Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]1[C:10]([OH:12])=[O:11].[CH:13]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:13][C:4]1([C:10]([OH:12])=[O:11])[CH2:5][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CC2(CCC2)C1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC2(CCC2)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A slurry of 2.15 g (44.2 mmol) of sodium hydride (50% in oil) in 45.0 ml of dry THF was stirred under argon at -20° C. A solution of 5.52 g (40.0 mmol) of spiro[3.3]heptane-2-carboxylic acid in 5.0 ml of dry THF was added dropwise. The reaction mixture was stirred for 0.5 hr at -20° C. A solution of 44.5 mmol of freshly-prepared, -20° C lithium diisopropylamide in 31.0 ml of THF was added to the reaction mixture. The reaction mixture was stirred for 0.3 hr at 0° C. Methyl iodide (2.80 ml, 44.5 mmol) was added, and the reaction mixture stirred an additional 2.0 hr at 25° C. The reaction mixture was cooled to -20° C and the reaction quenched by careful addition of cold 10% aqueous HCl. The mixture was extracted with 1:1 ethylacetate-ether. The extracts were washed with brine, then dried (MgSO4), filtered, and solvents evaporated in vacuo. The residue was dissolved in 1 N NaOH and extacted three times with ether. The aqueous layer was acidified with 6 N HCl and extracted with 1:1 ethyl-acetate-ether. These extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to yield 5.1 g of 2-methylspiro[3.3]heptane-2-carboxylic acid as a light yellow oil (82.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH3:26][CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:31]1[CH2:30][CH2:29][NH:28][CH:27]([CH3:26])[CH2:32]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1CN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 5-chloroindole-2-carboxylic acid (0.196 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g) in dichloromethane (10 mL) was treated with 2-Methyl-piperazine (0.15 g) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (50 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.229 g). 1H NMR (400 MHz, CDCl3): δ 10.99 (br s, 1H), 7.55 (d, J=1.76 Hz, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.14 (dd, J=1.96, 6.65 Hz, 1H), 6.63 (br s, 1H), 4.55 (br s, 2H), 3.23-2.61 (m, 5H), 1.76 (br s, 1H), 1.08 (d, J=5.87 Hz, 1H). MS (electrospray): exact mass calculated for C14H16ClN3O, 277.10; m/z found, 278.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[C:24]([C:28](Cl)=[O:29])=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21]>ClCCl>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[NH:10][C:28]([C:24]1[C:23]([N+:20]([O-:22])=[O:21])=[CH:27][NH:26][N:25]=1)=[O:29]
Reactant: O=C(Cl)c1n[nH]cc1[N+](=O)[O-]
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Method A A stirred solution of 4,5-dimethylphenylenediamine (4.32 g) and diisopropylethylamine (30 ml) in dichloromethane (200 ml) was treated with 4-nitropyrazole-3-carboxylic chloride (5 g) portionwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The solvent was removed in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was re-crystallised from ethyl acetate and methanol (10%) to give 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide (6.58 g) as an orange solid. LC-MS (METHOD B): RT=2.36 minutes, 276.09 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:11]1[C:16]2[C:15](=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][S:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1cnccn1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)c1cnccn1
Yield: 13 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoqunoline (300 mg, 2.08 mmol), pyrazine-2-sulfonyl chloride 443 (482 mg, 2.7 mmol), pyridine (3 ml), DMAP (cat.) and DCM (2 ml) gave the title compound (102 mg, 13%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13].Br[CH2:17][C:18](=[O:32])[CH2:19][C@H:20]1[C@H:25]([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][N:21]1[C:28]([O:30][CH3:31])=[O:29]>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:17][C:18](=[O:32])[CH2:19][C@H:20]1[C@H:25]([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][N:21]1[C:28]([O:30][CH3:31])=[O:29])[C:6]2=[O:13]
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2ccc(C(F)(F)F)cc12
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2ccc(C(F)(F)F)cc2c1=O
Yield: 24 %

Procedure:
By the method of Example 4, 6-trifluoromethylquinazolin-4(3H)-one and methyl trans-2-(3-bromo-2-oxopropyl)-3-methoxypiperidine-1-carboxylate were converted into the title compound in 24% yield; m.p. 137°-140° C. 1H-NMR(CDCl3) 1.4-1.9 (m, 4H), 2.9 (d, 3.3 (s, 3H), 3.5-3.9 (m, 4H), 3.7 (s, 3H), 5.2 (s, 2H), 7.7-8.7 (m, 4H).
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.[CH3:18][NH:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:29])[CH2:24][CH2:23]1>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[N:19]([CH3:18])[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:29])[CH2:24][CH2:23]1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1c(N(C)CCC2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (20.58 mg, 0.145 mmol) and triethylamine (81 μl, 0.579 mmol) in MeOH (483 μl) was warmed to 45° C. for 30 mins. 3,5-Dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (50 mg, 0.145 mmol) was added drop wise and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated under reduced pressure and the crude oily product was dissolved in water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure. The crude product was suspended in MeOH and sonicated. The resulting white solid was filtered and dried to afford the title compound;
Reaction SMILES: [NH:1]1[C@H:4]([C:5]([NH:7][C@H:8]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)=[O:6])[CH2:3][C:2]1=[O:25].C1C=CC2N(O)N=[N:32][C:30]=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CN>CN(C=O)C.CO>[NH:1]1[C@H:4]([C:5]([NH:7][C@H:8]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:32][CH3:30])=[O:20])=[O:16])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)=[O:6])[CH2:3][C:2]1=[O:25]
Reactant: On1nnc2ccccc21
Reactant: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CC(=O)N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 2 ml of DMF were dissolved 300 mg of Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-L-proline (13) (obtained in Example 3), 116 mg of HOBT, and 177 mg of DCC and after stirring for 7 hours at room temperature, the solution was cooled in an ice bath. Then 0.6 ml of a methanol solution of 30% methylamine was added to the solution and the mixture was reacted overnight with stirring at 2° to 6° C. Insoluble matters were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue thus formed was purified by column chromatography using LiChroprep Si 60 (size B). By using chloroform-methanol-aqueous ammonia (40:10:1) as the eluant. Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-N-methyl-L-prolinamide (46) was obtained. The product was dissolved in water and then lyophilized. The amount of the product thus obtained was 149 mg.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[C:4]2[CH:19]=[CH:20][C:21]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[N:22][C:3]1=2.C(Cl)[Cl:41]>Cl.CO.CCOCC>[ClH:41].[CH3:1][N:2]1[C:11]2[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]=2[C:4]2[CH:19]=[CH:20][C:21]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[N:22][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CC(C(=O)OC(C)(C)C)NCC2
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A suspension of tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-d]azepine-6(5H)-carboxylate (149 mg, 0.276 mmol) in 1.25 M HCl in MeOH (3.0 mL) was stirred under N2 at ambient temperature for 18 h. CH2Cl2 (1.5 mL) was added to the suspension and the resulting solution was stirred at ambient temperature for 18 h. CH2Cl2 (1.0 mL) and 1.25 M HCl in MeOH (1.0 mL) were added to the solution, and the resulting solution was stirred at ambient temperature for 6 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added to the solution, and the resulting solution was stirred for 18 h. The solution was diluted with Et2O, and the resulting solids were collected by filtration to afford the title compound (104 mg, 79%) as a light-yellow powder: mp 308-312° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J=2.0 Hz, 1H), 9.04 (s, 2H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.85 (dd, J=7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.49-3.46 (m, 2H), 3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method A) 98.1% (AUC), tR=13.4 min.
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]([O:28][CH3:29])[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25].P(O)(O)([O-])=O.[Na+]>C1CCCCC1.O1CCCC1>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([C:6]([CH3:7])([CH3:8])[CH:22]([CH:21]([O:28][CH3:29])[O:20][CH3:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: COC(=O)C=CC(OC)OC
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
3.4 ml of a 1.95M butyllithium in cyclohexane solution were slowly added at -70° C. to a solution of 1.24 g of p-tolyl isopropyl sulfone in 13 ml of tetrahydrofuran and the mixture was stirred at -70° C. for 15 minutes. Then, a solution of 1 g of methyl 4,4-dimethoxy-2-butenoate in 20 ml of tetrahydrofuran was slowly added to the mixture which was stirred at -70° C. for one hour and poured into a aqueous monosodium phosphate solution. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1--1 ether-petroleum ether (b.p.=40°-70° C.) mixture to obtain 1.1 g of methyl 4-p-toluenesulfonyl-4-methyl-3-dimethoxymethyl-pentanoate melting at 110° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:11]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:11][C:8]1[CH:9]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(F)c1O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
596 mg of 3-fluoro-2-hydroxybenzaldehyde was dissolved in 5 ml of acetonitrile, and 770 mg of N-bromosuccinimide was added. The solution was stirred for 15 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was evaporated, to give 928 mg of 5-bromo-3-fluoro-2-hydroxybenzaldehyde.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH2:5][NH:6][C:7](=[O:10])[NH:8][NH2:9].[CH:12]([O-])([O-])OCC>>[CH3:2][CH:3]([CH3:11])[CH2:4][CH2:5][N:6]1[CH:12]=[N:9][NH:8][C:7]1=[O:10]
Reactant: CC(C)CCNC(=O)NN
Reactant: CCOC([O-])[O-]
Agent: Cl
Product: CC(C)CCn1cn[nH]c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 13.0 g of 4-(3-methylbutyl)semicarbazidehydrochloride (71.6 mmol) and 60 ml of ethyl orthoformate was stirred at 110° C. for two hours. After cooling, the mixture was subjected to column chromatography using silica-gel (eluate; ethyl acetate:hexane=1:2 to 2:1 to ethyl acetate to ethyl acetate:methanol=10:1). The desired fraction was concentrated. The crystals thus given was recrystallized from ethyl acetate-petroleum ether to give 7.0g of 4-(3-methylbutyl)-3(2H,4H)-1,2,4-triazolone (63%) as colorless needles.
Reaction SMILES: [I-].[I:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:33]([C:35]([CH3:40])([CH2:38][CH3:39])[CH:36]=O)[CH3:34]>O1CCCC1>[CH2:33]([C:35]([CH3:40])([CH2:38][CH3:39])/[CH:36]=[CH:3]\[I:2])[CH3:34]
Reactant: CCC(C)(C=O)CC
Reactant: IC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(/C=C\I)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of (iodomethyl)triphenylphosphonium iodide (0.530 g, 1 mmol) in tetrahydrofuran (3 mL) was treated dropwise at room temperature with sodium bis(trimethylsilyl)amide (1 mL, 1M solution in THF, 1 mmol) for 2-3 minutes. The solution was then cooled to −78° C. and a solution of 2-ethyl-2-methyl-butanal (0.100 g, 0.88 mmol) in tetrahydrofuran was added dropwise. The cooling bath was removed and stirring continued at room temperature for 1 hour. The reaction mixture was diluted with hexane, filtered and evaporated. The crude compound was purified by silica gel chromatography (hexane) and afforded the title compound (0.130 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH2:21])=[O:20].N1C=CC=CC=1>BrC1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:22][CH:23]=[CH:24][N:25]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: NC(=O)c1cccnc1Cl
Solvent: Brc1ccccc1
Solvent: c1ccncc1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3C(N)=O)cc12
Temperature: 156 °C
Yield: 36 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloronicotinamide were used. Pyridine was used as base, bromobenzene was used as solvent, and the reaction was heated at reflux (156° C.) for 18 hours. Chromatography followed by recrystallization (methanol/water) of the resulting solid in afforded the title compound (36%) as a yellow solid: mp, 127.0°-129.0° C.; 13C NMR (CD3OD) δ173.0, 157.9, 152.2, 139.0, 135.4, 132.4, 129.0, 123.9, 119.1, 113.7, 113.2, 113.0, 112.5, 111.3, 61.4, 45.4, 24.3; HRMS calculated for C18H21N5O 323.1748, found 323.1726. Anal. calcd. for C18H21N5O.H2O; C, 63.33; H, 6.79; N, 20.51. Found: C, 63.19; H, 6.50; N, 20.30.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[CH:32]([C:34]1[CH:35]=[N:36][N:37](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:38]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:32][C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: O=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (3.71 g) and 4-formyl-1-(triphenylmethyl)pyrazole (3.66 g) in 1,2-dichloroethane (80 ml) was added sodium triacetoxyborohydride (2.86 g). After stirring at room temperature for 3 hours, aqueous sodium bicarbonate solution was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (40 ml) and added to a mixture of trifluoroacetic acid (30 ml) and anisole (15 ml). After stirring for 7.5 hours at room temperature, the mixture was quenched with 10% sodium hydroxide (150 ml) and aqueous sodium bicarbonate and extracted with dichloromethane. The extract was washed with aqueous sodium bicarbonate solution and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (3:7) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (2.84 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(N)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: COc1cc(N)ccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
4-Iodo-3-methoxy-phenylamine (3.17 g, 12.7 mmol) and ethynyl-trimethyl-silane (3.5 mL, 25 mmol) in dry acetonitrile were purged with nitrogen and treated with TEA (17.6 mL, 127 mmol), CuI (123 mg, 0.635 mmol) and Pd(Ph3P)2Cl2 (447 mg, 0.635 mmol). The reaction was stirred at room temperature for 2 h. The volatiles were evaporated, the residue was taken up with EtOAc (200 mL), washed with water (50 mL), dried over sodium sulfate and purified by flash chromatography on silica gel (hexane/EtOAc 55/45) to afford the title compound (1.86 g, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.N1CCCCC1.[O:25]1[CH2:37][CH:26]1[CH2:27][CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>C1(C)C=CC=CC=1>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][CH2:27][CH:26]([OH:25])[CH2:37][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: C1CCC(OCCCC2CO2)OC1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CCCOC3CCCCO3)ccc12
Temperature: 100 °C

Procedure:
A solid mixture of 7-hydroxyflavone (32.0 g, 0.134 mol), piperidine (0.5 ml), and 2-(4,5-epoxypent-1-oxy)tetrahydropyran (50 g, 0.268 mol) was stirred and heated under nitrogen at 100° C. for 14 hours; it became a stirrable mixture after 6 hours heating at 100° C. The cooled reaction mixture was purified through a pad of silica gel eluting with CH2Cl2 initially and then CH2Cl2 --EtOAc (1:1). The resulting solid was stirred with ether and filtered, giving 43.9 g (77% crude yield) of an off-white solid; pure white crystals, mp 110°-112° C., were obtained from recrystallization from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[C:13]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[N:4]=1.CN(C=O)C.[CH:40]#[C:41][CH2:42][CH2:43][CH3:44]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([C:40]#[C:41][CH2:42][CH2:43][CH3:44])[C:13]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[O:15])[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cccc(OS(=O)(=O)C(F)(F)F)c2C(=O)OCC[Si](C)(C)C)n1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC[Si](C)(C)C
Temperature: 0 °C
Yield: 62.8 %

Procedure:
In a 100 ml flask equipped with a thermometer, a cooling tube and a nitrogensintroducing tube, there were charged 2-trimethylsilylethyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-trifluoromethylsulfonyloxybenzoate (4.72 g, 9.0 mmol), bis(triphenylphosphine)palladium dichloride (300 mg, 0.4 mmol), DMF (30 ml) and triethylamine (5 ml), and the resultant mixture was stirred at room temperature for 1 hour under nitrogen stream. Thereafter, 1-pentyne (2.0 g, 29.40 mmol) was added to the resultant mixture, and the mixture was reacted at 80°-90° C. for 3 hours. After cooling, the mixture was poured into an ice water, and was extracted with ethyl acetate. The organic layer thus obtained was washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The residue thus obtained was then purified by silica gel column chromatography to obtain 2.50 g (yield: 62.8%) of the aimed product (red-brown transparent viscous liquid).