Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:24][CH2:25]1
Reactant: c1coc(N2CCNCC2)c1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1coc(N2CCN(CCCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-furyl) piperazine (4.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.0 g compound (I-12) with a yield of 61.5%. ESI-MS [M+H]+: m/z 325.2.
Reaction SMILES: C([O:4][C:5](=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[CH3:9])C#N)(=O)C.[OH-:20].[Na+:21]>O>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[C:5]([O-:4])=[O:20])=[CH:11][CH:12]=1)[CH:17]([CH3:19])[CH3:18].[Na+:21]
Reactant: [OH-]
Reactant: CC(=O)OC(C#N)=C(C)c1ccc(CC(C)C)cc1
Agent: [Na+]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 25 °C

Procedure:
55.41 g. portion of the crude enol-acetate solution from part A, representing 49.3 mmoles of 2-acetoxy-3-(4'-isobutylphenyl)-3-methylacrylonitrile (V) was placed in a 250 ml. one-necked flask and stirred magnetically while 10 ml. of water and 16.0 g. (200 meq.) of 50 percent sodium hydroxide solution were added. The mixture was stirred at 70° C. for 7 hours and cooled to 25° C. to effect hydrolysis of the enol-acetate and to form the sodium salt (VI). The ph of the mixture was adjusted to 11 with 12 percent sulfuric acid (3.5 ml.). Sodium hypochlorite solution (15 percent W/V, 30 meq.; 24.8 ml.) was added over 30 minutes with ice water cooling of the flask. Methylene chloride (10 ml.) and 0.8g. of a filter aid (Celite) were added and the mixture was slowly cooled to 0° C. After 3 hours the solids were filtered (3 minutes on a coarse frit) and washed with cold brine (8 ml. of saturated sodium chloride solution plus 3 ml. of ice) and with 10 ml. of cold methylene chloride. The cake was dried to give 9.68 g. A 1 gram sample was removed for cyanide assay; it showed 40 parts per million sodium cyanide. The remaining salt, 8.68 g. was slurried with water. The slurry gave a negative picric paper test, and then 56 ml. of Skellysolve B (SSB) and 8 ml. of 12 N sulfuric acid were added, with warming to 40° C. The mixture was filtered and phases were separated. The upper phase was washed with 20 ml. of warm water. The combined aqueous phase were back washed in sequence with a 20 ml. portion of SSB. The two SSB phases were then stirred with a mixture of sodium sulfate and decolorizing charcoal (0.5 g.), filtered through a filter aid and concentrated to about 15 ml. volume. The resulting acid solution was seeded with crystals of 2-(4'-isobutylphenyl)propionic acid and held at 0° C. for 2 hours. The resulting precipitate of 2-(4'-isobutylphenyl)propionic acid (1) was filtered, washed with two 3 ml. portions of cold SSB and dried overnight at 50° C. The yield of 2-(4'-isobutylphenyl)propionic acid, based upon the glycidonitrile starting material, with correction for removed analysis samples of the sodium salt was 8.00 g. (78.8 percent). A thin layer chromatogram analysis showed no impurity. The mother liquor still contained 0.120 g. of the acid (I).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:4][C:3]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:4][C:3]1=[S:21]
Reactant: CCCCCC(CCC1CN(C)C(=O)N1)OC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: CCCCCC(CCC1CN(C)C(=S)N1)OC(C)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2.5 g (9.2 mmol) of 1-methyl-2-oxo-4-(3-acetoxyoctyl)-imidazolidine (Example 11) are dissolved in 80 ml of absolute toluene, 10 g of beach sand are added and the mixture is warmed to 90° C., with stirring. 2.50 g of P4S10.anisole are then added and stirring is continued at 90° C. for 2 hours. The reaction mixture is filtered, the residue on the filter is washed with toluene and the toluene phase is concentrated. The residue is chromatographed on silica gel in cyclohexane/ethyl acetate 1:1.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:3].Cl.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:16][CH3:17])=[O:11])=[CH:8][CH:7]=1)=[O:3]
Reactant: NC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(CNC(N)=O)cc1
Reaction time: 2 h

Procedure:
38.0 g (0.196 Mol) of 4-(aminocarbonylaminomethyl)benzoic acid were dissolved in 1.5 l of anhydrous ethanol and refluxed for 5 hours while dry hydrogen chloride was introduced. The small amount of insoluble matter was filtered off, the filtrate was concentrated down to a volume of about 100 ml, diluted with 1 l of water and treated with solid potash until the development of carbon dioxide had ended and a distinctly alkaline reaction was obtained. The mixture was left to stand for 2 hours, the crystals formed were suction filtered, washed thoroughly with water, then with diisopropylether and diethylether and dried in vacuo. 32.8 g (75% of theory) of colourless crystals were obtained, Mp. 173-175° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15](=[NH:18])[NH:16][CH3:17])=[O:13])[CH3:2].[CH3:19]C(=O)CCC>CCCCCC>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:11]1[CH:17]=[N:16][C:15]([NH:18][CH3:19])=[N:14][C:12]1=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Reactant: CCCC(C)=O
Solvent: CCCCCC
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O

Procedure:
The same procedure is followed as in Example 4 above using 1-(2',6'-diethylphenyl)-3-methylamidinourea as the starting material and using as the recrystallization medium a mixed solvent of pentanone and hexane (30:10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:31][CH2:32][CH2:33]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc2ccccc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (3.62 g) in dimethylformamide (40 mL) under argon was treated with 55% sodium hydride (0.875 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthyloxy)ethanol (5.48 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was crystallized from dichloromethane-hexane to provide 4.2 g of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: NC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 114 %

Procedure:
The procedure is carried out as in Example 1, starting with 189 mg of 2,6-dichloropurine, 5 ml of butanol and 150 mg of 4-aminobenzamide. 329 mg of the expected product are thus obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][OH:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][S:14]([O:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCC#CCOC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC#CCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10.24 ml (15.15 g, 0.1323 mol) of 2-butyne-1,4-diol monotetrahydropyranyl ether was added dropwise to a solution of 15 g (0.088 mol) of methanesulfonyl chloride and 19.79 ml (14.25 g, 0.141 mol) of triethylamine in 250 ml of anhydrous methylene chloride at such a rate to maintain the reaction temperature at 0° C. The reaction mixture was stirred for 30 minutes further at 0° C. Then the reaction mixture was poured into 200 ml of aqueous saturated sodium bicarbonate solution and extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and the solvent removed in vacuo, to yield crude 4-tetrahydropyranyloxy-butyn-1-ol methanesulfonate. This crude product was dissolved in 50 ml of acetone and treated with a solution of 40.34 g (0.4636 mol) of lithium bromide in 200 ml of acetone, stirring the reaction mixture at room temperature for 1 hour. The solvent was then evaporated and the residue diluted with water (100 ml) and extracted with methylene chloride, the organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified bysilica gel column chromatography using hexane:ethyl acetate (95:5) as eluant to yield 1-bromobut-2-yn-4-ol-tetrahydropyranyl ether, as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:32]([OH:41])=[O:31])=[CH:34][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-formyl-benzoic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 527.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17]O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CO)cc2C1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccc(CN3CCCC3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.25 g 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (5.01 mmol) in 14 ml dichloromethane was slowly added 0.781 ml methanesulfonyl chloride (10.03 mmol) at room temperature. Subsequently the mixture was heated for 4 hours at reflux. LCMS control indicted a near complete formation of the corresponding mesylate, which was not isolated. After cooling to room temperature, 1.244 ml pyrrolidine (15.04 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was complete according to LCMS. Water was added to the reaction mixture, the acidic aqueous phase was extracted two times with dichloromethane, and the water phase was basified and extracted three times with ethyl acetate. The combined ethyl acetate solutions were extracted with brine, dried over Na2SO4, filtered, and the organic solvent was removed under reduced pressure to provide the title compound. The dichloromethane phase was extracted two times with diluted NaOH, once with brine and then dried over Na2SO4. Filtration and removal of the organic solvent under reduced pressure provided additional title compound. Both fractions were combined and used in the next step without further purification. LCMS: m/z 303.2 (M+H).
Reaction SMILES: [C:1]1(=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH:2]1[C:11]1C=CN=C[CH:12]=1.[C:18]([N:37]1C=C(C=O)[N:39]=[CH:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:37]1[CH:12]=[C:11]([CH:2]2[C:1](=[O:17])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:10])[N:39]=[CH:38]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1c2ccccc2C(=O)C1c1ccncc1
Product: O=C1c2ccccc2C(=O)C1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 67 %

Procedure:
The condensing of commercially available 1-trityl-1H-imidazole-4-carboxaldehyde (I) with phtalide to form 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) is performed under the conditions that are similar to those used for synthesis of 4-(indane-1,3-dionyl)pyridine J. Org. Chem. 1971, vol. 36, p. 1563. surprisingly, the bulky 1-trityl-1H-imidazole-4-carboxaldehyde (I) reacted as expected and produced 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) in over 67% yield. Both ethyl acetate and dioxane can be used as reaction media.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:44]I>C1COCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:26][CH3:44])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (35.5 mg, 0.059 mmoles) in THF (0.3 mL) at 0° C. under nitrogen was added sodium hydride (4.8 mg, 0.12 mmoles, 60% dispersion in mineral oil). The reaction was stirred for 30 min., allowing it to warm to room temperature. The reaction mixture was then treated in a dropwise manner with methyl iodide (11 μL, 0.179 mmoles) at 0° C. The ice bath was removed after the addition and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified using silica gel chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to yield the title compound (30.1 mg, 83%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (m, 6H) 1.5 (m, 1H) 1.6 (m, 2H) 1.7 (m, 1H) 1.9 (d, J=12.9 Hz, 1H) 3.1 (s, 3H) 4.1 (d, J=7.1 Hz, 1H) 4.2 (s, 3H) 4.7 (d, J=15.8 Hz, 1H) 4.7 (s, 2H) 4.9 (d, J=16.2 Hz, 1H) 7.3 (s, 1H) 7.5 (d, J=7.9 Hz, 1H) 7.6 (d, J=8.3 Hz, 1H) 7.7 (s, 2H) 7.8 (s, 1H). MS (ES+) Calc: 609.2, Found: 610.4 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:51])[CH2:40][CH:41]2[C:46](=[O:47])[O:45][C:44]([CH3:49])([CH3:48])[O:43][C:42]2=[O:50])=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.C(OCC)C>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:51])[CH2:40][CH:41]3[C:46](=[O:47])[O:45][C:44]([CH3:49])([CH3:48])[O:43][C:42]3=[O:50])=[CH:35][CH:34]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)OC1(C)C
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(Br)cc2)C(=O)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)C(=O)O1
Temperature: 80 °C
Yield: 75.6 %

Procedure:
A solution of 2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran (500 mg, 1.22 mmol) in anhydrous DMSO (5 mL) was added to a stirred suspension of 5-[2-(4-bromophenyl)-2-oxoethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (436 mg, 1.22 mmol) and tripotassium phosphate (1.04 g, 4.88 mmol) in anhydrous DMSO (5 mL). [1,1′-bis-(Diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (100 mg, 0.12 mmol) was added as a solid, and the resulting suspension was heated to 80° C. for 2 hrs. The reaction mixture was cooled to room temperature, diluted with diethyl ether (150 mL), washed with water (2×50 mL), brine (3×50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 50-60% ethyl acetate/heptane as eluent, afforded the title compound as an off-white solid (502 mg): 1H-NMR (DMSO-d6, 300 MHz): δ 8.12 (2H, d, J=8 Hz, Ar-H), 7.92 (4H, d, J=6 Hz, Ar-H), 7.53-7.69 (4H, m, Ar-H), 7.26 (7H, m, Ar-H), 4.82 (1H, s, CH), 4.26 (2H, s, PhCH2), 3.86 (2H, CH2CO), 1.84 (3H, s, Me), 1.74 (3H, s, Me).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn2c(-c3cccc(Cl)c3)cc(Cl)nc2c1I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2c(-c3cccc(Cl)c3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 130.9 %

Procedure:
5-Chloro-7-(3-chlorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (237 mg), DIPEA (0.2 mL) and (S)-2-pyrrolidinemethanol (120 mg) are stirred at 90° C. for 2 hours in an acetonitrile (15 mL) solvent. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (360 mg). 1H NMR (CDCl3, 300 MHz): δ 7.84 (s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.45 (m, 3H), 6.10 (s, 1H), 4.47 (bs, 1H), 3.83-3.53 (m, 4H), 2.36 (s, 3H) 2.18-1.98 (m, 3H), 1.78 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>C(#N)C>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O[C@@H]1CCNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O[C@@H]1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
(R)-(+)-3-Pyrrolidinol (1.0 g, 11.5 mmol) (Aldrich) and triphenylchloromethane (1.00 g, 3.59 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 3 hours. The mixture was allowed to cool to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, followed by extraction with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.73 g, 62% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@H]1F
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1S*,2R*,4S*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f73) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([NH:29][C:30]([N:14]1[CH2:15][CH2:16][C:11]2[C:10](=[O:17])[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]=2[CH2:13]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)CC1(c2cccc(Cl)c2)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC(C)CC1(c2cccc(Cl)c2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
A mixture of 3-(3-chlorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (70 mg, 0.23 mmol) and benzyl isocyanate (42 μL, 0.34 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (105 mg, 100%). 1H NMR (300 Hz, CDCl3) δ 0.85 (d, J=6.0, 3H), 0.93 (d, J=6.0, 3H), 1.55-1.70 (m, 1H), 1.72-1.82 (m, 1H), 2.20-2.40 (m, 3H), 3.15-3.29 (m, 1H), 3.49-3.61 (m, 1H), 3.89 (d, J=18.0, 1H), 4.39 (d, J=3.0, 2H), 4.48 (d, J=18.0, 1H), 5.22 (t, J=6.0, 1H), 7.14-7.38 (m, 9H).