Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.O.[C:15]1(O)([CH3:24])[CH2:20][CH2:19][CH:18]([C:21]([CH3:23])=[CH2:22])[CH:17]=[CH:16]1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:12]=[C:1]([OH:13])[C:2]([C@@H:17]2[C@@H:18]([C:21]([CH3:23])=[CH2:22])[CH2:19][CH2:20][C:15]([CH3:24])=[CH:16]2)=[C:3]([OH:4])[CH:5]=1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: C=C(C)[C@H]1CCC(C)=C[C@@H]1c1c(O)cc(CCCCC)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
A mixture of olivetol (3.6 g, 20 mmol), zinc chloride (3.5 g, 26 mmol), water (3.5 mL, 19 mmol) and dichloromethane (35 mL) was refluxed for 1 hour. A solution of (−)-p-mentha-2,8-dien-1-ol (3.0 g, 20 mmol) in dichloromethane (10 mL) was added drop-wise over 0.75 hour to the refluxing mixture, and the resultant reaction mixture was mixed for 0.5 hours at reflux. The mixture was cooled to 25° C., ice water (50 mL) was added, and the resultant biphasic mixture stirred for 20 minutes at 0° C. The resultant organic phase was collected, washed with water (2×20 mL) and 5% NaHCO3 (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.0 g of first crude (+)-CBD residue. Analysis (GC) of the first crude (+)-CBD residue indicated that it contained (+)-CBD (46.9%) and abn-(−)-CBD (19.7%). The first crude (+)-CBD residue was purified by column chromatography on silica gel (eluent MTBE/hexane) to provide 2.4 g of a second crude (+)-CBD residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[NH:36][C:37]1[CH:42]=[C:41]([C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:39][N:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([CH3:28])=[C:30]([NH:36][C:37]4[CH:42]=[C:41]([C:43]5[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=5)[CH:40]=[CH:39][N:38]=4)[CH:31]=3)=[O:21])=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cccnc2)ccn1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cccnc2)ccn1

Procedure:
This compound was prepared in the same manner as in Example 34, except that 4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 13) and 4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline (Reference Example 23) were used, and that the resulting crude crystals obtained by purification with silica gel column chromatography were recrystallized from n-hexane-ethyl acetate.
Reaction SMILES: [CH:1]1([CH3:30])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11](=[O:29])[CH:12]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23](=[O:28])C(Cl)(Cl)Cl)[C:13](OCC)=[O:14])[CH2:2]1.Cl.[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[C:35]([F:41])[CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([CH3:30])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][C:11]([CH:12]2[N:18]3[CH:22]=[CH:21][CH:20]=[C:19]3[C:23](=[O:28])[N:38]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([Br:32])=[CH:34][C:35]=3[F:41])[C:13]2=[O:14])=[O:29])[CH2:2]1
Reactant: CCOC(=O)C(C(=O)OC1CC(C)CCC1C(C)C)n1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Temperature: 75 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid ethyl (-)-menthyl ester (87.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (53.0 g) and triethylamine (66.4 g, 91.0 ml) in anhydrous dimethylformamide (200 ml) was stirred under the stream of nitrogen at 75° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with 5% cold hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from methanol to give the title compound (74.0 g, 78.7%) as colorless crystals, mp 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=1>C1(C)C(C)=CC=CC=1>[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:18])[CH:12]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: Cc1cccc(C(=O)Nc2nc(C(Cl)(Cl)Cl)ns2)c1
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 16.0 g (0.1 mole) 3-toluoyl chloride in 250 ml xylene was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and the resulting precipitate removed by filtration. The crude product was washed with petroleum ether and then recrystallized twice from toluene to obtain 4.0 g (12% yield) of pure product; m.p. 142° C.
Reaction SMILES: [F:1][C:2]([C:5]([CH2:13][CH2:14]C)=[C:6](OCC)OCC)([F:4])[F:3].[N:16]#N.N.C1[CH2:23][O:22]CC1>[B]>[OH:22][C:23]1[CH:6]=[C:5]([C:2]([F:1])([F:3])[F:4])[CH:13]=[CH:14][N:16]=1
Reactant: N#N
Reactant: C1CCOC1
Reactant: CCCC(=C(OCC)OCC)C(F)(F)F
Agent: N
Agent: [B]
Product: Oc1cc(C(F)(F)F)ccn1
Reaction time: 2.5 h

Procedure:
5 g (0.036 mol) trifluoromethyldiethoxypentene acid ethyl ester (mixture of isomers) were dissolved in 40 g THF. The solution was metered during 150 minutes into a 250° C. hot tube reactor, which was filled with a boron doped zeolite catalyst. As carrier gas a mixture of 100 l N2/h and as reactant 50 l NH3/h were pumped through the reactor. The outcoming gas was cooled and quenched into THF yielding to a mixture auf 90% of the desired product as well as 5% 2-ethoxy-4-(trifluoromethyl)pyridine.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[CH:9]([C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)/[CH:15]=[N:16]/[S@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:11])[CH3:10]>C1COCC1>[CH3:22][C:19]([S@@:17]([NH:16][C@H:15]([C:14]1[CH:23]=[CH:24][CH:25]=[C:12]([CH:9]([CH3:11])[CH3:10])[CH:13]=1)[C:2]([F:4])([F:3])[F:1])=[O:18])([CH3:20])[CH3:21]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)c1cccc(/C=N/[S@@](=O)C(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)c1cccc([C@@H](N[S@@](=O)C(C)(C)C)C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Tetra-n-butylammonium difluorotriphenylsilicate (TBAT) (1.19 g, 2.13 mmol) and (trifluoromethyl)trimethylsilane (TMS-CF3) (0.371 mL, 2.33 mmol) was added to a solution of (S,E)-N-(3-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (0.487 g, 1.937 mmol) in anhydrous THF (16 mL) at −20° C. under argon. The reaction was allowed to proceed for ˜2 h where the starting material appeared to have been consumed as determined by analytical-HPLC. A saturated solution of NH4Cl (20 mL) was added to quench and the mixture was extracted with EtOAc (100 mL×3) and dried over Na2 SO4. The organic partition was then concentrated to an oil and the title compound was isolated by flash chromatography using silica gel (EtOAc:Hexanes). ESI-MS (m/z): 321 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[CH:14]([O:17][P:18]([CH2:24][O:25][C@@H:26]([CH3:33])[CH2:27]OS(C)(=O)=O)([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:16])[CH3:15]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:33][C@@H:26]([O:25][CH2:24][P:18]([O:20][CH:21]([CH3:23])[CH3:22])([O:17][CH:14]([CH3:16])[CH3:15])=[O:19])[CH3:27])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)OP(=O)(CO[C@@H](C)COS(C)(=O)=O)OC(C)C
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(CO[C@@H](C)Cn1cnc2c(Cl)nc(N)nc21)OC(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
2-Amino-6-chloropurine (1.40 g, 8.3 mmol) was added portionwise to a slurry of sodium hydride (0.25 g, 80% dispersion in oil, 8.3 mmol) in dimethylformamide (50 mL) at room temperature. Vigorous bubbling was noted during the addition. After 30 minutes, the clear, yellow solution was treated with a solution of (S)-2-O-[(diisopropylphosphono)methyl]-1-O-methanesulfonyl-1,2-propanediol (2.50 g, 7.5 mmol) in dimethylformamide (5 mL), and the reaction mixture was heated to 100° C. After 5 hours, the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1, 2% to 4% to 8% methanol/methylene chloride) to provide 1.89 g (62%) of the title compound as a viscous pale yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[C:7]([O:9]CC)=[O:8].C[C:14](C)(C)[C:15]([O-])([O-:17])[O-:16].C(O)(=O)CCCCC.[OH-].[Na+]>C1C2C(CCCC2)CCC1.CO>[C:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[CH2:14][C:15]([OH:17])=[O:16])([OH:9])=[O:8]
Reactant: CCOC(=O)C(O)c1ccco1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC(=O)O
Solvent: C1CCC2CCCCC2C1
Solvent: CO
Product: O=C(O)Cc1ccoc1CC(=O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 2-(furan-2-yl)-2-hydroxyacetate (11.05 g, 64.5 mmol), trimethylorthoacetate (29.8 mL, 387 mmol) and hexanoic acid (2 mL) in decalin (195 mL) is heated at 180° C. for 12 hours. The reaction is cooled and extracted with methanol to provide a mixture of diester and decalin. This mixture is dissolved in methanol (250 mL), cooled to 0° C., treated with 2 M NaOH (150 mL) and stirred for 12 hours. The methanol is removed and the crude reaction is extracted with ether, and the basic layer is acidified with 6 N HCl and extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated to give 2,3-di(carboxymethyl)furan.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(C)=O>[Br-:19].[CH2:20]([N+:1]1[CH:5]=[CH:4][N:3]([C:15](=[O:16])[N:14]([CH3:18])[CH3:13])[CH:2]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCBr
Reactant: c1c[nH]cn1
Reactant: CN(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCC[n+]1ccn(C(=O)N(C)C)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
To 13.6 gm (0.2 mole) of imidazole (Aldrich Chemical Co., Milwaukee, Wis., 99%) and 20.2 gm of triethylamine (Aldrich, 99%) in 100 ml dry acetone (Fisher Scientific Co., Pittsburgh, Pa.) in a magnetically stirred 250 ml round bottom flask under dry nitrogen was added 21.5 gm (0.2 mole) dimethylcarbamyl chloride (Aldrich, 99%) dropwise over a 20 min. period from a side-arm pressure equalizing addition funnel. A white precipitate formed during the addition under conditions of mild exothermicity. The addition funnel was replaced with a reflux condensor and the reaction refluxed for a further one hour. After cooling to room temperature, the precipitate was isolated by Buchner filtration onto Wattman #1 paper, rinsed on the filter with acetone, and discarded. The combined filtrate and rinse acetone solution was divided into two equal parts, each containing 0.1 mole of 1-dimethylcarbmnoylimidazole. To one of these parts was added 22.1 gm (0.1 mole) of 1-bromodecane (Aldrich 98%) and the solution refluxed for seven hours under dry nitrogen. The acetone was evaporated at water aspirator vacuum in a rotoevaporator to the point where two layers formed. The upper layer contained largely unreacted bromodecane and the lower yielded 12 gm (0.043 mole for a 21.4% theorical yield) of the imidazolium salt as a waxy solid upon cooling to 5° C. The purity and identity of this product was confirmed by proton and carbon NMR in deuterium oxide solution.
Reaction SMILES: [CH3:1][O:2]C1C=CC(C2SCCS2)=CC=1.COC1C=C(C=CC=1)C(Cl)Cl.CO[C:27]1[CH:28]=[C:29]([C:33]([Cl:36])([Cl:35])[Cl:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:1][O:2][C:32]1[CH:27]=[CH:28][C:29]([C:33]([Cl:34])([Cl:35])[Cl:36])=[CH:30][CH:31]=1
Reactant: COc1cccc(C(Cl)(Cl)Cl)c1
Reactant: COc1ccc(C2SCCS2)cc1
Agent: COc1cccc(C(Cl)Cl)c1
Product: COc1ccc(C(Cl)(Cl)Cl)cc1

Procedure:
5.8 gm (0.0274 moles) of the dithiolane of Example 4 was reacted following the procedure of Example 6 to give 5.01 gm of a 3.8:1 mixture of 3-methoxybenzaldichloride and 3-methoxybenzotrichloride (b.p. 83°-84° C. at 0.3 mm/Hg). NMR and GC/MS Analysis for Product: 1H--NMR (CDCl3), δ3.63 (S, 3H, OCH3), 6.7 (d, J=13.5 Hz, 2H), 7.65 (d, J=13.5 Hz, 2H); GCMS (70 ev), M/e (% rel. int.) 228 (M+ +4, 3.3), 226 (M+ +2, 9.2), 224 (M+, 9), 193 (17), 191 (93), 189 (100).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=4)[CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][I:35]>CN(C=O)C>[I-:35].[CH3:34][N+:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=4)[CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(/C=C/c1cccc(-c2cccc([N+](=O)[O-])c2)c1)Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)/C=C/c3cccc(-c4cccc([N+](=O)[O-])c4)c3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
In DMF (6 ml) was dissolved (E)-N-[4-(piperidinomethyl)phenyl]-3-(3-nitrophenyl)cinnamamide (0.59 g), and to the mixture was added methyl iodide (0.57 g). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give (E)-1-methyl-1-[4-(3-(3-nitro-phenyl)cinnamamido)benzyl]-piperidinium iodide (Compound 77) (0.75 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([S:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+]([O-])=O)=C[CH:31]=1)=[O:28].N1C=CC=CC=1.C1([C@H](O)C)CC1>CCOC(C)=O.ClCCCl>[CH:35]1([C@H:30]([O:29][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:22]4[CH2:23][CH2:24][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([S:19][CH2:20][CH3:21])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:31])[CH2:34][CH2:33]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCSc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Agent: C[C@@H](O)C1CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCSc1ccc2c(C#N)c(-c3ccc(NC(=O)O[C@H](C)C4CC4)cc3)n(C3CCC3)c2c1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (230.0 mg, 0.66 mmol) was combined with p-nitrophenyl chloroformate (266 mg, 1.32 mmol), DCE (3.0 mL), and pyridine (104.7 mg, 1.32 mmol) and stirred at room temperature for 2 h. (R)-1-Cyclopropylethanol (115.0, 1.34 mmol) was added and mixture was heated at 80° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. aq. K2CO3 (2×15 mL), water, and brine. The organic layer was dried, concentrated and purified on silica gel (EtOAc/hexane 10%)) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-ethylsulfanyl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (209 mg, 69%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:7]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH:2]=[CH2:3].C>C(O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3]
Reactant: C=CCc1cc(CC=C)c2oc(C(=O)O)cc(=O)c2c1
Solvent: CCO
Product: CCCc1cc(CCC)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
A solution of 6.2 parts of 6,8-dially-4-oxo-4H-1-benzopyran-2-carboxylic acid in 100 parts of ethanol was hydrogenated at room temperature for 45 minutes at a pressure of 45 p.s.i. in the presence of 5% palladised charcoal. The solution was filtered and evaporated to afford 6.1 parts of 6,8-di-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, melting pont 183°-184° C after recrystallization from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9])(=[O:14])[CH3:13]
Reactant: Cc1csc2ccc(F)cc12
Reactant: CC(=O)Cl
Product: CC(=O)c1sc2ccc(F)cc2c1C

Procedure:
The titled compound (7.43 g) was prepared as colorless crystals from 5-fluoro-3-methylbenzo[b]thiophene (9.97 g) and acetyl chloride (5.55 ml) by the similar reaction and purification procedure as described in Reference Example 35.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=N[C:17]=2[CH:18]=1.C(N(CC)CC)C.[NH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1.CN([CH:47]=[O:48])C>>[C:47]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)(=[O:48])[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzoic add (0.123 g) in DMF (5 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.231 g), HOBT (0.163 g) and triethylamine (0.56 ml) and stirred at room temperature for 1 h. A solution of 3-amino-1-N-Boc-piperidine (0.3 g) in DMF (1 ml) was then added and stirring continued for 18 h. The solution was concentrated under reduced pressure to give an oil which was partitioned between ethyl acetate and water. The separated organic extracts were washed with water, hydrochloric acid (2N), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.120 g) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][C:38](=[O:39])[O:40][CH3:41])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Yield: 11.2 %

Procedure:
Prepared using General Procedure 15: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (20.0 mg, 0.05 mmol) in DMF (1 mL) was added DIEA (19.4 mg, 0.15 mmol) and methyl chloroformate (9.5 mg, 0.1 mmol) for 4 h at room temperature. The solvent was evaporated and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC to afford 2.35 mg (11%) of (R)-methyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 149. LCMS-ESI (m/z) calculated for C23H22N4O4: 418.2; found 419.1 [M+H]+, tR=3.85 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.54-7.44 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.43-5.18 (m, 1H), 5.03 (d, J=8.6 Hz, 1H), 4.90-4.63 (m, 1H), 3.77 (d, J=27.4 Hz, 3H), 3.59-3.35 (m, 1H), 3.27-3.01 (m, 1H), 2.68 (ddd, J=12.7, 8.2, 4.7 Hz, 1H), 2.05-1.75 (m, 1H), 1.47 (t, J=5.6 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 167.82, 163.56, 157.51, 151.63, 139.77, 137.77, 128.85, 128.63, 123.19, 122.08, 121.53, 117.97, 111.55, 110.03, 108.32, 98.67, 51.00, 46.99, 28.68, 26.28, 24.46, 16.50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:29])[CH:11]=2)[CH:6]=1
Reactant: CB(O)O
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(C)cc23)nc1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (30 mg, 0.07 mmol, methyl ester of example 12-1), methylboronic acid (7 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol), potassium phosphate (45 mg, 0.21 mmol) and toluene (0.5 mL) was stirred at 115 overnight under an argon atmosphere. The resulting mixture was diluted with water (5 mL), and then extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether) to give [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-methyl-naphthalen-2-yl]-acetic acid methyl ester (20 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][CH2:18][C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(-c2n[nH]c3ccc(NCc4ccncc4)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a solution of N-[3-(4-fluorophenyl)(1H-indazol-5-yl)]-4-pyridylcarboxamide (50 mg, 0.12 mmol) in THF (3 mL) was added lithium aluminum hydride (LAH) (9 mg, 0.24 mmol). The solution was stirred for 3 hours when an additional equivalence of LAH was added. The reaction was stirred for another 3 hours when it was quenched with ethyl acetate and water (100 mL) was added. The layers were separated and the water layer extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated to an oil. The oil was taken up in methanol (10 mL) and 6N HCl (10 mL) and heated to 80° C. for 2 hours when it was quenched with NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (7.5 mg, 20% yield). 1H NMR (CDCl3) δ 8.6 (br s, 1H), 7.76 (dd, 2H), 7.35 (d, 2H), 7.24 (d, 2H), 7.15 (t, 2H), 6.9–6.8 (m, 2H), 4.43 (s, 2H); ES-MS (m/z) 319 [M+1]+.