Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([O:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:21][CH:17]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([O:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])=[C:2]([F:1])[CH:3]=1)[CH:18]([CH3:20])[CH3:19])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(OCOC)c1ccc(C(O)C(C)C)cc1F
Product: CCCCC(OCOC)c1ccc(C(OC(C)=O)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 1-[3-fluoro-4-[1-(methoxymethoxy)pentyl]phenyl]-2-methylpropanol (104 mg), acetic anhydride (66 mg) and N,N-dimethylaminopyridine (2 mg) was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (85:15) to give 1-[3-fluoro-4-[1-(methoxymethoxy)pentyl]phenyl]-2-methylpropyl acetate (113 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:14]=[C:13]([Br:12])[CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Brc1cccc(Br)c1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Clc1ccc(Oc2cccc(Br)c2)cc1
Temperature: 165 °C
Reaction time: 21 h
Yield: 29.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 13.6 grams (0.106 mole) of 4-chlorophenol in 50 mL of diglyme was stirred, and 24.1 mL (0.106 mole) of methanolic 25% sodium methoxide was added dropwise. Upon completion of addition, the reaction mixture was heated to about 165° C. to remove methanol. After the methanol was removed, the heating was ceased, and 25.0 grams (0.106 mole) of 1,3-dibromobenzene and 1.3 grams of cuprous bromide were added. Upon completion of the additions, the reaction mixture was heated to reflux where it was stirred for about 21 hours. The reaction mixture was then cooled and filtered. The filter cake was washed with diethyl ether, and the wash was combined with the filtrate. The combination was extracted with two 20 mL portions of aqueous 20% sodium hydroxide and then with two 75 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under vacuum, yielding about 9.0 grams of 3-(4-chlorophenoxy)phenyl bromide, bp 110° C./0.5 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:10][CH2:9]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:19]([O:18][C:16](=[O:17])[N:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH2:13][CH2:12]1)[CH3:15])([CH3:20])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.57 g (4.82 mmol) 4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-but-2-enoic acid ethyl ester and 200 mg of Pd/C (10%) in 20 ml of MeOH was stirred at RT under H2-atmosphere for 3 h. After filtration, the solution was concentrated under reduced pressure to dryness, to give 1.58 g of clean trans-4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-butyric acid ethyl ester. 1.58 g (4.82 mmol) trans-4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-butyric acid ethyl ester in 20 ml of THF, was treated at RT with 390 mg of LiAlH4. After stirring the solution for 30 min at RT, the excess of LiAlH4 was destroyed by adding dropwise 10 ml of saturated brine under ice-cooling. The reaction mixture was partitioned between Et2O/1M HCl and H2O. The ether-solution was concentrated in vacuo, to give 1.37 g (99%) of pure trans-[4-(4-Hydroxy-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/C=C/CCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OC/C=C/C=C/CCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of ethyl (2E,4E)-7-phenylhepta-2,4-dienoate (7.32 g) in dry toluene (75 ml) was cooled to −78° C. DIBAL-H (1M in hexanes, 65.2 ml) was added dropwise and the mixture was stirred for 3 h. The mixture was allowed to warm-up to room temperature and hydrolyzed with 1M aqueous HCl with cooling in ice/water bath. Additional, 3M aqueous HCl was added until pH=1. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to yield a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].Cl.Cl.[CH:10]1([C:16]2[NH:20][C:19](=[O:21])[C:18]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.N#N>C(Cl)Cl>[CH:10]1([C:16]2[NH:20][C:19](=[O:21])[C:18]3([CH2:22][CH2:23][N:24]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:25][CH2:26]3)[N:17]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C1NC(C2CCCCC2)=NC12CCNCC2
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
2-Chloro-ethanesulfonyl chloride (440 μl, 4.21 mmol) was added to a solution of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (1.50 g, 3.24 mmol) and triethylamine (2.7 ml, 19.4 mmol) in CH2Cl2 (30 ml) at room temperature in an N2 atmosphere. The mixture was stirred at room temperature for 30 minutes, and then washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with AcOEt-hexane, and the solid was then collected by filtration and dried to give 2-cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a colorless solid (692 mg, 66%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15](=O)[C:14]3=[CH:18][C:19]([S:21][CH3:22])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C(#N)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]=[C:15]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:14]3=[CH:18][C:19]([S:21][CH3:22])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:23]=1
Reactant: CSc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CSc1cc2n(c1)Cc1cc(Cl)ccc1N=C2N1CCNCC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Add phosphoryl chloride (5 equiv; 2.21 mL, 3.64 g, 23.76 mmoles) to 7-chloro-2-(methylsulfanyl)-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1.38 g, 4.75 mmoles) in chloroform (20 mL) and heat and stir at 45° C. for 2 h. Raise the temperature of the reaction to 60° C. and stir for a further 2 h. Remove the chloroform in vacuo and dissolve the residue in DCM (100 mL) and wash with saturated sodium bicarbonate solution (100 mL). Filter the DCM layer through a phase separation frit and evaporate the solvent in vacuo to give a viscous oil. Dissolve the oil in acetonitrile (10 mL) and add cesium carbonate (3 equiv; 4.65 g, 14.26 mmoles). Add to this mixture piperazine (10 equiv; 4.09 g, 47.52 mmoles) in dry acetonitrile (10 mL) and heat and stir the mixture under reflux overnight. Cool the reaction mixture and add saturated ammonium chloride solution (100 mL) and extract into EtOAc (2×50 mL). Combine the organic layers and wash with water (3×100 mL), dry over MgSO4, filter and evaporate the solvent in vacuo to give 7-chloro-2-(methylsulfanyl)-11-(piperazin-1-yl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.0 g, 60%). MS (m/z): 347.13 (M+1).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:9][C@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To D-alanine tert-butyl ester hydrochloride (1 g) in methylene chloride (35 ml) solution, triethylamine (1.7 ml) and 4-chlorobenzenesulfonyl chloride (1.1 g) were added under ice cooling and the mixture was stirred at room temperature for 2 hours. The methylene chloride was distilled off in vacuo, then the residue was diluted with ethyl acetate. The obtained solution was successively washed with distilled water, saturated potassium hydrogensulfate aqueous solution, and saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The residue was recrystallized from ethyl acetate/hexane to obtain the title compound (1.47 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 49G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(N(CC)CC)C>[C:1]([O:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:17][CH:16]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 64.6 %

Procedure:
From the reaction of 52.3 g (0.5 m) methacryloyl chloride and 76.6 g (0.5 m) of p-nitrobenzyl alcohol and 50.6 g triethylamine was isolated 71.5 g (64.5%) of p-nitrobenzyl methacrylate as pale-yellow crystals, mp--87°-88° C.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:7]([O:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)C(N)=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(OC(=O)c1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a solution of 2-hydroxypropionamide (10.8 g, 121 mmol) in pyridine (40 mL) was added benzoyl chloride (14.2 mL, 122 mmol) at 0° C. and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure to give a residue. To the residue an aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extracts were washed with an 1N hydrochloric acid twice and brine. The organic solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (17.9 g, yield 77%).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:4][CH:3]=[CH:2][CH2:1]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: C/C=C\C
Solvent: Cc1ccccc1
Product: C1=CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 171.7 g (1.6 mol) of benzylamine was added dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 57.0 g of 1-benzyl-3-pyrroline (yield 89.5%) was obtained.
Reaction SMILES: [N+:1]([O-:17])([O:3][CH2:4][CH:5]([O:13][N+:14]([O-:16])=[O:15])[CH2:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][OH:10])=[O:2].[C:18](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:19][C@@H:20]1[CH2:24][O:23][C@@H:22]2[C@H:25]([OH:28])[CH2:26][O:27][C@H:21]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:18](=[O:29])([O:19][C@@H:20]1[CH2:24][O:23][C@@H:22]2[C@H:25]([OH:28])[CH2:26][O:27][C@H:21]12)[O:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][CH:5]([O:13][N+:14]([O-:16])=[O:15])[CH2:4][O:3][N+:1]([O-:17])=[O:2]
Reactant: CC(C)(CCO)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCOC(=O)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (0.962 g, 3.10 mmol) in DCM (40 ml), (prepared as described in EXAMPLE 7, Step C), 6-hydroxy-4,4-dimethylhexane-1,2-diyl dinitrate (0.780, 3.10 mmol) and 4-dimethylaminopyridine (0.379 g, 3.10 mmol) were added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (2×30 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: [N:1]1([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Nc1ccc(-n2cnc3cnccc32)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2cnc3cnccc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
The 4-(imidazo[4,5-c]pyridin-1-yl)aniline prepared in Step B was dissolved in 10 mL of dichloromethane, and 30 mg (0.137 mmol) of 4-chloro-3-(trifluoromethyl)phenyl isocyanate was added thereto and the mixture solution was stirred at room temperature for three hours. The solvent was distilled under reduce pressure, and the obtained crude product was recrystallized from ethyl acetate to obtain 35.0 mg (51%) of 1-(4-chloro-3-(trifluoromethyl)-phenyl)-3-(4-imidazo[4,5-c]pyridin-1-ylphenyl)urea (Table 1, Compound No. 1) as a colorless crystal.
Reaction SMILES: Br[CH:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1([O:10][CH2:11][CH2:12]Cl)C.[CH2:14]([Li])CCC>C1COCC1>[CH3:14][C:7]1[C:2]2[CH2:12][CH2:11][O:10][C:3]=2[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: CC1=CC(C)(OCCCl)C(Br)C=C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 1-bromo-2-(2-chloroethoxy)-2,4-dimethylbenzene obtained in Reference Example 217 (8.70 g, 33.0 mmol) in THF (210 mL) was quickly added n-butyllithium (1.6 M hexane solution, 31 mL, 49.5 mmol) under argon atmosphere at 0° C., and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, to which ice was added, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, was filtered, and then was concentrated under reduced pressure to obtain 4.70 g (yield 96%) of the title compound. Oily matter.
Reaction SMILES: [C:1]1(C)[CH:6]=CC=C[CH:2]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.CC(C)=O>[Pt].O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:1]([CH3:6])[CH3:2])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccccc1
Agent: [Pt]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 42.5 °C
Reaction time: 2 h

Procedure:
520 parts of toluene, 423 parts (3 mol) of 4-fluoronitrobenzene, 192 parts (3.3 mol) of acetone and 8 parts of catalyst (5% Pt on charcoal, water-moist, water content 50%) are placed in a hydrogenation autoclave. After the gas space has been flushed three times with each of nitrogen and hydrogen, the mixture is heated to from 80°=0 to 85° C. with stirring and reduced at a hydrogen pressure of from 0.2 to 1.0 MPa. When after about 2 hours the uptake of hydrogen falls sharply, the pressure is raised to 2.0 MPa and stirring is continued at 85° C for 30 minutes until there is no longer any drop in pressure. The batch is cooled to 60° C., the autoclave is let down and flushed with nitrogen, and the catalyst is filtered off on a pressure filter at from 50° to 60° C. The aqueous phase is separated off from the filtrate and toluene is distilled off until the water content of the solution is <0.02%. The solution is processed further in accordance with Example 2.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:23](Br)([CH3:25])[CH3:24]>CN(C)C=O>[CH:23]([N:3]1[N:2]=[N:1][C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4]1)([CH3:25])[CH3:24]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nnc(-c2cnc3ccccn3c2=O)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of 0.9 g (0.0042 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 25 ml of dimethylformamide, 1.15 g (0.0084 moles) of anhydrous potassium carbonate and 1.1 ml (0.0126 moles) of isopropyl bromide was stirred at 90° C. for 1 hour. The hot yellow solution was filtered, the filtrate evaporated. To the crystalline residue 25 ml of water was added, and the crystals were collected. 0.6 g (55.8%) of the title compound was obtained, in the form of white crystals, m.p.: 146°-148° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][CH2:13][C:14]1[CH2:31][N:29]2[CH2:30][C@H:16]([CH2:17][C@:18]([C:65]([O:67][CH3:68])=[O:66])([C:32]3[CH:33]=[C:34]4[C@:42]56[C@@H:46]7[C@:47]([CH2:62][CH3:63])([C@@H:51]([O:58][C:59]([CH3:61])=[O:60])[C@:52]([OH:57])([C:53]([O:55][CH3:56])=[O:54])[C@@H:41]5[N:40]([CH3:64])[C:35]4=[CH:36][C:37]=3[O:38][CH3:39])[CH:48]=[CH:49][CH2:50][N:45]7[CH2:44][CH2:43]6)[C:19]3[NH:27][C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]=3[CH2:28]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:12][CH2:13][C:14]1[CH2:31][N:29]2[CH2:30][C@@H:16]([CH2:17][C@:18]([C:65]([O:67][CH3:68])=[O:66])([C:32]3[CH:33]=[C:34]4[C@@:42]56[C@@H:41]([N:40]([CH3:64])[C:35]4=[CH:36][C:37]=3[O:38][CH3:39])[C@@:52]([OH:57])([C:53]([O:55][CH3:56])=[O:54])[C@H:51]([O:58][C:59]([CH3:61])=[O:60])[C@:47]3([CH2:62][CH3:63])[CH:48]=[CH:49][CH2:50][N:45]([C@H:46]53)[CH2:44][CH2:43]6)[C:19]3[NH+:27]([O-:6])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[CH2:28]2)[CH:15]=1
Reactant: CCC1=C[C@@H]2CN(C1)Cc1c([nH]c3ccccc13)[C@@](C(=O)OC)(c1cc3c(cc1OC)N(C)[C@H]1[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]4(CC)C=CCN5CC[C@]31[C@@H]54)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1=C[C@H]2CN(C1)CC1=C([NH+]([O-])c3ccccc31)[C@@](C(=O)OC)(c1cc3c(cc1OC)N(C)[C@H]1[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]4(CC)C=CCN5CC[C@]31[C@@H]54)C2
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Vinorelbine N′b-oxide was synthesized using essentially the same procedure used to prepare vinblastine N′b-oxide. m-Chloroperoxybenzoic acid (45 mg, 0.26 mmol) in CHCl3 (2.5 mL) was added at 0° to a stirred solution of purified vinorelbine (150 mg, 0.20 mmol) in CHCl3 (4.5 mL) under nitrogen. After 15 min, the mixture was poured into an aqueous sodium carbonate (27 mL, 40 g/L) and was extracted by CHCl3 (20 mL). After drying over sodium sulfate and filtration, the CHCl3 extract was evaporated under reduced pressure affording crude vinorelbine N-oxide (125 mg, 83%). Thin-layer chromatography (silica; 9:1 CHCl3/MeOH) indicated the presence of a small amount of starting vinorelbine (vinorelbine Rf=0.37, vinorelbine N′b-oxide Rf=0.18). Radial chromatography on silica gel (eluent, 9:1 CHCl3/MeOH) gave vinorelbine N′b-oxide as an off-white solid (100 mg; 75%). The sample was dissolved in ethyl acetate/hexanes and then the open flask was placed in a sealed container containing an open flask of hexanes. As the hexanes diffused slowly into the vinorelbine N′b-oxide solution, vinorelbine N′b-oxide precipitated out as an off-white powder (80 mg; 53%). The 300 MHz 1HNMR spectrum was consistent with the assigned structure. The configuration of the N′b-oxide oxygen atom is assigned the same stereochemistry as that found in vinblastine N-oxide by x-ray crystallography.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:20][CH3:21])=[N:12][C:13]([CH3:19])=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])[C:11]([O:20][CH3:21])=[N:12][C:13]=1[CH3:19])([CH3:17])[CH3:18]
Reactant: COc1nc(C)c(C(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc(C(C)C)c(C)nc2OC)CC1
Yield: 64 %

Procedure:
Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.