Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH:11]([C:10]([CH3:18])([CH3:17])[CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:21]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)(C)C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 627.7 %

Procedure:
Lithium diisopropylamide (21.7 mL of 1.8M solution, 40 mmol) was added to a solution of ethyl 3,3-dimethylbutyrate (5.76 g, 40 mmol) in 40 mL of tetrahydrofuran at -35° C. After stirring for 30 minutes and further cooling to -50° C., 4,4'-difluorobenzophenone (4.36 g, 2 mmol) was added. The reaction was stirred for 2 hours at -50° and for 2 hours at -20° C. The mixture was quenched with 2N hydrochloric acid and extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was crystallized from petroleum ether to give 4.55 g of the title compound; m.p. =93°-96° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([N:9]([CH3:11])[CH3:10])=[N:6][NH:7][CH:8]=1.CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[Br:3][C:4]1[C:5]([N:9]([CH3:11])[CH3:10])=[N:6][N:7]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:8]=1
Reactant: CN(C)c1n[nH]cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Sodium hydride (0.498 g, 60% in mineral oil) was added to a stirred solution of 4-bromo-N,N-dimethyl-1H-pyrazol-3-amine (1.97 g) dissolved in DMF (20 ml) under argon. The resulting mixture was stirred at 23° C. for 30 minutes. A solution of Tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (3.19 g) in DMF (10 ml) was added and the reaction mixture was stirred at 95° C. for 5 hours and left at 23° C. overnight. DMF was evaporated and the residue was taken up in dichloromethane, washed with H2O and sat NaCl. The organic was dried (magnesium sulphate), filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 30% ethyl acetate in petroleum ether. The solvent was evaporated to afford tert-butyl 4-(4-bromo-3-dimethylamino-pyrazol-1-yl)piperidine-1-carboxylate (1.700 g) as a clear colorless oil which crystallised on standing. NMR Spectrum: (DMSOd6) 1.40 (s, 9H), 1.65 (d, 1H), 1.71 (d, 1H), 1.89-1.87 (m, 2H), 2.74 (s, 6H), 2.85 (bs, 2H), 3.93-4.06 (m, 2H), 4.09-4.17 (m, 1H), 7.82 (s, 1H); Mass spectrum: M+H+ 373-375
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[OH:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[C:1]([O:25][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1c(Cc2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A solution of acetic anhydride (3.27, 0.032 mol) in pyridine (50 mL) was stirred at 0°. 2-Phenylmethyl-1-naphthol (5.00 g, 0.021 mol) was added and the mixture was stirred while warming to room temperature. After 18 h, water was added and the mixture was extracted with ether. The ether phase was washed with dilute hydrochloric acid, then with water, then with brine and was dried over MgSO4. Concentration afforded a brown oil which was flash chromatographed (5% ethyl acetate/hexane). The resulting oil crystallized on standing and was recrystallized (hexane) to provide the title compound (4.75 g, 82%) as white needles: mp 67°-69°; NMR (CDCl3) 7.9-7.6 (m, 3H), 7.45 (m, 2H), 7.20 (m, 6H), 4.01 (s, 2H), 2.40 (s, 3H); IR (mull) 1760; Mass Spec (EI) 276 (9), 234 (100), 156 (20); Calcd. for C19H16O2;C-82.57 H-5.84., Found: C-82.66 H-5.93
Reaction SMILES: [C:1]1([C@H:7]([CH3:17])[CH2:8][NH:9][C:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])=O.[Na+].CC(OC(C)=O)=O>>[C:1]1([C@H:7]([CH3:17])[CH2:8][N:9]2[C:10](=[O:11])[CH:12]=[CH:13][C:14]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CNC(=O)/C=C/C(=O)O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C[C@H](CN1C(=O)C=CC1=O)c1ccccc1
Temperature: 120 °C
Yield: 25.5 %

Procedure:
A mixture of (S)-E-3-(2-phenyl-propylcarbamoyl)-acrylic acid (1.44 g, 6.2 mmol), NaOAc (305 mg, 3.7 mmol), and Ac2O (6 mL) was heated at 120° C. for 5 h. The mixture was concentrated, and the residue was stirred vigorously with satd. aq. NaHCO3. The resulting mixture was extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (EtOAc/hexanes) to provide 340 mg (26%) of the desired maleimide as a white solid. 1H NMR (400 MHz, CDCl3): 7.32-7.26 (m, 2H), 7.24-7.17 (m, 3H), 6.60 (s, 2H), 3.70 (dd, J=13.7, 8.2, 1H), 3.61 (dd, J=13.7, 7.8, 1H), 3.23 (app. sextet, J=7.7, 1H), 1.26 (d, J=7.0, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:29](=[O:31])[CH3:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 68.4 %

Procedure:
To a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.35 g) in pyridine (30 ml), was dropwise added a solution of acetyl chloride (942 mg) in methylene chloride (5 ml) under stirring and ice-cooling over the period of 7 minutes. The mixture was further stirred for 70 minutes at room temperature. The pyridine was distilled off under reduced pressure and ethyl acetate was added to the residue. The resultant mixture was washed twice with water and adjusted to pH 4 with hydrochloric acid and then an aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give an oily substance. This oily substance was crystallized by treating with a mixture of diethyl ether and a small amount of n-hexane, and collected crude crystals (2.5 g) were washed with n-hexane and thus obtained crystals were recrystallized from diethyl ether to give pure crystals (1.78 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 89° to 90° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]([O:15]CC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+].CS(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: O=C(O)C1CC1COCc1ccccc1

Procedure:
A solution of 0.23 mol of the compound obtained in Step 1 in 500 ml of ethanol, 230 ml of 1N sodium hydroxide solution and 5 ml of dimethyl sulphoxide is heated at reflux for 2 hours and is then concentrated. The residue is taken up in a mixture of water/ether. After conventional treatment, the combined organic phases are concentrated. Chromatography of the residue over silica gel (dichloromethane/tetrahydrofuran: 97/3) allows a cis/trans mixture of the products obtained to be isolated, some of the fractions of which have a preponderance of the cis isomer and some a preponderance of the trans isomer.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[CH:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:13]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: c1ccc2ccccc2c1
Product: O=S(=O)(O)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
1,050 g of sulfuric acid was added to 1,280 g of naphthalene, and the reaction was carried out at 160° C. for 2 hours. Unreacted materials were separated and discharged outside the container under a reduced pressure. Then, 857 g of 35% by weight concentration formalin was added and reacted at 105° C. for 5 hours to obtain a condensation product formed by methylene type bonding of β-naphthalene sulfonic acid. After being neutralized with ammonium water, the condensation product was filtrated to yield a filtrate liquid.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:20]([CH3:29])=[C:19]2[C:30]([O:32][CH3:33])=[O:31])[CH:14]=[CH:15][C:16]=1[F:17])C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][NH2:51])[CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[F:17][C:16]1[CH:15]=[CH:14][C:13]([CH:18]2[C:19]([C:30]([O:32][CH3:33])=[O:31])=[C:20]([CH3:29])[NH:21][C:22]([CH3:28])=[C:23]2[C:24]([O:26][CH3:27])=[O:25])=[CH:12][C:11]=1[NH:10][C:5]1[C:6](=[O:9])[C:7](=[O:8])[C:4]=1[NH:51][CH2:50][CH2:49][CH2:48][N:45]1[CH2:44][CH2:43][CH:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=2)[CH2:47][CH2:46]1
Reactant: CCOc1c(Nc2cc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)ccc2F)c(=O)c1=O
Reactant: COc1cccc(C2CCN(CCCN)CC2)c1
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(F)c(Nc2c(NCCCN3CCC(c4cccc(OC)c4)CC3)c(=O)c2=O)c1

Procedure:
The compound of Example 2 (98.3 mg, 0.215 mmol) and 4-(3-methoxyphenyl)piperidine-1-propanamine (64 mg, 0.258 mmol) were stirred in 2 mL DMF at room temperature for 64 hours. The crude reaction mixture was evaporated to dryness under high vacuum (0.1 mmHg) at 50-55° C. The resulting gum was triturated with methylene chloride followed by the addition of hexanes. The titled compound precipitated out as fine creamy white crystalline solid (120 mg, 84.6%): mp 205-207° C.; 1H NMR (DMSO-d6) δ 9.38 (br. s, 1H), 8.96 (br. s, 1H), 8.04 (br. t, 1H, J=3 Hz), 7.80 (d, 1H, J=7.2 Hz), 7.10 (m, 2H), 6.77 (m, 4H), 4.85 (s, 1H), 3.71 (s, 3H), 3.65 (q, 2H, J=6.0 Hz), 3.53 (s, 6H), 2.95 (d, 2H, J=10.5 Hz), 2.40 (m, 3H), 2.25 (s, 6H), 1.97 (m, 2H), 1.67.(m, 6H), 13C NMR (DMSO-d6) δ 184.94, 179.65, 169.52, 167.32, 163.03, 159.26, 147.95, 146.23, 145.07, 129.25, 126.76, 126.62, 119.68, 118.81, 114.66, 114.40, 112.41, 111.35, 100.93, 55.14, 54.83, 53.73, 50.60, 32.93, 27.84, 18.31. Anal Calcd. for C36H41 FN4O7•0.14 H2O: C, 65.19; H, 6.27; N, 8.45. Found: C, 65.20; H, 6.28; N, 8.37.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([F:41])([F:42])[F:43])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(F)(F)F)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CC(F)(F)F)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])[CH3:17])=[CH:12][CH:11]=1)#[N:9].Cl[C:29]([S:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[S:30].O>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:29]([S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[S:30])[CH3:17])=[CH:26][CH:27]=1)#[N:9]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: S=C(Cl)Sc1ccccc1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=S)Sc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 68.6 %

Procedure:
0.5 g of N-methylmorpholine was added to a suspension containing 1.4 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15° C. After 0.9 g of phenyl chlorodithioformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and, warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.4 g of the desired product in the form of a yellow glutinous substance (yield: 66%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:17]1[CH2:19][CH2:18]1)[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][C@H:8]([CH:17]1[CH2:19][CH2:18]1)[C:9]([N:11]1[CH2:12][CH:13]([C:15]#[N:16])[CH2:14]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(C(=O)[C@H](N)C2CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (190 mg, 0.69 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (1.8 ml, 23.4 mmol). The reaction mixture was stirred at room temperature for 2.5 h then concentrated to afford 1-((R)-2-amino-2-cyclopropyl-acetyl)-azetidine-3-carbonitrile trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][NH:11]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[H-].[Na+].CC([O:34][C@H:35]1[CH:39]=[CH:38][C@@H:37](O)[CH2:36]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:38]2[CH2:39][C@H:35]([OH:34])[CH:36]=[CH:37]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: CO
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (5 g 13.4 mmol) under an atmosphere of argon is added dry deoxygenated tetrahydrofuran (100 ml) and dry dimethyl sulfoxide (2 ml). Sodium hydride 95% (0.32 g, 13.4 mmol) is then added and the solution is stirred at 40° C. Separately to (1S,4R)-cis 4-acetoxy-2-cyclopenten-1-ol (1.89 g. 13.4 mmol) and triphenylphosphine (0.53 g, 2.0 mmol) in dry deoxygenated tetrahydrofuran (20 ml) is added tris(dibenzylideneacetone)dipalladium(0) (0.69 g, 0.67 mmol) and the mixture stirred at room temperature for 10 minutes. This solution is added to the anion solution via syringe and the resulting mixture is then stirred at 80° C. The reaction is shown to be complete by LCMS after 2 hours. The reaction mixture is allowed to cool, methanol is added and a solid is filtered. The filtrate is concentrated in vacuo and the title compound is obtained by precipitation from dichloromethane/hexane. 1H NMR (MeOD, 400 MHz); 8.15(s, 1H), 7.40-7.15(m, 10H), 6.20(m, 1H), 5.95(m, 1H), 5.50(m, 2H), 4.75(m, 2H), 4.55(m, 1H), 4.10(m 2H), 3.90(s, 2H), 3.80(s, 1H), 2.9(m, 1H), 1.75(m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[F:18])[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=3[F:18])[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1ccc(F)c(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)ccc3F)C[C@H]2OC)nc1Cl
Yield: 85 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-4-fluorobenzoate obtained in Example (181b) (18 mg, 0.06 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (10.6 mg, 0.06 mmol), WSC hydrochloride (34.9 mg, 0.18 mmol) and HOBt (8.2 mg, 0.06 mmol), to obtain 22.7 mg of the title compound as a pale yellow solid (85%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:17]1([CH2:20][NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:17]1([CH2:20][NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([O:34][C:13]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:8]=[C:7]([C:5]([N:1]6[CH2:4][CH2:3][CH2:2]6)=[O:6])[S:15][C:14]=45)=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:19][CH2:18]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NCC1CC1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 53.8 %

Procedure:
This material was prepared by reacting 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (88 mg, 0.35 mmole) with 6-hydroxy-2-methyl-1-benzo[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide 130a (110 mg, 0.42 mmole) and Cs2CO3 (228 mg, 0.70 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (90 mg, 54%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.46 Hz), 7.96 (1H, d, J=2.26 Hz), 7.89 (1H, s), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz), 6.75 (1H, d, J=5.46 Hz), 4.62 (2H, t, J=7.72 Hz), 4.10 (2H, t, J=7.82 Hz), 3.20 (2H, t, J=6.31 Hz), 2.62 (3H, s), 2.35 (2H, m), 1.07 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]([C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])(=[O:13])[CH3:12]>[O-]CC.[Na+]>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:12][C:11](=[O:13])[C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])[CH3:10]
Reactant: CC(=O)c1ocnc1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)c1ocnc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a sodium ethoxide solution (2.7 g of sodium and 50 ml of ethanol), a mixture of diethyl oxalate (14.48 g) and 5-acetyl-4-methyloxazole (12.4 g) was added dropwise at 0° C. The resulting mixture as stirred at room temperature for 1.5 hours, and concentrated. The residue was treated with 150 ml of water, and neutralized with 6N HCl. The resulting mixture was filtered to afford 17.5 g of 2,4-diketo-4-(4-methyloxazol-5-yl)butyric acid ethyl ester as white solids. NMR: 1.41 (t, 3H), 2.60 (s, 3H, oxazolyl methyl), 4.40 (q, 2H), 6.93 (s, 1H), 7.99 (s, 1H, 2-oxazolyl H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:30])[CH2:28][CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, yellow solid (61 mg, 64%), MS (ISP) m/z=383.4 [(M+H)+], mp 162° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and propionic acid.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([CH:11]1[CH2:19][C:18]2[C:13](=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([O:20]C)[CH:17]=2)[C:12]1=[O:24])[CH:9]=[CH2:10]>>[CH2:8]([CH:11]1[CH2:19][C:18]2[C:13](=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([OH:20])[CH:17]=2)[C:12]1=[O:24])[CH:9]=[CH2:10]
Reactant: C=CCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: C=CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 195 °C
Reaction time: 0.75 h

Procedure:
Dry pyridine hydrochloride (500 gm.) is melted and heated to 195° C. and 2-allyl-6,7-dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one (45.4 gm., 0.167 mole) is added with stirring. The reaction mixture is kept at 195° C. for 45 minutes and then poured with vigorous stirring into crushed ice (2 kg.). The crude product is collected by filtration, washed with water and dried. The 2-allyl-6,7-dichloro-5-hydroxy-2,3-dihydro-1H-inden-1-one is recrystallized from a mixture of ethanol and water.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12]
Reactant: C=C1CC(=O)O1
Reactant: CNCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)N(C)CC=Cc1ccccc1

Procedure:
0.736 g (5.0 mmol) of methyl-(3-phenyl-2-propene-1-yl)amine, 0.386 ml (5.0 mmol) of ketene dimer and 0.07 ml (0.50 mmol) of triethylamine were heated at 70° C. under stirring in 5 ml of toluene overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the thin-layer silica gel chromatography (ethyl acetate) to obtain the title compound.