Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:11][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[C:2]([Br:1])=[C:3]([O:12][CH2:6][C:5]2[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH:4]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
To a stirred solution of 4-bromo-3,5-dihydroxy-benzoic acid (350 g, 1.5 mol) in dry DMF (2 L) were added K2CO3 (725 g, 5.25 mL) and BnBr (769 g, 4.5 mol) in one portion. The mixture was stirred at room temperature for 2 days and then filtered. The filter cake was washed with CH2Cl2. The combined filtrates were concentrated to give the title compound (225 g, 40% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.22-7.52 (m, 17 H), 5.38 (s, 2 H), 5.21 (s, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)=[N:7][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][NH:14][CH3:15])=[N:7][C:6]=12
Reactant: CN(CCNc1ccn2ncc(Br)c2n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The tert-butoxycarbonyl was removed by dissolving 600 mg (1.62 mmol) of tert-butyl (2-((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)(methyl)carbamate in 4 mL of DCM, and then adding 4 mL TFA, stirring for 0.5 hr at rt, and concentrating the mixture to afford the TFA-salt of the desired product in 100% yield (622 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:27]([O:25][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:26])[CH2:3][CH:4]=1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Temperature: 80 °C

Procedure:
To 200 mg (0.51 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonapth-2-yl)ethynyl]benzoate (Compound 1) was added 0.13 ml (1.5 mmol) of acetic anhydride and 10 mg (0.05 mmol) of p-toluenesulfonic acid. The mixture was heated at 80° C. for 12 hours, cooled to room temperature and concentrated in vacuo to an oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[C:20]1(/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(Cl)=O)C(C)C>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:28](=[O:29])/[CH:27]=[CH:26]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Agent: CC(C)COC(=O)Cl
Product: O=C(/C=C/c1ccccc1)NC1CCN(CCC2CCOc3ccccc32)CC1
Yield: 61 %

Procedure:
N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine was coupled to 3-phenyl-2E-propenoic acid utilizing the isobutylchloroformate protocol described in Example 6. This afforded the title compound; (61% yield) m.p. 168°-70°, Anal: C25H30N2O2 0.3 H2O, Calc. C, 75.84; H, 7.79; N, 7.08; Found, C, 75.90; H, 7.94; N, 7.32.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.CN(C)[CH:27]=[O:28]>>[CH:17]1([NH:23][C:27](=[O:28])[O:16][CH2:15][C:13]2[C:12]3[C:7]([CH:6]=[C:5]4[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: CN(C)C=O
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: Cl
Product: O=C(NC1CCCCC1)OCc1c2ccccc2cc2ccccc12
Reaction time: 1 h
Yield: 92 %

Procedure:
To the solution dissolved 8.92 g of N,N′-carbonyldiimidazole (55 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 40 mL of dimethylformamide (DMF), 10.4 g of 9-anthracenemethanol (50 mmol; produced by Wako Pure Chemical Industries, Ltd.) was added under cooling with ice, then, the solution was reacted by stirring for 1 hour at the same temperature. Subsequently, 6.94 g of monocyclohexylamine (70 mmol; produced by Wako Pure Chemical Industries, Ltd.) was added to this solution, and the solution was reacted by stirring for 2 hours at room temperature. After completing reaction, the reaction solution was poured into 110 mL of 3.5% hydrochloric acid, the resultant crystal was filtered, then, the resultant crystal was dried, the crystal after drying was added to 100 mL of toluene, and was hot-dissolved to hot-filtered at the temperature of 100° C. Subsequently, the filtrate obtained by filtration was cooled with ice, and the precipitated crystal was filtered, then, the resultant crystal was dried to obtain 15.4 g of 9-anthrylmethyl N-cyclohexylcarbamate (yield: 92%) represented by the above-described formula [15] as yellow crystal. Measurement results of 1H-NMR and melting point are shown as the follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].CO.C1COCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (4.09 g, 15.34 mmol) in THF (70 mL) was added triethyl amine (4.50 mL, 32.29) and triphenylmethyl chloride (4.67 g, 16.76 mmol) and the solution was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10%-40% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate. A solution of ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate (6.34 g, 12.47 mmol), sodium hydroxide (0.74 g, 18.39 mmol), methanol (10 mL), THF (20 mL), and water (10 mL) was stirred at room temperature for 16 hour and was then concentrated in vacuo. The aqueous was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3.0 grams (0.009 mole) (±)-1-S-hexadecyl-2-O-methylthioglycerol in 200 milliliters of DCM and 1.0 milliliter (0.010 mole) of triethylamine was added 1.2 grams (0.012 mole) of methanesulfonyl chloride and the reaction stirred at room temperature for 24 hours. The reaction mixture was then extracted twice with 200 milliliter portions of water, twice with 200 milliliter portions of 5% HCl, once with 200 milliliters of saturated NaHCO3, and once with 200 milliliters of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 3.4 grams (89%) of a colorless oily residue. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 28H, (CH2)14 ], 2.58(m, 2H, S--CH2), 2.62(m, 2H, CH--CH2 --S), 3.08(s, 3H, SO2 --CH3), 3.40-3.50(m, 4H, CH, CH3 --O), 4.35 (m, 2H, CH2 --OSO2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([NH:29][CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:29]([CH2:30][CH3:31])[C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCNC1CCCCC1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CCN(C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1)C1CCCCC1

Procedure:
N-Cyclohexyl-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-cyclohexyl-N-ethylamine using method I.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12]=O.O.[CH3:15][NH:16][CH3:17]>>[OH:9][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=[CH:7][C:6]=1[CH2:15][N:16]([CH3:12])[CH3:17]
Reactant: CNC
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: C=O
Solvent: O
Product: CN(C)Cc1ccc(C(F)(F)F)cc1O
Temperature: 15 °C
Reaction time: 20 h

Procedure:
195 g of 3-trifluoromethylphenol are initially charged in 160 ml of 40% aqueous dimethylamine solution and cooled to 15° C. At 155° C., 108 ml of 37% aqueous formaldehyde solution are added dropwise within 40 min. Subsequently, the mixture is stirred at room temperature for 20 hours. The mixture is cooled again to 15° C., admixed with 8 ml of 40% aqueous dimethylamine solution and 5.5 ml of 37% aqueous formaldehyde solution are added dropwise. Subsequently, the mixture is stirred at room temperature for a further 4.5 hours. The mixture is cooled again to 15° C. and admixed with 32 ml of 40% aqueous dimethylamine solution, and 21 ml of 37% aqueous formaldehyde solution are added dropwise. Subsequently, stirring is continued at room temperature for 17 hours. The mixture is admixed with 150 ml of water. The organic phase is removed, the aqueous phase is extracted twice with dichloromethane, the combined organic phases are washed once with water and the solvent is distilled off under reduced pressure. The crude product is taken up in 250 ml of water and adjusted to pH 1-2 with cooling in an ice bath using dilute hydrochloric acid. The acidic solution is extracted once with dichloromethane and subsequently adjusted to pH 11 with cooling in an ice bath using dilute sodium hydroxide solution. The alkaline reaction solution is extracted twice with dichloromethane, the combined organic phases are washed once with water and dried, and the solvent is distilled off under reduced pressure. The crude product is subsequently fractionally distilled under reduced pressure. 186 g (71% of theory) of a light yellow liquid having a boiling point of 91° C. at 14 mbar are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCCC1
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccc(Oc2cncc(Br)c2)cc1)N1CCCC1
Temperature: 120 °C
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-3-pyridinol (2.61 g, 15 mmol), dimethylacetamide (50 mL), 1-((4-fluorophenyl)sulfonyl)pyrrolidine (5.8 g, 25 mmol) and potassium carbonate (4.1 g, 30 mmol) was heated at 120° C. for 18 h, then cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (200 mL) and the organic phase washed with water (3×100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography, eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 3.4 g (59%) of a red solid (m.p. 148° C.)
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]Br)C.[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:15].NC1C=CC=CC=1>>[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:11][C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:4]2=[O:13])=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: CCOC(=O)C=Cc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
By using 2-bromomethyl-benzoic acid ethyl ester and 4-aminocinnamic acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 3-[4-(1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-acrylic acid ethyl ester (Compound 23) as white crystals.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and Cul (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CSc1ccccc1
Reaction time: 2 h

Procedure:
To (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (3.00 g) in methanol (100 ml) were added thiophenol (1.5 ml) and triethylamine (2.0 ml), followed by 2 hour' stirring under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 4.14 g of (2S)-1-(t-butoxycarbonyl)-2-[1-hydroxy-2-(phenylthio)ethyl]pyrrolidine.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:8][C:7]3[C:2]([I:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=3)=[CH:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1ccc(O)c(I)n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3ccc(C)nc3I)ccnc2cc1OCc1ccccc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Iodo-6-picolin-3-ol (10 g), 4-chloro-7-benzyloxy-6-methoxyquinoline (6.8 g), and 4-(N,N-dimethylamino)-pyridine (12.2 g) were dissolved in 1,2-dichlorobenzene (400 ml) to prepare a solution, and the mixture was stirred at 125° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with chloroform, and the chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform-acetone to give 7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxy-quinoline (5.2 g, yield 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH2:18][O:19]C)=[C:6]1[CH2:22][CH2:23][CH3:24].B(Br)(Br)Br>ClCCl.CO.O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH2:18][OH:19])=[C:6]1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(C(=O)COC)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCCc1c(C(=O)CO)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: -12 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-3-methoxyacetyl-2-propylindole-6-carboxamide (168 mg) in a mixture of dichloromethane (10 ml) and methanol (0.5 ml) was added 1M solution or boron tribromide in dichloromethane (2.5 ml) at -53° C. The reaction mixture was warmed gradually to -12° C. during 3 hours. Then 1M solution of boron tribromide in dichloromethane (2.5 ml) was added, and the mixture was stirred for 20 minutes at -12° C. The reaction mixture was diluted with water and extracted with 10% methanol in chloroform. The organic phase was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate and washed with hexane to give 1-(2-chlorobenzyl)-3-hydroxyacetyl-2-propylindole-6-carboxamide (120 mg) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1)C(OCC)=O)C.[OH-].[K+]>O.CO>[CH:11]1([CH2:5][C:4]([OH:17])=[O:3])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: CCOC(=O)C(C(=O)OCC)C1C=CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1C=CCCC1

Procedure:
100 g of 2-(2-cyclohexenyl)malonic acid diethyl ester and 52 g of potassium hydroxide in 100 ml of water/methanol=1/4 was refluxed overnight. Then the alcohol was withdrawn on a forced circulation evaporator, the residue was diluted with about 200 ml of water and then combined under ice cooling with about 70 ml of concentrated hydrochloric acid to pH 1. The mixture was repeatedly extracted with ether, the combined organic phases were washed with saturated sodium chloride solution and evaporated to dryness. The residue was heated for 4 hours to 130° C. with liberation of CO2 and thereafter distilled under vacuum, thus obtaining 55.5 g, bp1 98°-107° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[N:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1>O1CCCC1.O.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>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[N:5]1[N:4]=[C:3]([CH2:2][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([C:26]([F:43])([F:42])[F:25])[CH:32]=2)[C:7]([CH3:8])=[N:6]1
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1nn(-c2ccc(F)cc2F)nc1CBr
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: C1CCOC1
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2F)nc1Cc1ccnc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
To a solution of 4-(bromomethyl)-2-(2,4-difluorophenyl)-5-methyl-2H-1,2,3-triazole (i.e. the product of Step C, 0.30 g, 1.0 mmol) in tetrahydrofuran/water (3:1, 4 mL total), was added tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol), potassium phosphate tribasic (0.43 g, 2.0 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (0.31 g, 1.15 mmol). The mixture was heated to 70° C. and stirred for 96 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by twice by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes, and then was purified by reverse-phase chromatography on C18 silica gel to afford the title compound (0.18 g) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:26][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=3[F:18])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Reactant: OCc1cccc(F)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 221.5 mg (1.537 mmol) of (2,3-difluorophenyl)methanol (CAS 75853-18-8), 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h, some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and dried under reduced pressure, which gave 190 mg (67% of theory, 97% pure) of the target compound.