Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: BrCc1ccccc1CBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206-209° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>C(OC(=O)C)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ncc(Br)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1ncc(Br)s1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 104 %

Procedure:
A 100 mL round bottom flask is charged with (5-bromothiazol-2-yl)methanol (2.5 g, 12.9 mmol), imidazole (1.75 g, 25.8 mmol), dimethylformamide (25 mL), and chlorotriisopropylsilane (3.4 mL, 15.5 mmol). The reaction is stirred at room temperature under nitrogen for 72 hours. Contents are diluted with ethylacetate (150 mL), washed with 0.5M hydrochloric acid (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated under vacuum to afford the title compound (4.7 g): m/z (Cl) M+H 350+352.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].O.[OH-].[Cs+]>CN(C=O)C>[Si:34]([O:33][CH2:32][CH2:31][N:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 3 h
Yield: 56.6 %

Procedure:
To N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol) in DMF (5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg, 0.16 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves (2 g). The reaction mixture was stirred for 3 hours and then concentrated. Purification by silica gel chromatography (DCM/MeOH 10:1) gave the desired product (16 mg).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[C:14](Cl)([Cl:16])=[O:15]>C1(C)C=CC=CC=1>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]([Cl:16])=[O:15])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCNCCCCC
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCN(CCCCC)C(=O)Cl
Reaction time: 0.5 h

Procedure:
A mixture of 7.86 g. (50.0 mmole) of dipentylamine, 18.05 ml (50.0 mmole) of 2.77M NaOH solution and 60 ml of toluene was vigorously stirred at -7° to -5° C., and 60 ml (115.8 mmole) of 1.93M phosgene in toluene was added dropwise over 1 hour. After stirring an additional 30 min., the cold mixture was separated and the toluene layer was dried over solid NaCl. After filtering, nitrogen was bubbled through the solution for 1 hour and the solution was concentrated in vacuo to 10.5 g. (95%) of light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][N:13]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CNCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(CCOc1ccccc1)c1ncnc2ccccc12
Reaction time: 7 h
Yield: 88.3 %

Procedure:
To a solution of 2.5 g (0.015 mole) of 4-chloroquinazoline in benzene were added 2.3 g (0.015 mole) of N-methyl-N-phenoxyethylamine and 1.5 g (0.015 mole) of triethylamine. The mixture was then refluxed, with stirring, for 7 hours. After completion of the reaction, the benzene was removed by evaporation. Water was added to the residue and the mixture was extracted with chloroform and the extract was dried. The chloroform was removed by evaporation and the resulting oil was purified by column chromatography through silica gel (eluted with a 1:1 by volume mixture of benzene and ethyl acetate) to give 3.7 g (88%) of the desired Compound No. 4 in the form of a pale yellow liquid having a refractive index nD27 1.6329.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)[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].[OH:29][CH2:30][CH2:31][CH2:32]O.B(F)(F)F.CCOCC>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:32][CH2:31][CH2:30][OH:29])=[O:25])=[CH:27][CH:28]=1)[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: OCCCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCCCO)cc1

Procedure:
As in Example 23, the title compound is prepared by the reaction of 4-(hexadecylamino)hydrocinnamic acid with 3-hydroxypropanol and boron trifluoride etherate.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C@@H:5]2[OH:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1([F:10])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C:5]2=[O:9]
Reactant: O[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Silica gel 60 (particle size, 0.040-0.063 mm, CAS #63231-67-4, from EMD Chemical Inc. 4.0 g) was added to a solution of (1R,2S,4R)-5,5-difluorobicyclo[2.2.1]heptan-2-ol (0.800 g, 5.40 mmol) in anhydrous dichloromethane (20.0 ml). The mixture was cooled to 0° C., and pyridinium chlorochromate (1.86 g, 8.64 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred at this temperature overnight. After this time, the mixture was diluted with dichloromethane (30 mL) and then filtered through a pad of silica gel. Removal of the solvents gave the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([NH:25][CH3:26])=[O:24])[C:5]([CH2:18][OH:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([O:19][CH2:18][C:5]1[N:4]([C:20]2[CH:21]=[C:22]([C:23]([NH:25][CH3:26])=[O:24])[CH:27]=[CH:28][C:29]=2[CH3:30])[C:3](=[O:31])[C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:6]=1)(=[O:40])[CH3:39]
Reactant: CNC(=O)c1ccc(C)c(-n2c(CO)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(C)c(-n2c(COC(C)=O)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide, (225 mg, 0.50 mmol) stirred in CH12Cl2 was added pyridine (55 μL, 0.69 mmol). To the resulting homogeneous solution was then added acetic anhydride (47 μL, 0.51 mmol). The mixture was stirred at rt for 3 h. Additional pyridine (150 μL, 1.8 mmol) and acetic anhydride (100 μL, 1.05 mmol) were then added and the reaction was allowed to stir overnight at rt. The reaction was then quenched with 1N NHCl4 and diluted with CH2Cl2. The layers were separated and the organic layer was then extracted with CH2Cl2 (3×). The organics were then combined, dried, and concentrated in vacuo. The residue was then triturated with Et2O and filtered to give (150 mg, 61%) an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (br s, 1H), 7.87 (app d, J=7.8 Hz, 1H), 7.74-7.69 (m, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.40 (app t, J=8.1 Hz, 1H), 7.28-7.19 (m, 1H), 6.91 (s, 1H), 5.43 (s, 2H), 4.60 (s, 2H), 2.79 (s, 3H), 2.06 (s, 3H), 1.94 (s, 3H). ES-HRMS m/z 535.0676 (M+H calcd for C24H22N2F2BrO5 requires 535.0675).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)CCCC.[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:22])/[CH:17]=[CH:18]\[C:19]([O-])=[O:20]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH:17]([C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:18][C:19](=[O:20])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCOC(=O)/C=C\C(=O)[O-]
Reactant: NNc1ncccc1Cl
Solvent: CC(=O)O
Solvent: CCCCCO
Product: CCCCCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 75 °C
Yield: 23.8 %

Procedure:
0.75 g of sodium hydroxide was added to a mixed solution comprising 15 ml of 1-pentanol and 30 ml of toluene, followed by dehydration using an azeotropic dehydrator under reflux with heating, and then toluene was distilled off. Further, 20 ml of toluene was added to the reaction system and then toluene was distilled off with heating again, to obtain a 1-pentanol solution of sodium pentaoxide. 2.5 g of 3-chloro-2-hydrazinylpyridine was added to the reaction liquid at from 70 to 80° C. little by little over a period of 5 minutes, and then 5 ml of 1-pentanol was added, followed by heating at from 70 to 80° C. for 25 minutes. Then, a mixed solution comprising 5.1 g of pentyl maleate and 5 ml of 1-pentanol was dropwise added over a period of 15 minutes, followed by reaction at from 70 to 80° C. further for 2 hours. After the reaction liquid was stood to cool, acetic acid was added to the reaction liquid for neutralization, followed by concentration under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate, and the organic layer was washed with diluted hydrochloric acid and a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/4 to 0/1) to obtain 1.29 g of the desired product (melting point: 66 to 68° C.) in the form of brown crystals.
Reaction SMILES: O1CCCC1.[CH:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[CH3:14][N:15]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[CH:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16](=[O:17])[N:15]([CH3:14])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=CN1CCNCC1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)C(=O)N1CCN(C=O)CC1
Yield: 49.7 %

Procedure:
Into 600 ml of tetrahydrofuran, were dissolved 41 g of 1-formylpiperazine and 54.5 g of triethylamine. To the solution, while being stirred and cooled in ice, was added dropwise 56 g of 2,4,4-trimethylallophanyl chloride. The mixture was allowed to react at room temperature for 6 hours and the precipitate was removed by filtration. The filtrate was concentrated and the residue was recrystallized from tetrahydrofuran to obtain 41 g of 1-formyl-4-(2,4,4-trimethylallophanoyl)piperazine. This compound was mixed with 800 ml of 6N hydrochloric acid and the mixture was heated with stirring at 60° C. for one hour. The reaction mixture was concentrated and the residue was recrystallized from ethanol to obtain 35.2 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride having a melting point of 215° C.
Reaction SMILES: C([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6]([O:19][C@@H:20]2[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]2[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:5]1)(=O)C.C(=O)(O)[O-].[K+].C(O)(=O)C>CO>[F:18][C:13]1[CH:12]=[C:11]([CH2:10][C:7]2[C:6]([O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])=[N:5][NH:4][C:8]=2[CH3:9])[CH:16]=[CH:15][C:14]=1[CH3:17]
Reactant: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(C)c(F)c2)c1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(Cc2c(O[C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]3OC(=O)C(C)(C)C)n[nH]c2C)cc1F
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of 1-acetyl-4-[(3-fluoro-4-methylphenyl)-methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.75 g) in methanol (5 mL) was added potassium bicarbonate (0.030 g) under stirring at room temperature. The mixture was stirred at 50° C. for 3 hours. To the mixture was added glacial acetic acid (0.022 g) at 60° C., and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/5) to give 4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.610 g).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]1([CH2:11][CH2:12][CH2:13][C:14]([Cl:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1cccc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCc1cccc2ccccc12
Temperature: 70 °C

Procedure:
0.37 g of 4-Naphthalen-1-yl-butyric acid was dissolved in 5.0 ml of toluene, and 0.35 ml of thionyl chloride and 1 drop of dimethylformamide were added, followed by heating at 70° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a crude 4-naphthalen-1-yl-butyryl chloride. To the resulting crude 4-naphthalen-1-yl-butyryl chloride was added 2.3 ml of a toluene solution of 0.40 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine, followed by stirring at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Wako-gel C-200, chloroform:methanol=10:1) to give 0.58 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyryl)piperazine as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[S:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][C@@H:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>>[CH3:19][C@@H:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[S:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=S)[nH]1
Reactant: C[C@@H]1Cc2ccccc2N1
Agent: [Na+]
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=S)[nH]1

Procedure:
The product is prepared by following the procedure described in example 1e (step 4e) using 200 mg of sodium (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate obtained in example 1e (step 2e) and 106 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)). After purification by silica column chromatography (eluent: 98/02 dichloromethane/ethyl dichloromethane), 71 mg of 1-((R)-2-methyl-2,3-dihydroindol-1-yl)-2-(4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)ethanone are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].C([SiH](CC)CC)C>C(Cl)Cl>[CH3:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]2[C:14]([C:18]([F:21])([F:19])[F:20])=[N:15][NH:16][CH:17]=2)=[CH:12][C:5]=1[S:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C
Temperature: 0 °C
Yield: 19.3 %

Procedure:
0.98 g (3.1 mmol) of 2-propylthio-4-(3-trifluoromethylpyrazolyl)benzaldehyde (Compound No. V-159 of the Present Invention) prepared in the same manner as in Example 8 (9) was dissolved in 10 ml of methylene chloride and stirred together with 1.44 g (12.4 mmol) of triethylsilane and 0.63 ml (6.8 mmol) of boron trifluoride diethyl ether complex at room temperature for 22 hours. The reaction mixture was poured into 50 ml of ice-cold water, and 20 ml of methylene chloride was added. The methylene chloride layer was separated, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the methylene chloride was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.18 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl]propyl sulfide (yield 19.3%) as a colorless liquid (nD2 unmeasurable).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[N:8]=1.[F:15][C:16]([F:33])([F:32])[C:17](=[O:31])[CH2:18][C:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])([CH3:21])[CH3:20]>C1COCC1>[F:33][C:16]([F:15])([F:32])[C:17]([CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[N:8]=1)([OH:31])[CH2:18][C:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])([CH3:21])[CH3:20]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1cc(C)nc(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)n1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to a solution of 2,4,6-trimethylpyridine (0.12 g) in THF (0.5 mL) cooled to −70° C. under argon. The mixture was stirred at −70° C. for 15 minutes and 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.10 g) (Example 1) in THF (0.5 mL) was added. The reaction mixture was stirred for 20 minutes and then quenched with acetic acid. The mixture was diluted with EtOAc, washed with water, dried, filtered, and concentrated in vacuo. Fractionation by preparative layer chromatography on silica gel (methylene chloride-hexanes) followed by crystallization gave 43 mg of the title compound, m.p. 95° C.-98° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:14]([OH:23])[C@@H:15]([CH:20]2[CH2:22][CH2:21]2)[CH2:16][N:17]=[N+]=[N-])(=O)=O)=CC=1.CCN(C(C)C)C(C)C>CO.[Pd]>[CH:20]1([C@H:15]2[CH2:16][NH:17][CH2:12][C@@H:13]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@@H:14]2[OH:23])[CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](CN=[N+]=[N-])C2CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C2CC2)[C@H]1O
Reaction time: 3 h

Procedure:
A mixture of (2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-4-cyclopropyl-3-hydroxypentyl 4-methylbenzenesulfonate (0.506 g, 1.11 mmol), DIPEA (0.31 mL, 1.8 mmol), and 10% palladium (dry basis) on activated carbon (wet, Degussa type E101 NE/W) (0.1 g) in MeOH (5 mL) was stirred under an atmosphere of hydrogen introduced via a balloon. After 3 h, the crude reaction mixture was filtered through a pad of diatomaceous earth and the solids were washed thoroughly with MeOH. The volatile organic solvents were removed under reduced pressure and the residue was dried under high vacuum to afford the sub-title compound as a solid. The crude product was used directly in the subsequent displacement reaction without further purification. LCMS (ESI) m/z calc. for C13H25N2O3 257.2 [M+H]+. found 257.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.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.[NH2:50][N:51]1[C:59]2[C:54](=[C:55]([F:60])[CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52]1>CN(C=O)C>[F:60][C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:54]=1[CH:53]=[CH:52][N:51]2[NH:50][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][CH:9]=1)=[O:16]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Nn1ccc2c(F)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A solution of 2-(pyridine-2-yl)-4-methylpyrimidine-5-carboxylic acid (0.11 g) and HATU (0.19 g) in dry DMF (7 mL) is treated with DIPEA (0.09 mL) and stirred at rt under N2 for 30 min. 1-Amino-4-fluoroindole (0.112 g) is added and the mixture is stirred at rt for 24 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine and dried (MgSO4), filtered, and concentration in vacuo. The residue is purified by silica gel chromatography eluting with 75% EtOAc to afford 2-(pyridin-2-yl)-4-methylpyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.085 gms, 50%). MS: 348 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.82 (s, 3H), 6.65 (d, 1H), 6.93-6.97 (q, 1H), 7.19-7.26 (m, 1H), 7.35-7.38 (d, 1H), 7.62 (d, 1H), 7.74-7.78 (m, 1H), 8.20-8.25 (t, 1H), 8.58-8.61 (d, 1H), 8.85-8.86 (d, 1H), 9.33 (s, 1H), 12.15 (s, 1H).