Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C1COCC1.[Li+].[OH-].Cl>O.CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-methyl 4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoate (105 mg, 0.225 mmol) and THF (2 mL):MeOH (1 mL) was added 1M LiOH (1 mL). The solution was stirred at room temperature. After 16 h, the reaction was diluted with water. The aqueous solution was acidified with 1 N HCl to a pH of 7 and extracted with EtOAc (3×15 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid. 1H NMR (300 MHz, MeOH-d4) δ ppm 8.49 (d, J=4.7 Hz, 1H), 8.06-8.15 (m, J=8.5 Hz, 2H), 7.89-8.00 (m, J=8.5 Hz, 2H), 7.64 (t, J=9.1 Hz, 1H), 7.31-7.51 (m, 4H), 6.70 (s, 1H). MS (ESI pos. ion) m/z: 453.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[N:13]1([CH2:18][C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1.CCOC(C)=O>O1CCOCC1>[N:13]1([CH2:18][C:19]2[CH:20]=[C:21]([NH:22][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Nc1cccc(Cn2ccnc2)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cnn2ccc(Nc3cccc(Cn4ccnc4)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-((1H-imidazol-1-yl)methyl)aniline (115 mg, 0.663 mmol). The mixture was heated in microwave for 120 minutes at 120° C. EtOAc was added to the mixture, and washed with water. The organic layer was then dried over Na2SO4 and solvent was removed under reduced pressure to yield 5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The resulting solid was used in the next step without further purification. LCMS (M+1=319)
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:31][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:29][NH:30][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=2[CH3:11])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: Cc1c(F)cccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 3-fluoro-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=431.2, tR (minutes, Method D)=0.79
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=[CH2:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:29].[Na+].OO>C1COCC1.C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26 g, 63 mmol) in THF (200 mL) was cooled in an ice-bath, followed by dropwise addition of 10 M BH3SMe2 (6.3 mL). After stirring for 5 hr, 10% NaOH solution (32 mL) followed by 30% H2O2 (32 mL) were added carefully. The reaction mixture was stirred at rt for 16 hr. The reaction mixture was diluted with diethyl ether (500 mL) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (19.6 g, 72%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:10].[Na+].[OH2:15]>CO>[O:15]=[S:1]1(=[O:10])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: OCC1CCSCC1
Reactant: O
Agent: [Na+]
Solvent: CO
Product: O=S1(=O)CCC(CO)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At room temperature, a solution of 500 mg (3.78 mmol) of tetrahydrothiopyran-4-ylmethanol in 10 ml of methanol was added with cooling to a solution of 1.86 g (8.70 mmol) of sodium periodate in 18 ml of water. The mixture was stirred at 60° C. for another 1 h, and methanol was then distilled off under reduced pressure and the resulting precipitate was filtered off with suction. The aqueous phase that remained was extracted twice with 10 ml of diethyl ether, twice with 10 ml of dichloromethane, twice with 10 ml of dichloromethane/methanol (1:1, v/v) and, after addition of 5 ml of water, twice with 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The aqueous phase was extracted four more times with 20 ml of 2-methyltetrahydrofuran. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. Combined yield: 406 mg (65% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].Cl[C:32]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.ICC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Solvent: CCI
Product: CCO[C@H]1Cc2ccccc2[C@@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and iodoethane and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.81, 1.17–1.21, 1.30–1.34, 1.51–1.59, 1.98, 3.90–3.96, 4.02–4.08, 6.71–6.73, 7.04–7.07, 7.19; MS (ESI+) for C25H27Cl2N3O m/z 457 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][I:8]>C(O)(C)C>[I-:8].[I-:8].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH3:7])[CH:3]=1.[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH3:7])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: CI
Solvent: CC(C)O
Product: Cn1cc[n+](C)c1
Product: [I-]
Reaction time: 12 h

Procedure:
21.3 ml (267 mmol) of N-methylimidazole are dissolved in 150 ml of isopropanol. After addition of 17.3 ml (280 mmol) of methyl iodide, the mixture is heated at the boiling point for 8 hours. After cooling, the solution is allowed to stand for 12 hours to crystallize. The crystalline 1,3-dimethylimidazolium iodide (1a) is filtered off and washed with 50 ml of diethyl ether and 50 ml of THF. Yield: 57 g (96%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC1CCCCC1C(=O)O
Product: CC1CCCCC1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use 2-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (60% yield). 1H NMR (300 MHz, CDCl3) δ 8.08, 8.00, 7.00, 3.50-4.00, 2.70, 2.05, 1.20-1.90, 0.90, 0.75, 0.45, 0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:1].[ClH:1].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH2:22][N:15]1[CH2:16][CH2:17][N:12]([CH2:3][C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:13][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1CN1CCN(CC(=O)c2ccccc2)CC1
Yield: 133.4 %

Procedure:
A mixture of N-phenacyl piperazine dihydrochloride (1.7 g, 6.1 mmol), 2-methoxy-5-nitro-benzylbromide (1.5 g, 6.1 mmol) and K2CO3 (2.7 g, 19.5 mmol) in 40 ml of acetone was treated according to general preparation 2 to give 1.80 g of compound (IV-23), yield 60%. M+ 368.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[CH3:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[NH2:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:21]([NH:22][C:14](=[O:16])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=1)([CH3:24])[C:20]([O:19][CH3:18])=[O:25]
Reactant: Cc1ccc(C(=O)O)nc1OCC(F)(F)F
Reactant: COC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C)c(OCC(F)(F)F)n1
Yield: 123.9 %

Procedure:
A solution of 5-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (30 mg, 128 μmol), 2-methyl-alanine methyl ester hydrochloride (23.5 mg, 153 μmol), HATU (CAN 148893-10-1, 97.0 mg, 255 μmol) and DIEA (82.4 mg, 109 μl, 638 μmol) in DMF was stirred at ambient temperature for 72 h. The crude reaction mixture was concentrated in vacuo to give 53 mg of a yellow solid. This solid was purified by preparative TLC (silica gel, 2.0 mm, 1:1 heptane/i-PrOAc) and eluted from the silica gel with i-PrOAc. Filtration over speedex and evaporation under reduced pressure provided the title compound (10 mg, 23%) as colorless liquid, MS (EI): m/e=335.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]=2[OH:25])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:28]([F:38])=[C:29]([CH:35]=[CH:36][CH:37]=1)C(N=[N+]=[N-])=O.C[N:40](C)[CH:41]=[O:42]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([NH:24][C:41]([NH:40][C:37]3[CH:36]=[CH:35][CH:29]=[C:28]([F:38])[C:27]=3[Cl:26])=[O:42])[C:18]=2[OH:25])(=[O:15])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Reactant: [N-]=[N+]=NC(=O)c1cccc(Cl)c1F
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(F)c3Cl)c2O)CC1
Yield: 66 %

Procedure:
A solution of 1d (3.8 g, 9.7 mmol) and 3-chloro-2-fluorobenzoyl azide (1b) (2.9 g, 14.5 mmol) in 5 mL of N,N-dimethylformamide was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), gave 3.6 g (66%) of 1e. LC-MS (m/z) 562.8 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(-c2csc(N3CCN(C(=O)Nc4onc(C)c4C)CC3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 43.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (244 mg, 0.848 mmol), 1-[4-(3-methylphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.269 ml, 1.54 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 132 mg (43.0%) of the desired product as a solid. mp 175-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 87 mg of 4-fluoro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 6.90 (t, 1H, J=8.8 Hz, 4.4 Hz), 7.17 (t, 1H, J=7.6 Hz), 7.38–7.46 (m, 5H), 7.52 (d, 2H, J=8 Hz), 7.60 (t, 1H, J=7.2 Hz), 7.70 (d, 1H, J=8.8 Hz), 7.83 (td, 1H, J=8.4, 1.8 Hz), 10.09 (s, 1H). MS: m/z 390.9 (M++1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CC1CCC([OH:16])CC1.C1(=O)CCCCC1.C1(O)CCCCC1>>[CH3:1][CH:2]1[CH2:3][CH2:4][O:8][C:5](=[O:16])[CH2:6][CH2:7]1
Reactant: CC1CCC(=O)CC1
Reactant: CC1CCC(O)CC1
Solvent: O=C1CCCCC1
Solvent: OC1CCCCC1
Product: CC1CCOC(=O)CC1
Yield: 45.6 %

Procedure:
The procedure of Example 25 was repeated, except that 4-methylcyclohexanone (2 mmol) and 4-methylcyclohexanol (20 mmol) were respectively used in stead of cyclohexanone and cyclohexanol. As a result, γ-methyl-ε-caprolactone was formed in yield of 45.6% (on 4-methylcyclohexanone basis).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18])([CH3:15])[CH3:14].[CH3:22][O:23][CH2:24]Cl>C1COCC1>[CH:13]([C:16]1([CH2:22][O:23][CH3:24])[CH2:21][CH2:20][O:19][C:17]1=[O:18])([CH3:15])[CH3:14]
Reactant: COCCl
Reactant: CC(C)C1CCOC1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1(C(C)C)CCOC1=O
Temperature: -70 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of diisopropylamine (13.1 mL) in THF was treated dropwise with butyl lithium (58.4 mL of 1.6M solution in hexanes) at −10° C. Then the reaction mixture was cooled to −70° C. and treated dropwise with 2-isopropyl-γ-butyrolactone (9.30 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the mixture was stirred for 3 h at −70° C., then warmed-up to −40° C. and treated dropwise at this temperature with chloromethyl methyl ether (7.50 mL). After that, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature for 80 h. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, then washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 7.00 g (57%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([C:18]([OH:20])=O)=[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:35][CH3:36])=[C:26]([C:28]2[N:32](C)[N:31]=[CH:30][C:29]=2[NH2:34])[CH:27]=1.[CH:37](N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:35][CH3:36])=[C:26]([C:28]2[C:29]([NH:34][C:18]([C:17]3[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[N:13][C:12]=34)=[O:20])=[CH:30][N:31]([CH3:37])[N:32]=2)[CH:27]=1
Reactant: COc1ccc(Cl)cc1-c1c(N)cnn1C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)O
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1c(NC(=O)OC(C)(C)C)nn2cccnc12
Temperature: 50 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (88 mg, 0.32 mmol), 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (75 mg, 0.32 mmol), 4-dimethylaminopyridine (7.7 mg, 0.063 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.95 mmol) in DMF (3 mL) was added PyAOP (200 mg, 0.38 mmol). The reaction mixture was stirred for 14 hrs at 50° C., then diluted with EtOAc. The organic layer was washed twice with water, and once with brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc to afford 98 mg (62%) of tert-butyl 3-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate. 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 9.65 (s, 1H), 8.76 (dd, J=6.8, 1.7, 1H), 8.44 (dd, J=4.3, 1.7, 1H), 8.20 (s, 1H), 7.56 (d, J=2.7, 1H), 7.36 (dd, J=8.8, 2.7, 1H), 6.97 (d, J=8.9, 1H), 6.90 (dd, J=6.9, 4.3, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=3)[C:19]3[C:18](C4C=CC=CC=4)=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[B:44](OC)([O:47]C)[O:45]C.Cl>O1CCCC1>[C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][C:29]([B:44]([OH:47])[OH:45])=[CH:28][CH:27]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(C2(c3ccccc3)c3ccccc3-c3cccc(-c4ccccc4)c32)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
First, 4.0 g (10 mmol) of 9-phenyl-9-(4-bromophenyl)-phenyl-9H-fluorene was put in a 500 mL three-neck flask, the atmosphere in the flask was replaced with nitrogen, 100 mL of dehydrated tetrahydrofuran (abbreviation: THF) was then added to the flask, and the temperature was lowered to −78° C. Into this mixture solution, 7.6 mL (12 mmol) of a 1.59 mol/L n-butyllithium hexane solution was dropped, and the mixture was stirred for 2 hours. To this mixture, 1.4 mL (15 mmol) of trimethyl borate was added, and the mixture was stirred at −78° C. for 2 hours and at room temperature for 18 hours. After the reaction, this reaction solution was stirred while 1M diluted hydrochloric acid was added thereto until the solution became acid. This solution was subjected to ethyl acetate extraction, and an organic layer obtained was washed with a saturated saline. After the washing, magnesium sulfate was added to the organic layer to adsorb moisture. This suspension was filtered, the obtained filtrate was concentrated, and hexane was added thereto. The mixture was irradiated with ultrasonic waves and then recrystallized to obtain 3.5 g of the objective white powder in 97% yield. The reaction scheme of the synthesis method is shown in the following (A-1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)=O.[CH2:27]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:38]=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C1=C(c2cccc(OCc3ccccc3)c2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Using 1-tert-butyl 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridin-1,3(2H)-dicarboxylate and 3-benzyloxyphenylboronic acid, the title compound was obtained in a similar manner to Reference Example 550.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(Br)cc1
Yield: 102.3 %

Procedure:
A solution of 20.02 g of 4-bromophenol (0.116 mol) in 100 mL of dry THF was treated with 15.0 mL of pivaloyl chloride (0.126 mol), followed by 35.5 mL of triethylamine (0.255 mol). A large amount of white solid precipitated so 50 mL of additional THF was added to the mixture to afford a free-flowing slurry. The reaction mixture was filtered and the precipitate was washed with 200 mL THF and then discarded. The filtrate was concentrated in vacuo to a liquid which solidified when dried under reduced pressure to yield 30.5 g (100%) of 4-bromophenyl pivalate.