reveals the existence of approximately a 1:1 ratio of rotational isomers. 1H NMR (CDCl3): δ1.331 (s, 4.5H, tert-butyl ester), 1.369 (s, 4.5H, tert-butyl ester), 1.833 (m, 3H, pyrrolidine C4 methylene and pyrrolidine C3 syn-H), 2.181 (m, 1H, pyrrolidine C3 anti-H), 3.500 (m, 2H, pyrrolidine C5 methylene), 4.113 (m, 0.5H, pyrrolidine methine), 4.362 (m, 0.5H, pyrrolidine methine), 7.158 (d, J=9 Hz, 0.5H, H3), 7.334 (d, J=9 Hz, 0.5H, H3), 7.661 (m, 1H, H4), 7.762 (m, 1H, H6), 8.131 (m, 1H, H6′), 8.312 (m, 1H, H5′), 8.388 (m, 1H, H3′), 10.274 (s, 0.5H, NH), 10.347 (s, 0.5H, NH).
Reaction SMILES: C(O[N:6]1[C@H:15]2[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[NH:9][C:8](=[NH:16])[CH2:7]1)(C)(C)C.Cl>CCOC(C)=O>[NH:16]=[C:8]1[CH2:7][NH:6][C@H:15]2[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[NH:9]1
Reactant: CC(C)(C)ON1CC(=N)N[C@H]2CCCC[C@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C1CN[C@@H]2CCCC[C@@H]2N1
Yield: 102.3 %

Procedure:
To 46 mg of 4-t-butoxy-2-imino-decahydro-cis-quinoxaline 3 mL of EtOAc saturated with HCl was added. The reaction turned clear momentarily and another solid was formed. After 30 min the solid was filtered washed with Et2O and dried to furnish 32 mg of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].[C:16]([O:20][C:21](=O)[O:22]C(C)(C)C)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
L-tyrosine methyl ester hydrochloride 2 (104.3 g, 0.45 mol) and di-t-butylcarbonate (DBC, 98.2 g, 0.45 mol) were suspended in toluene (521.3 g), and triethylamine (50.1 g, 0.495 mol) was added dropwise thereto at 20° C. over 1.5 hrs. After further keeping at 20° C. for 4 hrs, the reaction mass was washed with 5% hydrochloric acid (328.1 g) and 5% aqueous sodium bicarbonate (378.1 g). The toluene solution thus obtained was dried over suitable amount of magnesium sulfate and then concentrated to about a half of the volume under reduced pressure. To the concentrate was added dropwise n-hexane (329.5 g) at room temperature over 1 hr. After keeping at 0° C. overnight, precipitates were filtered and dried under reduced pressure to give N-Boc-L-tyrosine methyl ester 3 (126.9 g, yield 95.5%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1>C(O)C.[Pt]>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)nc1Cl
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)nc1Cl
Reaction time: 1 h

Procedure:
To a solution of (E)-ethyl 3-(2,6-dichloropyridin-3-yl)acrylate (500 mg, 2.032 mmol) in Ethanol (15 mL) was added 10% platinum on carbon (96 mg, 0.049 mmol). The flask was alternately evacuated and filled with hydrogen five times. The solution was stirred under 1 ATM (balloon) of hydrogen for 1 h, then filtered through celite, while washing well with MeOH and EtOAc. The filtrate was concentrated in vacuo to provide the title compound which was used without further purification. 1H NMR δ (ppm) (CHCl3-d): 7.62 (1H, d, J=7.92 Hz), 7.24 (1H, d, J=7.8), 4.15 (2H, q, J=7.15 Hz), 3.05 (2H, t, J=7.35 Hz), 2.69 (2H, t, J=7.35 Hz), 1.31˜1.24 (3H, m). MS (M+H)+: 247.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl.CO.ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH2:8][C:9]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:11])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(CC(=O)N2CCOCC2)c1
Temperature: 40 °C
Yield: 78.9 %

Procedure:
2-(5-Methyl-2-nitro-phenyl)acetic acid (250 mg, 1.28 mmol) and HATU (443 mg, 1.17 mmol) were suspended in dichloromethane (5 mL) and treated with triethylamine (162 μL, 1.17 mmol) and morpholine (112 μL, 1.28 mmol). The solution was heated at 40° C. for 10 min. The reaction was washed with 1 N HCl and saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (1-10% methanol/dichloromethane) provided 2-(5-methyl-2-nitro-phenyl)-1-morpholino-ethanone as a white solid (267 mg, 87% yield). LC/MS m/z 265.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) S 7.97 (d, J=8.3 Hz, 1H), 7.33 (dd, J=1.3, 8.3 Hz, 1H), 7.27 (s, 1H), 4.10 (s, 2H), 3.66-3.64 (m, 2H), 3.59-3.54 (m, 4H), 3.43-3.41 (m, 2H), 2.39 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28](=[O:30])[CH3:29])=[C:23]([CH3:31])[CH:22]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:23]1[CH:22]=[C:21]([O:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:26]=[C:25]([CH3:27])[C:24]=1[C:28](=[O:30])[CH3:29]
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc(Oc2ccc(C(F)(F)F)cc2)cc1C
Temperature: 100 °C
Yield: 19.1 %

Procedure:
To a solution of 1-chloro-4-(trifluoromethyl)benzene (6.60 g, 36.6 mmol), K3PO4 (12.9 g, 60.9 mmol), 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (5.00 g, 30.5 mmol) in toluene (60.9 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (388 mg, 0.91 mmol) and Pd(OAc)2 (288 mg, 1.28 mmol). The reaction was heated at 100° C. for 120 min under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (1.8 g) as yellow oil in 19% yield: 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=8.5 Hz, 2 H), 7.04 (d, J=8.5 Hz, 2 H), 6.70 (s, 2 H), 2.50 (s, 3 H), 2.25 (s, 6 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[O:11]=[C:12]1[C:17]2[S:18][CH:19]=[C:20]([S:21](Cl)(=[O:23])=[O:22])[C:16]=2[CH2:15][CH2:14][CH2:13]1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[S:21]([C:20]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:11])[C:17]=2[S:18][CH:19]=1)(=[O:22])=[O:23]
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: CNCCc1cccnc1
Product: CN(CCc1cccnc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From methyl-(2-pyridine-3-yl-ethyl)-amine (the compound of Preparation Example 15) (82 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo-[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (150 mg), the title compound (138 mg) was obtained as a colorless oily matter, in the same way as Preparation Example 41.
Reaction SMILES: [OH-].[Na+].[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[Na].C(O)(=O)C1C(=CC=CC=1)C(O)=[O:19].Cl>N1C=CC=CC=1>[OH:19][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1O
Yield: 75 %

Procedure:
To a flask was added 50 mL of 3N sodium hydroxide aqueous solution, and powdery phthalimide (8.8 g, 0.06 mol) was slowly added thereto with stirring. Then, the mixture was stirred at 97° C. for 2 hours to obtain an aqueous solution containing sodium salt of phthalic acid. To the aqueous solution was added diluted hydrochloric acid at ordinary temperature to convert into phthalic acid, and phthalic acid was recovered by condensation and filtration. Then, after hydroxylamine hydrochloride NH2OH.HCl (8.3 g, 0.12 mol) was dissolved in 100 mL of pyridine, the recovered phthalic acid was added thereto, stirred at 50° C. for 1 hour, and further stirred for 3 hours with elevating the temperature to 95° C. to form N-hydroxyphthalimide (7.3 g, yield 75%).
Reaction SMILES: [CH2:1]([Br:3])[CH3:2].[Mg].[CH2:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH3:6]>C1C=CC=CC=1.C([Cd]CC)C.[Cl-].[Cd+2].[Cl-]>[Br:3][CH:1]([CH3:2])[C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=1)=[O:12]
Reactant: CCBr
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: CC[Cd]CC
Agent: [Cd+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCc1ccc(C(=O)C(C)Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethylcadmium is then prepared, as described in Example 8, from 63 g of ethyl bromide, 13.8 g of magnesium and 53 g of cadmium chloride. It is suspended in 400 ml of benzene, and a solution of 48.7 g of the previously prepared 4-ethylbenzoyl chloride diluted in 100 ml of benzene is then added dropwise, while cooling to below 10° C. After the addition, the mixture is stirred for one hour at ambient temperature and then for 2 hours at the reflux temperature. It is then cooled to 10° C. and poured onto a mixture of ice and salt, with stirring; the resulting mixture is filtered and the organic phase is separated from the filtrate, extracted twice with dilute sodium hydroxide solution, washed with water, dried over magnesium sulphate and evaporated. 48.4 g of an oily residue remain, which is distilled under a high vacuum (13 Pa). A fraction consisting of 35.6 g of virtually pure 4'-ethylpropiophenone passes over at between 65° and 80° C. In order to effect bromination of the propiophenone, 34.8 g thereof are dissolved in 1,000 ml of tetrahydrofuran, and 17.5 ml of pyrrolidinone and then 114 g of pyrrolidinone hydrotribromide are added. The mixture is heated under reflux, with stirring; it decolourises gradually and pyrrolidinone hydrobromide precipitates. The reaction is complete after one hour, the hydrobromide is filtered off and rinsed with ethyl acetate and the solvents are evaporated off from the filtrate. The partially crystalline, oily orange residue is taken up in a mixture of water and methylene chloride. The organic phase is separated off, washed twice with water, dried and evaporated in vacuo. The greenish oily residue is dissolved in toluene, pentane is added, a small greenish gummy fraction is filtered off on paper and the filtrate is evaporated. An oily residue remains, which is used as such in a subsequent step.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[C:38](Br)=[CH:37][CH:36]=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:18].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[C:38]([C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:8][CH:9]=4)=[CH:37][CH:36]=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCOCC4)cc3)c2o1
Temperature: 100 °C

Procedure:
444 mg (2.15 mmol) of 4-(4-morpholinyl)phenylboronic acid and 4.3 ml of 1N sodium hydroxide solution are added to a mixture of 500 mg (0.143 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 105 mg (0.14 mmol) of PdCl2(dppf) in 5 ml of DMF. The reaction mixture is heated at 100° C. overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered through kieselguhr. Purification takes place by preparative HPLC. The product fractions are concentrated and dissolved in methanol, and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. Drying under high vacuum results in 393 mg (59% of theory) of the title compound.