Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][NH2:10])[N:3]=1.COC=[CH:14][CH2:15][C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=O.[CH2:23](O)C>>[NH2:1][C:2]1[N:3]=[C:4]([N:9]2[C:16]([CH2:15][CH3:14])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:23]=[N:10]2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCO
Reactant: COC=CCC(=O)CC(=O)OC
Reactant: NNc1cc(Cl)nc(N)n1
Product: CCc1c(C(=O)OC)cnn1-c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
After suspending 7.79 g portion of 2-amino-4-chloro-6-hydrazinopyrimidine in 100 ml of ethanol, 10.7 g of methyl methoxymethylenepropionylacetate was added thereto, and the mixture was stirred at room temperature for 20 minutes and then at 80° C. for 3 hours. After allowing the reaction solution to stand at 0° C. for 48 hours, the resulting precipitate was collected by filtration and dried to obtain 12.88 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:10])=[C:4]([CH3:9])[CH:5]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: Cc1cc(N)cc(C)c1O
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cc(C)c(O)c(C)c1
Yield: 60.8 %

Procedure:
2,6-Dimethyl-4-aminophenol (0.78 g, 5.69 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.0 g, 3.79 mmol) in dioxan (35 ml) were refluxed under nitrogen for 2.5 hours. The solvent was evaporated, and the residue treated with saturated sodium bicarbonate solution and chloroform. The resulting solid was filtered, washed with chloroform and water, boiled in methanol and filtered again to give the title compound (0.84 g) m.p. 287°-9° (dec).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[H-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18]([N:7]1[C:8]2[C:4](=[C:3]([N+:12]([O-:14])=[O:13])[C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:11])=[O:19]
Reactant: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)n1c(C)cc2c([N+](=O)[O-])c(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-methyl-4-nitro-1H-indole (1.62 g, 7.69 mmol) is dissolved under an atmosphere of argon in dry DMF (30 ml). After addition of a NaH suspension (60% in mineral oil, 369 mg, 9.22 mmol) the mixture is stirred for 1 hour at RT. Methyl chloroformate (0.72 ml, 9.22 mmol) is added slowly during 10 minutes, and the reaction mixture is stirred at RT for 1 hour to form a yellowish suspension. After filtration and drying, the title compound is obtained in pure form. 1H NMR (DMSO, 400 MHz) δ 2.53 (s, 3H), 4.06 (s, 3H), 6.71 (s, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.30 (d, J=9.0 Hz, 1H); ES-MS: 268 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]([Cl:15])=[O:12])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ncc(Cl)c(C(=O)Cl)n1
Yield: 91.7 %

Procedure:
With stirring, 15 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid were added a little at a time to 40.8 g (25 ml, 0.34 mol) of thionyl chloride and 0.47 g (0.5 ml, 6.5 mmol) of N,N-dimethylformamide, and the reaction mixture was then heated under reflux until a marked evolution of gas was no longer noticeable. The mixture is taken up in a little methylene chloride. Concentration gives 15 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carbonyl chloride, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([CH:17]=[CH:16][CH:15]=1)[O:1][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:6]
Reactant: O=C(NCc1ccccn1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)NCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
23.8 g (0.10 mol) of 3-hydroxy-N-(pyridin-2-ylmethyl)-benzamide (stage B of Example 42) are added portionwise to the suspension of 4.5 g (0.10 mol) of sodium hydride (55% dispersion in oil) in 400 ml of N,N-di-methylformamide at 0° C. under argon, followed, after 10 minutes, by 15.4 ml (0.10 mol) of tert-butyl 2-bromo-acetate. The mixture is stirred at ambient temperature for 1 hour. The reaction medium is diluted with ethyl acetate and extracted with water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The white solid is taken up in diisopropyl ether, filtered and dried, to give 26.3 g (74%) of a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([F:9])[CH:3]=1.[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+].[C:16](#[N:18])[CH3:17]>ClCCCN1CCC[C@H]1C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:13][CH2:10][CH2:17][CH2:16][N:18]2[CH2:6][CH2:7][CH2:2][C@H:3]2[CH3:4])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: C[C@@H]1CCCN1CCCCl
Agent: [Cs+]
Product: C[C@@H]1CCCN1CCCOc1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a suspension of 4-bromo-2-fluorophenol (0.57 g) and cesium carbonate (1.6 g) in acetonitrile (2.5 mL), (2R)-1-(3-chloropropyl)-2-methylpyrrolidine obtained in Example 62-(1) (0.40 g) was added and the mixture was heated to 100° C., at which it was stirred for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 3:1) to give the titled compound (0.73 g, 94%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]([F:26])([F:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:11]2=[O:27])=[CH:6][CH:5]=1.[Br:29]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]([F:25])([F:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:12]([Br:29])[C:11]2=[O:27])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-n2c(C)cc(OC(F)(F)c3ccccc3)cc2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccc(-n2c(C)cc(OC(F)(F)c3ccccc3)c(Br)c2=O)cc1
Yield: 85.5 %

Procedure:
Methyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (Step 2) (6.74 g, 17.49 mmol) suspended in acetonitrile (100 mL) was cooled in an ice-bath. N-bromosuccinimide (3.27 g, 18.36 mmol) was added. After 1 hour the ice-bath was removed and after an additional 30 minutes the reaction was diluted with acetonitrile (20 mL). The precipitate was collected by filtration to provide the title compound as an off-white solid (6.94 g, 85%). 1H NMR (300 MHz, CDCl3) δ8.20 (d, J=8.7 Hz, 2H), 7.61 (q, J=7.9 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 7.02-6.96 (m, 1H), 6.90 (app dt, J=2.4, 9.5 Hz, 1H), 6.14 (s, 1H), 5.28 (s, 2H), 3.98 (s, 3H), 2.00 (s, 3H). ES-HRMS m/z 464.0304 (M+H calcd for C21H16BrF2NO4 requires 464.0301).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:19].[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(Br)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with 5-bromo-3-(4-fluorophenoxy)picolinonitrile (10 g, 34 mmol) and sulfuric acid (50 mL). The reaction was stirred at ambient temperature overnight. Water (500 mL) was added carefully and the mixture was adjusted to pH 5.0 using 50% sodium hydroxide. The mixture was extracted with dichloromethane and ethyl acetate, dried and concentrated to afford 5-bromo-3-(4-fluorophenoxy)picolinamide (10.6 g, 34 mmol, 100% yield) as yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CI>O>[CH3:3][O:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(OC)c1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimethylformamide which has been cooled to 0° C. is added dropwise a solution of 0.01 moles of ethyl 3-hydroxy-4-cyclohexylphenylglyoxylate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 3-methoxy-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][CH2:24][O:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18](C)(C)C)CO)=[CH:8][CH:7]=1.S(Cl)(Cl)=O.Br[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([NH2:39])[CH:33]=1.[F-].[Cs+].N[CH:43]1CCCCC1N>[Cu](I)I.C(O)=O>[NH:39]1[C:34]2[CH:33]=[CH:32][C:37]([N:15]3[C@@H:12]([C:9]4[CH:8]=[CH:7][C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:23][CH2:24][O:25][CH3:26])=[CH:11][CH:10]=4)[CH2:18][O:17][C:16]3=[O:22])=[CH:36][C:35]=2[N:38]=[CH:43]1
Reactant: NC1CCCCC1N
Reactant: COCCN(CCOC)c1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: Nc1ccc(Br)cc1N
Agent: I[Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: O=S(Cl)Cl
Solvent: O=CO
Product: COCCN(CCOC)c1ccc([C@H]2COC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized according to method 6 starting from tert-butyl (R)-1-(4-(bis(2-methoxyethyl)amino)phenyl)-2-hydroxyethylcarbamate (0.350 g, 0.951 mmol), thionyl chloride (0.55 mL, 7.608 mmol), 4-bromo-1,2-diamino benzene (111 mg, 0.598 mmol), cesium fluoride (165 mg, 1.08 mmoles) and copper iodide (15 mg, 0.081 mmoles), 1,2-diaminocyclohexane (0.06, 0.598 mmoles) formic acid (5 mL). Yield: 0.04 g (10.8%). MS m/z 411.4 (M+H)+; 1H-NMR 400 MHz, CDCl3): δ 7.89 (d, 1H); 7.60-7.45 (m, 2H); 7.26-7.11 (merged with CDCl3, 3H); 6.61 (d, 2H); 5.60 (t, 1H); 4.77 (t, 1H); 4.33 (t, 1H); 3.60-3.49 (m, 8H); 3.32 (s, 6H), HPLC (λ=214 nm, [A]: rt 10.09 min (96%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.C(N(C(C)C)CC)(C)C.[Br:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][C:41](=[O:42])[CH2:40][Br:39])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: O=C(Cl)CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran (12 mL) was added diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction mixture was stirred at ambient temperature for about 15 minutes then 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 hours then additional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred for an additional 15 minutes then concentrated under reduced pressure to provide the title compound as a brown solid. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C)=O)[CH2:11]3)[CH2:9][N:8]([C:20](=[O:28])[NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:5]2=[CH:6][CH:7]=1.[CH3:29][NH2:30].O1CCCC1.N.CO>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:30][CH3:29])=[O:18])[CH2:11]3)[CH2:9][N:8]([C:20]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:28])[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Reactant: CN
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 45, with the exceptions that the methyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate obtained in Example 58 was used instead of ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate, and that a solution of methylamine-tetrahydrofuran was used instead of a saturated solution of ammonia-methanol.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13](Cl)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Mg].C(Br)C.[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21].[CH3:25][NH2:26]>C1COCC1.Cl>[CH3:25][NH:26][C:19](=[O:23])[C:20]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:21]
Reactant: Clc1ccccc1Oc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CNC(=O)C(=O)c1ccccc1Oc1ccccc1

Procedure:
In a stream of nitrogen gas, 2-chlorodiphenyl ether (10.23 g, 0.05 mol) in dry THF (20 ml) was dropwise added to a mixture of magnesium (1.34 g, 0.055 mol) and ethyl bromide (0.19 ml) in dry THF (15 ml) under reflux over 30 minutes. After further reflux for 6 hours, the reaction mixture was diluted with dry THF (15 ml) and cooled below 20° C. This mixture was dropwise added to oxalyl chloride (7.62 g, 0.06 mol) in dry THF (100 ml) at -10° to 0° C. over 15 minutes, followed by stirring at -10° to 0° C., and methylamine gas was introduced into the mixture, followed by stirring at room temperature for 15 minutes. After completion of the reaction, in 1N HCl (100 ml) was added to the reaction mixture which was then extracted with toluene (300 ml). The extract was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give N-methyl-2-(2-phenoxyphenyl)-2-oxoacetamide (8.07 g) as colorless crystals. The mother liquor was purified by silica gel chromatography (ethyl acetate/hexane) to give the objective compound (1.42 g). The total yield was 9.49 g (74%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:9][C:7]=2[CH:8]=1)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:9][C:7]=2[CH:8]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C#N)cc3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The tert-butyl 4-[2-(aminocarbonyl)-1-benzofuran-5-yl]piperazine-1-carboxylate (85 mg, 0.246 mmol) was dissolved in 5 mL of DCM and cooled to 0° C. under nitrogen. Triethylamine (0.075 mL, 0.541 mmol) was added, followed by trifluoroacetic anhydride (0.038 mL, 0.271 mmol). The reaction was stirred for 1 hour, then was diluted with additional 20 mL of DCM and washed with water (2×40 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford tert-butyl 4-(2-cyano-1-benzofuran-5-yl)piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:24])=[C:11]([CH:15]([C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.C[C:37]1(C)[CH2:42][CH2:41][CH2:40][C:39](C)(C)[NH:38]1.ClC1C=NC=C[N:48]=1.C(OC1C(F)=C(C=CC=1)C=O)C1C=CC=CC=1>C1COCC1>[NH2:48][C:22]1[C:17]2[N:18]([C:39]([CH:40]3[CH2:41][CH2:42][CH2:37]3)=[N:38][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:24])[CH:19]=[CH:20][N:21]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: Clc1cnccn1
Reactant: OC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl
Agent: O=Cc1cccc(OCc2ccccc2)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
(3-Benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl) carbinol: In a 100 mL three-necked round-bottom flask equipped with a N2-inlet and a thermometer was placed THF (28 mL). This was cooled to −40° C. and there was added 2.5 M solution of n-BuLi in hexane (11.52 mL, 28.8 mmole) followed by 2,2,6,6-tetramethylpiperidine (4.84 mL, 28.8 mmole). The temperature of the mixture was allowed to rise to 0° C. and stirring was continued at −5 to 0° C. for 30 minutes. The mixture was then cooled to −70° C., and the chloropyrazine (1.28 mL, 14.4 mmole) was added slowly over 15 minutes and the stirring was continued for 30 minutes. A solution of 3-benzyloxy-2-fluorobenzaldehyde (3.04 g. 13.2 mmole) in THF (7 mL) was then added at −70° C. and stirring was continued at −70 to −60° C. for 2 h. There after the temperature was allowed to rise to room temperature over 1 h. The reaction mixture was quenched with 2 N HCl (6 mL) and stirred overnight at room temperature. The mixture was then evaporated on a rotary evaporator to remove most of the THF. Ethyl acetate (20 mL) was added to the residue. The organic layer was separated, washed with water (10 mL), finally with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude residue obtained was 4.4 g. The above reaction was repeated four times and the products were combined. This was purified by silica-gel column chromatography using as the eluent ethyl acetate:hexane (30:70) and the title compound (3.8 g, 21%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:11][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
87.5 g of 2,4-dichlorobenzaldehyde are added slowly to a solution of 50 g of pinacolone in 200 ml of ethanol and 1 ml of sodium hydroxide solution (50% by weight), keeping the internal temperature at 30° C. or below. The mixture is stirred at 20° C. for 24 hours and then the precipitate is filtered off with suction and dried. 105.5 g (82%) of tert-butyl 2,4-dichlorostyryl ketone are obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 936.7 %

Procedure:
In analogy to example 1 were reacted 6.36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 4.38 g (2 mmol) of lauroyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 9.4 g (94%) dodecanoic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:51]=[C:52]([CH:57]=[CH:58][CH:59]=1)[O:53][CH2:54]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:54][O:53][C:52]2[CH:57]=[CH:58][CH:59]=[C:50]([F:49])[CH:51]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCOc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCOc4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 31.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (55 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (83 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(3-fluorophenoxy)-1-ethanol (43 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (28 mg, yield 29%).