Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCCCCOCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCc2ccccn2)cc1

Procedure:
2-[2-[(6-Bromohexyl)oxy]ethyl]pyridine (6.3 g) was added to benzylamine (20 ml) at 140° under nitrogen. After 1 h at 140° the reaction mixture was cooled and partitioned between 2M sodium hydroxide (100 ml) and ether (100 ml). The organic layer was washed with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation under reduced pressure to leave the title compound as a yellow oil (6.8 g), t.l.c. (toluene-ethanol-0.88 ammonia 80:20:2) Rf 0.44.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[SH:26]>C1(C)C(C)=CC=CC=1>[Cl:7][C:8]1[C:9]([S:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium carbonate (13.8 g) is added to a solution of 1,2-dichloro-3-nitrobenzene (19.29 g) and 2,4-dichlorothio-phenol (17.9 g) in xylene (250 ml), and the resulting mixture is heated for 5 hours at reflux temperature. The precipitate is separated by filtration, washed with xylene and the combined organic phases are concentrated. The resultant residue is mixed with petroleum ether and stirred for 1 hour at room temperature. Following this, the crystalline material is suction filtered and washed with petroleum ether, and any remaining solvent is removed in a vacuum. Yield: 25.6 g of colourless crystals (76.6%).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCCC1.O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)#[N:10]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)c(Oc2ccccc2)nc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
2,3-Dicyano-5,6-dichloropyrazine (1.00 g; 0.005 mole) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to -15° to -10° C. A solution of 0.47 g (0.005 mole) of phenol and 0.21 g (0.005 mole) of sodium hydroxide in 25 ml of water was added dropwise over the period of 30 minutes. The mixture was stirred at -15° to -10° C. for 1 hour. The reaction mixture was poured into 100 ml of ice water, and the precipitate was collected by filtration. The precipitate was dissolved in 50 ml of chloroform, washed with 20 ml of a dilute aqueous solution of sodium hyroxide and 30 ml of water, dried over anhydrous calcium chloride, and concentrated under reduced pressure. The crude product was chromatographed on a column containing 60 g of silica gel using benzene as an eluent to afford 0.65 g (yield 50%) of 2,3-dicyano-5-chloro-6-phenoxypyrazine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].N1([C:22]2[CH2:28][CH2:27]C[CH2:25][CH2:24][CH:23]=2)CCCC1>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:25]2[CH2:24][CH2:23][CH2:22][CH2:28][CH2:27][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: C1=C(N2CCCC2)CCCCC1
Solvent: O
Product: O=C(CC1CCCCCC1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 32,6 g (0.15 mole) of p-fluorophenacylbromide in 100 ml. of dry dimethylformamide is added dropwise to a cooled solution of 25 g (0.15 mole) of 1-pyrrolidino-1-cycloheptene in 100 ml. of dry dimethylformamide. After stirring at ambient temperature for 20 hours, and at 100° C. for 5 hours, 250 ml. of water are added, and the mixture is stirred for 3 hours. The reaction mixture is poured into 1500 ml. of water, extracted with chloroform, and the chloroform extract is washed with water and dried. Removal of the chloroform leaves 2-(p-fluorophenacyl)cycloheptanone as an oil. Infrared and nuclear magnetic resonance spectra confirm the above structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=[S:21])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.O.[Cl-].[NH4+]>CCO.CCOC(C)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=[S:21])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Temperature: 25 °C

Procedure:
A solution of 3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazine]-3′(4′H)-thione from Step E (628 mg, 2.0 mmol) in EtOH (16 mL) and EtOAc (8 mL) is treated successively with water (8 mL), iron powder (558 mg, 10 mmol) and ammonium chloride (53.5 mg, 1.0 mmol). The mixture is heated at reflux for 3 h and is then cooled to rt and filtered, washing the solids with additional EtOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacua, The residue is purified by silica gel chromatography (gradient elution with 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:3]([NH:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].[C:28]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:7]([O:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:43](=[O:44])[C@H:39]([CH:40]([CH3:41])[CH3:42])[NH:38][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.9 g) in methylene chloride (30 ml) was added CBZ-(S)-valine (1.6 g), 1-hydroxybenzotriazole (0.9 g), triethylamine (1 ml), and N'-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (1.3 g). After stirring overnight at room temperature, the solution was partitioned between methylene chloride and water, and after the organic layer was dried over magnesium sulfate, solvent was removed under reduced pressure to give (R)-N-tert-butoxy-2-(CBZ-valinamido)-3-(4-phenoxyphenylsulfonyl)-propionamide, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5](C)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.54 mmol) in DMF (160 mL), iodomethane (35.72 g, 248 mmol) and sodium carbonate (26.28 g, 248 mmol) were added. Resulting reaction mass was stirred at 60° C. for 8 h. On completion, reaction mass was filtered and inorganic solid residue washed with ethyl acetate. Combined filtrates were concentrated under vacuum till dryness. The residue was re-dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution (700 mL) followed by 5M HCl solution (300 mL). Organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford desired compound (16 g, 95%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:23])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][N:14]1[CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2CN1CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (150 mg, 1 mmole) and 2-[2-(bromo)ethyl]isoindolin-1-one (240 mg, 1 mmole) in ethanol (15 ml) was added triethylamine (0.21 ml, 1.5 mmoles) and the mixture Was stirred at room temperature for 12 hours and heated at reflux for 2 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (15:1)] to obtain 238 mg of the desired product (77.0%, light brown solid).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH3:10])[CH2:2][CH3:3].[OH-].[Na+].[H][H]>[Ni].C(O)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=1)[CH3:10])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN)cc1
Yield: 98 %

Procedure:
14.6 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b), 292 ml of ethanol, and 102 ml of a 1N sodium hydroxide aqueous solution were charged in a 1-liter recovery flask. 1.46 g (10 wt %) of Raney nickel prepared using the method described in Example 1 was slowly added to the solution. After replacing the atmosphere in the flask with nitrogen and then with hydrogen, the mixture was stirred at room temperature for 17 hours using a hydrogen balloon. After confirming the disappearance of the raw material, the catalyst was removed by celite filtration, and the product was washed with 70% ethanol solution. The obtained filtrate was concentrated under reduced pressure. After the addition of 100 ml of distilled water to the residue, the product was extracted twice with 200 ml of hexane. The organic layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 14.5 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzylamine (13) as a yellow oily substance (yield: 98%, GC: 93%). [HPLC: 90% (HPLC measurement conditions A)]
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.CN(C)C=O.[Cl:24]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:7]([Cl:24])=[N:6][C:5]([O:8][CH:9]([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[CH:4][C:3]=1[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(OC(C(F)(F)F)C(F)(F)F)ncc1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC(C(F)(F)F)C(F)(F)F)nc(Cl)c1N
Reaction time: 1 h
Yield: 44.4 %

Procedure:
1.0 g of 5-amino-4-methyl-2-(2,2,2-trifluoro-1-trifluoromethylethoxy)pyri dine was introduced to 10 ml of N,N-dimethyl formamide, and 0.56 g of N-chlorosuccinimide was added at room temperature. The temperature was elevated to 60° C., and the mixture was stirred for 1 hour and poured into water. The mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thus obtained residue was purified by silica gel column chromatography (eluent:hexane:ethyl acetate=10:1) to give 0.50 g (yield 44%) of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[NH:14][C:15]([I:19])=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].I[CH3:23]>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]([CH3:23])[C:15]([I:19])=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(I)[nH]2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCc1cccc(-c2nc(I)c(I)n2C)c1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 8.45 g (17.6 mmol) of 2-(3-hexyl-phenyl)-4,5-diiodo-1H-imidazole in 150 ml of DMF was treated at 0° C. with 0.806 g (18.5 mmol) of sodium hydride (55% dispersion in mineral oil); 15 min later, a solution of 1.52 ml=3.47 g (24.2 mmol) of iodomethane in 25 ml of DMF was added drop by drop at 0° C. After 2 hours, the reaction mixture was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 1:0 to 4:1) to give 7.52 g (87%) of the title compound as light red oil. MS: 495.1 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]([CH:20]=[C:21]([Br:23])[CH:22]=2)[CH:18]=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]([C:18]4[O:19][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)[CH:20]=[C:21]([Br:23])[CH:22]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(Br)cc(-c2c3ccccc3cc3ccccc23)c1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cc(-c2nc3ccccc3o2)cc(-c2c3ccccc3cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g (27.7 mmol) of 3-(anthracen-9-yl)-5-bromobenzaldehyde and 3.6 g (33.2 mmol) of 2-aminophenol were dissolved in 100 ml of acetic acid, and then agitated at room temperature for 30 minutes. Next, 14.7 g (33.2 mmol) of lead (IV) acetate was added thereto. The resulting mixture was agitated at 50° C. for 1 hour. Then, water was poured therein. The resulting product was treated with ethyl acetate to perform extraction, and then the solvent was removed under a reduced pressure. The extract was separated through a column and dried, obtaining 4.5 g (Y=33%) of a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][CH2:10][C@H:11]2[O:23][C@@H:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([OH:24])[C@@H:13]([OH:25])[C@@H:12]2[OH:26])=[CH:6][C:5]=1[Cl:29])=[N+:2]=[N-:3].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH2:39]>N1C=CC=CC=1>[N:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][CH2:10][C@H:11]2[O:23][C@@H:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([O:24][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:13]([O:25][C:8](=[O:39])[C:7]3[CH:27]=[CH:28][CH:4]=[CH:5][CH:6]=3)[C@@H:12]2[O:26][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:6][C:5]=1[Cl:29])=[N+:2]=[N-:3]
Reactant: O
Reactant: O=C(Cl)c1ccccc1
Reactant: [N-]=[N+]=Nc1ccc(COC[C@H]2O[C@@H](Sc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Cl
Solvent: c1ccncc1
Product: [N-]=[N+]=Nc1ccc(COC[C@H]2O[C@@H](Sc3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of phenyl 6-O-(4-azido-3-chlorobenzyl)-1-thio-β-D-glucopyranoside (10) (580 mg, 1.32 mmol) in pyridine (5 ml) was added benzoyl chloride (609 μl, 5.28 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 2 hr. Thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-benzoyl-1-thio-β-D-glucopyranoside (11) as slightly yellow crystals (934 mg, yield 94%).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C(OC(C)C)(=O)C>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: CC(=O)OC(C)C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in isopropyl acetate were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in isopropyl acetate at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[OH-].[K+]>>[ClH:1].[CH3:23][N:3]([CH3:2])[CH2:4][CH2:5][CH:6]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7]1
Reactant: CN(C)CCC(Cc1ccccc1C(=O)O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)CCC1Cc2ccccc2C(=O)c2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 14.75 g (0.05 mole) of 2-(β-[2-dimethylaminoethyl] phenethyl)benzoic acid hydrochloride and 150 g polyphosphoric acid is heated at 110° C for 6 hrs. allowed to cool and poured onto crushed ice with stirring. The resulting solution is cooled on ice and made basic by the addition of solid potassium hydroxide, and extracted with methylene chloride. The methylene chloride is washed with water, dried over anhydride magnesium sulfate and evaporated in vacuo. The residue is dissolved in isopropanol, and treated with gaseous hydrogen chloride. The resulting precipitate is filtered and recrystallized from isopropanol to give the intermediate 10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one hydrochloride, m.p. 188°-190° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:20]Br>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:20][O:4][CH2:3][C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6]
Reactant: CC(CO)(CO)c1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CO)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-2-phenylpropane-1,3-diol (3.37 g, 20.3 mmol) was dissolved in DMF, NaH (812 mg, 60%, 20.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A DMF solution of 3,5-bistrifluoromethylbenzyl bromide (6.23 g, 20.3 mmol) was added in one portion and stirred for another 1 hour before it was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried with Na2SO4 before being concentrated. The crude product was purified by silica flash chromatography using 15% ethyl acetate in hexanes to yield 4.2 grams (52.8%) of the desired mono-alkylated product. 1H NMR (500 MHz, CDCl3) δ: 1.40 (s, 3 H) 1.78 (s, 1 H) 3.72 (d, J=9.16 Hz, 1 H) 3.82 (d, J=9.16 Hz, 1 H) 3.89 (m, 2 H) 4.64 (s, 2 H) 7.26 (m, 1 H) 7.37 (m, 4 H) 7.72 (s, 2 H) 7.79 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[F:16]C1C=CC=CC=1O.C([Li])(CC)C.[CH:29]([C:31]1[CH:43]=[CH:42][C:34]([C:35]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1)=[O:30]>ClCCl.CO>[Si:9]([O:8][C:3]1[CH:4]=[CH:5][C:6]([F:16])=[C:7]([CH:2]=1)[CH:29]([C:31]1[CH:43]=[CH:42][C:34]([C:35]([N:37]([CH2:38][CH3:39])[CH2:40][CH3:41])=[O:36])=[CH:33][CH:32]=1)[OH:30])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Oc1ccccc1F
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Agent: [Li]C(C)CC
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)cc1
Yield: 34 %

Procedure:
tert-Butyldimethylsilyl 2-fluorophenyl ether (2.73 g, 12 mmol), prepared from 2-fluorophenol by the method in Example 1, was treated with sec-butyllithium (11 mL of 1.1M solution in cyclohexane) and 4-formyl-N,N -diethylbenzamide, (2.46 g, 12 mmol) from Example 11, by the procedure described in Example 29. Chromatography on silica gel with 1% methanol in dichloromethane gave 1.77 g (34%) of 4-(5-(tert-butyidimethylsilyloxy)-2-fluoro-α-hydroxybenzyl)-N,N-diethylbenzamide as a yellow oil that crystallized on standing.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:14]N1C(=O)C2=CC=CC=C2C1=O>[Co+2].C(O)(=O)C>[OH:14][C:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]([C:11]([OH:13])=[O:12])([CH2:8]3)[CH2:2]1)[CH2:4]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [Co+2]
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 75 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 5.07 mol of 1-adamantanecarboxylic acid, 507 mmol of N-hydroxyphthalimide, 5.07 mmol of cobalt (II) acetylacetonato and 12500 ml of acetic acid was stirred at 75° C. under an oxygen atmosphere (1 atm) for 8 hours. The reaction mixture was concentrated, and was subjected to column chromatography on a silica gel (eluent: chloroform/methanol (8/1)), and the obtained purified product was further recrystallized with ethanol/n-hexane to give 3-hydroxy-1-adamantanecarboxylic acid (yield: 38%) at a conversion rate from 1-adamantanecarboxylic acid of 99%.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-:23].[Cs+].[Cs+]>>[CH3:7][N:6]1[C:2]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:20])([F:21])[F:11])=[CH:18][CH:17]=2)=[C:3]([C:9]([OH:10])=[O:23])[C:4]([CH3:8])=[N:5]1
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [Cs+]
Product: Cc1nn(C)c(Oc2ccc(C(F)(F)F)cc2)c1C(=O)O

Procedure:
The title compound was prepared using 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde and 4-(trifluoromethyl)phenol in the manner similar to the method in Production Example 1 above except cesium carbonate was used instead of potassium hydroxide.