Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>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>[C:13]([N:12]1[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)n1c(-c2ccccc2Br)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)cn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 5-[2-(2-bromo-phenyl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (70 mg, 0.17 mmol) in DMF (5 mL) and H2O (1 mL) are added 1-methylpyrazole-4-boronic acid pinacol ester (52 mg, 0.25 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol) and K2CO3 (23 mg, 0.17 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and then filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (24 mg, 34%) as a white solid. LCMS (ESMS): m/z 424.20 (M++1)
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:9][N+]1C=CC=CC=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[N+:26]([CH2:29][CH2:30][CH3:31])([O-:28])=[O:27].O>C(O)C>[CH2:30]([CH:29]([N+:26]([O-:28])=[O:27])[CH2:9][C:8]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:18]([OH:19])=[C:6]([C:2]([CH3:4])([CH3:3])[CH3:5])[CH:7]=1)[CH3:31]
Reactant: CCC[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C[n+]2ccccc2)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)[N+](=O)[O-]
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of 16.7 grams of 3,5-di-tert.butyl-4-hydroxybenzylpyridinium chloride in 50 milliliters of ethanol was added dropwise in 15 minutes to a slurry of 2.0 grams of sodium hydroxide and 13.4 grams of 1-nitropropane (200% excess) in 50 milliliters of ethanol. The reaction mixture as stirred for 3 hours and was then poured into 600 milliliters of water. The oil which precipitated was separated by extraction with hexane. The extract was evaporated to give 15.0 grams (98% of theory) of 1-ethyl-2-(3,5-di-tert.butyl-4-hydroxyphenyl)-1-nitroethane which melted at 55°-60° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:50]=[CH:49][CH:48]=[CH:47][C:13]=1[CH2:14][O:15][C:16]1[N:17]=[C:18]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][CH:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:19]([C:24]([NH2:26])=[O:25])=[N:20][C:21]=1[CH2:22][CH3:23].O1CCCC1.O.NN>C(O)C>[NH2:3][C:12]1[CH:50]=[CH:49][CH:48]=[CH:47][C:13]=1[CH2:14][O:15][C:16]1[N:17]=[C:18]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)[CH2:38][CH2:39]3)=[CH:32][CH:33]=2)[C:19]([C:24]([NH2:26])=[O:25])=[N:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OCc1ccccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OCc1ccccc1N
Temperature: 25 °C
Reaction time: 30 h
Yield: 72.3 %

Procedure:
A mixture of 5-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (540 mg), tetrahydrofuran (10.8 mL), ethanol (10.8 mL), and hydrazine monohydrate (160 mg) was stirred at room temperature for 30 hours. The reactant was subjected to liquid separation by the addition of water and chloroform. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; ethyl acetate, and then chloroform:methanol=97:3) to obtain 5-[(2-aminobenzyl)oxy]-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (315 mg) as a brown solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH:10]([CH2:32][OH:33])[CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:31])[C:16](=[O:30])[N:17]([CH3:29])[C:18]2=[O:28])=[CH:13]1.N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Si:1]([O:33][CH2:32][CH:10]([OH:9])[CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:31])[C:16](=[O:30])[N:17]([CH3:29])[C:18]2=[O:28])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO)cc2n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyldimethylsilyl chloride (0.695 g, 4.61 mmol) was added to a solution of 6-(2,3-dihydroxypropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.82 g, 4.19 mmol), imidazole (0.571 g, 8.38 mmol) and DMAP (0.512 g, 4.19 mmol) in DMF (13.97 mL). The mixture was stirred at room temperature for 3 hours, then diluted with 10% aqueous citric acid solution (15 mL) and extracted with DCM (3×30 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:36]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([F:30])[CH:26]=3)[N:20]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(F)cc3c(=O)[nH]2)c1
Yield: 45.5 %

Procedure:
According to the preparation of compound 42, 3 (1.0 g, 6.5 mmol) and 3-methoxybenzaldehyde (34) (0.9 g, 6.5 mmol) were used to afford 51 (0.8 g, 46.8%) as pale yellow needles.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=[CH:38][N:37](C(N2C=NC=C2)=O)[CH:36]=1.CNC>C1COCC1>[F:30][CH:29]([F:31])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH2:12]2)[CH2:18][C:19](=[O:21])[N:37]([CH3:38])[CH3:36])=[CH:23][C:24]=1[O:32][CH2:33][CH3:34]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 46.9 %

Procedure:
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 13 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and dimethylamine (1.7 ml, 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.4 g, 50% yield): mp: 135-137° C.; 1HNMR (CDCl3): δ 0.89 (m, 2H, c-CH2), 1.43 (t, J=7.0 Hz, 3H, OCH2CH3), 1.66 (m, 1H, c-CH). 2.93 (s, 3H, CH3CO), 3.04 (dd, J=5, 15 Hz, 1H, CH2), 3.10 (s, 3H, NCH3), 3.60 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 4.33 (d, J=17.5 Hz, 1H, CH2N), 4.44 (d, J=17.5 Hz, 1H, CH2N), 5.60 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.07 (m, 4H, Ar), 7.43 (t, J=7.5 Hz, 1H, Ar), 8.42 (d, J=7.5 Hz, 1H, Ar), 10.57 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.2, 14.6, 16.1, 35.6, 36.1, 37.3, 49.2, 54.0, 58.6, 64.7, 111.9, 113.5, 116.1, 116.7, 117.5, 117.6, 117.8, 119.2, 120.2, 122.7, 133.1, 138.0, 138.2, 139.7, 141.5, 159.7, 169.4, 169.7, 172.6; Anal. Calcd. for C26H29F2N3O5: C, 62.27; H, 5.83; N, 8.38. Found: C, 62.07; H, 5.65; N, 8.28.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])[CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN.C1COCC1.Cl>ClCCl>[O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:29][CH3:33])=[O:18])[CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][NH:3]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCN3)c1
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCN3)c1

Procedure:
The acid of Example 11 (0.66 mmol) is stirred overnight at ambient temperature in 50 ml of dichloromethane in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (0.80 mmol), diisopropylethylamine (0.80 mmol) and 2M methylamine solution in THF (1.32 mmol). The reaction mixture is then neutralised with 1N HCl solution, extracted with ethyl acetate, washed (saturated NaCl solution), dried (MgSO4), filtered and then evaporated under reduced pressure to yield, after triturating the residue in a dichloromethane/methanol mixture and filtering, the title product.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[C:9]([NH:12][C:13]1[C:18](=[O:19])[N:17](CC=C)[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:15][CH:14]=1)(=[O:11])[CH3:10].S([O-])([O-])(=O)=S.[Na+].[Na+].[O:36]1[CH2:40][CH2:39][CH2:38]C1>[Os](=O)(=O)(=O)=O>[C:9]([NH:12][C:13]1[C:18](=[O:19])[N:17]([CH2:38][CH:39]([OH:5])[CH2:40][OH:36])[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCn1c(-c2ccccc2)ncc(NC(C)=O)c1=O
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(O)CO)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
50% aqueous N-methylmorpholine-N-oxide (1.55 ml, 6.6 mmol) and 0.157 N aqueous osmium tetroxide (1.06 ml, 0.165 mmol) were added to a solution of 5-acetylamino-1-allyl-6-oxo-2-phenyl-1,6-dihydropyrimidine (888.6 mg, 3.3 mmol) in tetrahydrofuran (13 ml), and the mixture was stirred at room temperature for 2 days. After saturated aqueous sodium thiosulfate was added, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline. After dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) whereby the title compound (1.06 g, quant) was obtained as white solid. 1H-NMR (CDCl3); 2.25 (3H, s), 2.40-2.58 (1H, m), 3.29-3.63 (3H, complex), 3.78-3.95 (1H, m), 4.08-4.26 (2H, m), 7.41-7.54 (5H, s), 8.04 (1H, m), 9.00 (1H, s); MS (FAB) m/z=304 (M+1)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCO2

Procedure:
2,3-dihydrobenzofuran of formula II, ##STR5## is condensed with succinic anhydride in the presence of aluminum chloride in a chlorinated organic solvent and at a temperature below 5° C., to form 4-(2,3-dihydro-5-benzofuranyl)-4-oxobutanoic acid of formula III, ##STR6## which is reduced in acid medium in the heated state and in the presence of zinc and mercuric chloride to form 4-(2,3-dihydro-5-benzofuranyl)butanoic acid of formula IV, ##STR7## which is then subjected to the action of polyphosphoric acid in an apolar organic solvent and at a temperature of between 80° C. and 100° C. to form 2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-8-one of formula V, ##STR8## which is then:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.O1C[CH2:20][CH2:19][CH2:18]1>>[CH2:18]([C:4]1[N:3]([CH2:13][O:12][CH2:11][CH2:10][Si:9]([CH3:16])([CH3:15])[CH3:8])[CH:2]=[N:1][CH:5]=1)[CH2:19][CH3:20]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: CCCc1cncn1COCC[Si](C)(C)C
Temperature: 0 °C
Yield: 65 %

Procedure:
A solution of the imidazole from Preparation 76 (4.9 g, 44.6 mmol) in tetrahydrofuran (20 ml) was added dropwise to a solution of sodium hydride (1.96 g, 60% dispersion in mineral oil, 49.1 mmol) in tetrahydrofuran (20 ml) and, once addition was complete, the solution was stirred for an hour. The solution was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (8.28 ml, 46.8 mmol) was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The residue was partitioned between ether and water, the layers separated, and the aqueous phase extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol (95:5), to afford the title compounds of Preparation 71 and 72 respectively in a regioisomeric mixture of 3:1, 7 g, 65% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].[OH2:22]>C(#N)C>[C:14]([C:13]([C:6]1[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:22])[CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])#[N:15]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CC#N)c2c1OCCO2
Reactant: O
Solvent: CC#N
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2c1OCCO2
Yield: 56 %

Procedure:
To a solution of Compound 1a (6.2 g, 30 mmol) obtained in Step A in acetonitrile (94 mL) were added a 40% methanolic solution of Triton B (1.4 mL, 3.0 mmol) and methyl acrylate (27 mL, 300 mmol), followed by refluxing for 5 hours. The mixture was allowed to cool, and then poured into water, followed by extraction with ethyl acetate. The organic layer as washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 1b (6.4 g, 56%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of 21 mL (42 mmol, 2.0M in THF) of benzylmagnesium chloride at room temperature under nitrogen was added a solution of 6.80 g (50.0 mmol) of thrice-fused zinc chloride in 0 50 mL of THF. The resulting tan slurry was stirred for 1 hour. To this slurry was added 10.0 g (35.3 mmol) 1-bromo-4-iodobenzene and 450 mg (0.4 mmol) of tetrakis(tri-phenylphosphine)palladium in 30 mL of THF. The reaction was stirred at room temperature for 16 hours and then quenched with 50 mL of 2M hydro-chloric acid. The mixture was extracted thrice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (5×25 cm column, hexanes as elutent) to give 7.05 g (80%) of title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[O:23][CH3:24])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[O:23][CH3:24])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2)(=[O:36])=[O:35]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 1.3 (2.22 g, 6.52 mmol) dissolved in pyridine (14 mL) was added 2,4-dichlorobenzenesulfonyl chloride (1.76 g, 7.17 mmol). The resulting red solution was stirred at room temperature for 30 min., after which time LC-MS indicated no 13 remained. The reaction solution was concentrated in vacuo on a rotary evaporator and the concentrate partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic separation was washed with water then brine. The organic extract was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford an orange oil. The product was isolated by chromatography on silica gel, eluting with ethyl acetate/hexane gradient, to afford a faint yellow solid. LC-MS ESI (pos.) m/z: 549.0 (100%), 551.0 (68%), 550.0 (28%) (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([O:13]CC)=[O:12])=[CH:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:9])([F:10])[F:8])[C:4]([C:11]([OH:13])=[O:12])=[CH:3]1
Reactant: CCOC(=O)c1cn(C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 1-methyl-4-(trifluoromethyl)pyrrole-3-carboxylate (4.4 g, 0.02 mol) and 4N sodium hydroxide (5 ml, 0.02 mol) in ethanol is stirred for 24 hours at room temperature, diluted with water and extracted with ether. The aqueous phase is acidified with 10% HCl and filtered. The filter cake is washed with water and dried in vacuo at 45° C. to afford the title compound as an off-white solid, 2.4 g (62%), mp 210°-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[NH3:12].[H][H]>CO.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(N)Cc1ccc(Br)cc1
Reaction time: 3.5 h

Procedure:
A mixture of 25.0 g (0.12 mol) 4-bromophenylacetone and 400 mL 7N ammonia in MeOH is charged with 1.20 g Raney nickel. The mixture is stirred in an hydrogen atmosphere (15 psi) at r.t. over night. Again 0.6 g Raney nickel are added and the mixture is stirred again for 3.5 h. After complete reaction, the mixture is filtrated. The residue is washed with MeOH and the solvent of the filtrate is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>>[Cl:32][C:30]1[CH:29]=[C:16]([CH:15]=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:31]=1)[O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CNC(=O)c1ccc(COc2cc(N)cc(Cl)c2)cc1
Product: CNC(=O)c1ccc(COc2cc(Cl)cc(Nc3ccnc4nc(C)ccc34)c2)cc1

Procedure:
The product from Example 1d (100 mg, 0.56 mmol) was reacted with the product from Example 195d (160 mg, 0.56 mmol) for 15 h following the procedure from Example 1g giving the crude title compound which was purified by trituration with EtOAc providing the product (240 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3H), 2.79 (d, J=4.4 Hz, 3H), 5.26 (s, 2H), 6.90 (d, J=7.0 Hz, 1H), 7.14 (br-t, J=1.9 Hz, 1H), 7.18 (br-t, J=1.9 Hz, 1H), 7.20 (br-t, J=1.9 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 8.47 (br-s, 1H), 8.50 (d, J=7.0 Hz, 1H), 9.08 (d, J=8.8 Hz, 1H), 11.08 (br-s, 1H); MS (ESI+) m/z 433, 435 (M+H)+, (ESI−) m/z 431, 433 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[H][H]>[Pd].O1CCCC1>[OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCC(O)C2

Procedure:
For example, 6-hydroxynaphthalene-2-carboxylic acid in a solvent such as tetrahydrofuran is reduced with hydrogen gas in the presence of a reducing catalyst such as a palladium/carbon under elevated pressure to obtain 5,6,7,8-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid (1).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([C:60]2[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=2)[CH2:56][CH2:55]1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:54]3[CH2:59][CH2:58][CH:57]([C:60]4[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=4)[CH2:56][CH2:55]3)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Yield: 163.8 %

Procedure:
A solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 219.9, 40 mg, 0.13 mmol), DIEA (0.07 ml, 0.39 mmol), HOBT (34 mg, 0.19 mmol, with 20% water), EDCI (38 mg, 0.19 mmol), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 36 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel prep-TLC plate and developed using ethyl acetate/hexanes (1:1) to yield 0.1 g (68%) of the title compound as a white solid. m/z (ES+) 470 (M+H)+.