Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[N+:9]([O-])[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[N:9][C:10]([Cl:22])=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)N1C(=O)c2cc([N+](=O)[O-])c[n+]([O-])c2C1=O
Product: CC(C)(C)N1C(=O)c2cc([N+](=O)[O-])c(Cl)nc2C1=O

Procedure:
100 ml of phosphoryl chloride were treated with 7.5 g (0.028 mol) of N-tert-butyl-5-nitropyridine-2,3-dicarboximide-1-oxide at 60° C. and in portions in the course of 2 minutes with stirring and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in methylene chloride and the solution was stirred into ice-water. The organic phase was extracted in succession with water, saturated sodium hydrogencarbonate and sodium chloride solution and dried. After filtering off with suction through neutral alumina, it was concentrated and the residue was stirred with ether and ether/pentane, filtered off with suction and dried. 4.49 g (56% of theory) of the title compound of m.p. 100-104° C. were obtained (active compound Example 1.019).
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[N:13][C:14]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[C:19]([Cl:32])[CH:18]=2)[NH:9][N:8]=1>O.C(O)C>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:14]2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][N:8]=[C:7]([O:6][CH2:5][CH2:4][NH:2][CH3:1])[C:15]=23)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: CN
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Solvent: O
Solvent: CCO
Product: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 120 °C
Yield: 14 %

Procedure:
Methylamine in water (40% solution, 2 ml) was added to a suspension of 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12/0.4 g, 0.89 mmol) in ethanol (4 ml) and the reaction mixture was heated at 120° C. for 5 minutes in a microwave reactor. The resulting solution was concentrated in vacuo and the residue purified by chromatography using DCM to DCM-10% methanol/7N ammonia as eluant to give the title compound as a white solid (57 mg, 14%); Mass Spectrum: 443.3 (MH+/retention time 1.5 minutes).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5].[Mg].[Cl:9][C:10]1[C:11]2[C:12](=[O:23])[C:13]3[N:14]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1.[Cl-].[NH4+]>CCOCC.ClCCCl>[Cl:9][C:10]1[C:11]2[C:12]([OH:23])([CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5])[C:13]3[N:14]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1C2=NCCCN2c2cccc(Cl)c21
Reactant: COC(C)CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COC(C)CCC1(O)C2=NCCCN2c2cccc(Cl)c21

Procedure:
A solution of 1-bromo-3-methoxybutane (6.0 g) in dry ether (20 ml) was added dropwise under a nitrogen atmosphere to magnesium turnings (0.9 g) at such a rate as to maintain gentle reflux. After stirring at reflux for 0.5 hour the reaction mixture was chilled in ice and a solution of 9-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.5 g) in dry 1,2-dichloroethane (100 ml) was added dropwise. After stirring the reaction mixture for one hour at room temperature it was cooled and excess saturated ammonium chloride solution was added dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform. The extracts were combined with the organic phase, dried (MgSO4) and the solution evaporated under reduced pressure to leave an oil which was triturated with ether to give a solid. Recrystallisation from ethyl acetate gave the title compound as colourless needles m.p. 164°-5°. Treatment of a solution of these needles in methanol with ethereal hydrogen chloride, followed by evaporation in vacuo gave a solid which was recrystallised from propan-2-ol to give the title compound as the hydrochloride, colourless crystals (2.81 g) m.p. 264°-5°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Product: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 5, from (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide and 4-bromo-2-methylpyridine was prepared the title compound as yellow solid, MS (ESI+): m/z=394.0797 ([M+H]+, 1Br).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1C=C(C(C)(C)C)[C:23](O)=[C:22]([C:31](C)(C)C)[CH:21]=1.CC1C=CC(C=[S:42])=CC=1>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[S:42][CH:23]=[C:22]([CH3:31])[CH:21]=1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Reactant: Cc1ccc(C=S)cc1
Product: COc1c(O)c(C(=O)C=Cc2cc(C)cs2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyldimethylmethyloxyacetophenone (starting material 1) and 4-methylthiobenzaldehyde according to general method 2 described earlier.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH2:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-Hydroxyindole (1.00 g, 7.29 mmol) and potassium carbonate (1.38 g, 9.94 mmol) were taken up in 20 mL of dimethylformamide (DMF) and stirred at 60° C. for 0.5 hours. Allyl bromide (0.57 mL, 6.62 mmol) was added and the reaction was stirred for an additional 18 hours then cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (10% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[K+].[K+].[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1>O.C(Cl)(Cl)Cl>[I:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:1]=[S:2])=[C:14]([CH3:19])[CH:13]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(I)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To a stirred mixture of 9.9 g (0.086 mole) of thiophosgene, 5.0 g (0.036 mole) of potassium carbonate in 55 ml of water and 100 ml of chloroform was added a solution of 20.0 g (0.0862 mole) of 4-iodo-2-methylaniline in 50 ml of chloroform. Additional potassium carbonate was added to make the reaction mixture basic. An additional 9.9 g of thiophosgene was added, and the reaction mixture was stirred at room temperature for approximately 18 hours. The mixture was partitioned between water (100 ml) and chloroform (100 ml). The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride to yield 22.6 g of 4-iodo-2-methylphenyl isothiocyanate as a solid, mp 51°-53° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.2 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.50 g, 4.22 mmol), 1-bromoundecane (1.31 ml, 6.33 mmol) and potassium carbonate (874 mg, 6.33 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.78 g (yield: 85.2%)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) in dichloromethane (50 mL) was added thionyl chloride (3.8 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4-bromo-2-methylbenzyl chloride (9.8 g). To a suspension of sodium hydride (60%, 2.1 g) in tetrahydrofuran (90 mL) was added ethyl 4-methyl-3-oxopentanoate (7.5 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 1 hour. 4-Bromo-2-methylbenzyl chloride (9.8 g) was added to the reaction mixture, and the resulting mixture was stirred at 70° C. for 3 days. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a solution of the residue in toluene (20 mL) was added hydrazine monohydrate (5.4 mL), and the mixture was stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was treated with n-hexane-diethyl ether (10/1) to crystallize. The crystals were collected by filtration and washed with n-hexane, water and n-hexane successively, and dried under reduced pressure to give the title compound (12.4 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (41 mg, 39%), MS (ISP) m/z=421.2 [(M+H)+], mp 131° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and ethanesulfonyl chloride.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[Cl:16][C:17]1[N:18]([C:22]2[CH2:26][CH2:25][CH2:24][N:23]=2)[CH2:19][CH2:20][CH:21]=1>>[ClH:16].[N:23]1[CH2:24][CH2:25][CH2:26][C:22]=1[N:18]1[CH2:19][CH2:20][CH:21]=[C:17]1[N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: C1=C(N2c3ccccc3Oc3ccccc32)N(C2=NCCC2)CC1

Procedure:
Reaction of phenoxazine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 257.5°-263° C. (corr.), from ethanol-ether.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:9]=[N:10][C:3]=12
Reactant: Ic1ccnc2[nH]cnc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(I)ccnc21

Procedure:
850 mg (3.47 mmol) of 7-iodo-3H-imidazo[4,5-b]pyridine was dissolved in 3.5 mL DMF. 153 mg (3.82 mmol) of 60% sodium hydride was added followed by 670 μL (3.82 mmol) of trimethylsilylethoxymethyl chloride. Yield: 424 mg of an oily product, 90% pure.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]([O:8][C:9]([NH:11][CH:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]1[CH2:16][NH:15][CH2:14]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C.[Pd]>[C:21]([O:20][C:18]([NH:17][CH:12]([NH:11][C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH:13]1[CH2:14][N:15]([CH2:1][CH3:2])[CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)C1CNC1
Reactant: CC=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CC(C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of acetaldehyde (1.5 g) and 3-[bis-(tert-butoxycarbonyl-amino)methyl]azetidine (Intermediate 151, 1.0 g) in ethanol (20 mL) was stirred at room temperature for 30 minutes and then 10% palladium on carbon (0.3 g) was added. The mixture was stirred under an atmosphere of hydrogen overnight. The solid was filtered off and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) to give 3-[bis-(tert-butoxycarbonylamino)methyl]-1-ethylazetidine (0.83 g) as a colourless liquid, which was used without further characterization.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][NH:17][CH3:18]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][N:17]([CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:18]
Reactant: CNC
Reactant: COC(=O)c1oc2ccccc2c1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1oc2ccccc2c1CN(C)C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a solution of methyl 3-bromomethylbenzofuran-2-carboxylate (269 mg, 1.0 mmol) in DMF was added dimethylamine (2M solution in THF, 1.5 ml, 3 mmol). The reaction mixture was stirred for 1-2 h, diluted with ethyl acetate (50 ml), washed twice with saturated aqueous sodium bicarbonate solution (50 ml) and finally with brine (50 ml). The organic extract was dried over sodium sulfate and then concentrated in vacuo. Purification by flash chromatography on silica gel (5% methanol in dichloromethane) gave methyl 3-dimethylaminomethylbenzofuran-2-carboxylate (131 mg, 0.57 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and piperidine. Brown solid. MS (ESI): 381.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH:11]=[O:12].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([CH:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1c(Cl)cnc2[nH]ccc12
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: OC(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (3.0 g, 16 mmol, Adesis) in THF (100 mL) at about 0° C. was added cyclohexylmagnesium chloride (2 M in Et2O, 22.8 mL, 45.7 mmol). The reaction mixture was stirred at ambient temperature for about 2 h, then additional cyclohexylmagnesium chloride (2 M in Et2O, 8.3 mL, 16.6 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 h. Water (10 mL) was added to quench the reaction and the volatiles were removed under reduced pressure. The product was extracted into DCM (3×20 mL) and the combined organic phases were dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure and the crude material was purified by chromatography over silica gel using a gradient of 10 to 45% EtOAc in heptane as the eluent to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanol as an off white solid (1.97 g, 45%): LC/MS (Table 2, Method a) Rt=2.32 min; MS m/z: 265 and 267 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:15][C:14]([CH3:28])([CH3:27])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O.[Pd](Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:15][C:14]([CH3:28])([CH3:27])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)cc2O1
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C=Cc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
7.8 g (20 millimoles) of 6,7-dibenzyloxy-2,2-dimethyl-4-chromanone are dissolved in 100 ml of a 1:1 mixture of tetrahydrofurane and water, whereupon 5.3 g (30 millimole) of palladium chloride and 8.31 g (220 millimoles) of sodium tetrahydroborate are added. The reaction mixture is stirred at 0° C. for 3 hours, filtered, and the filtrate is extracted three times with 100 ml of ether each. The ether extracts are evaporated, the residue is dissolved in 300 ml of dichloro methane and allowed to stand at 35° C. in the presence of 15 ml of pyridine and 2 g of phosphorous oxychloride for an hour. The reaction mixture is poured into 100 ml of water washed with 5% hydrochloric acid and water. The organic phase is dried and evaporated. The residue is crystallized from methanol. Thus 6 g of the desired compound are obtained, yield 81%. Mp.: 50°-51° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18](O)(=[O:20])=[O:19])=[CH:16][CH:17]=1>CCO.O=[Pt]=O>[C:12]1([CH3:11])[CH:17]=[CH:16][C:15]([S:18]([O:10][CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: OCCCc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCCC2CCNCC2)cc1
Reaction time: 6 h
Yield: 112.1 %

Procedure:
To a solution of 3-(4-pyridyl)propan-1-ol (15.13 g, 0.1103 mol) in EtOH (100 mL) was added p-TsOH (20.98 g, 0.1103 mol) and PtO2 (1.5 g, 6.6 mmol). The resulting mixture was placed on a Parr apparatus and hydrogenated at 55 p.s.i. After 6 hr, the mixture was filtered (EtOH wash) and the filtrate concentrated in vacuo, giving 36.78 g (>100%) of the desired piperidine; 1H NMR (300 MHz, CDCl3) δ 7.7 (d, 2H), 7.2 (d, 2H), 3.55 (t, 2H), 3.3 (m, 4H), 2.95 (bt, 2H), 2.38 (s, 3H), 1.95 (bd, 2H), 1.58 (m, 2H), 1.3 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH2:13][CH2:14][CH3:15])[CH3:30]
Reactant: CCCNCCCCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(CCCCNC(=O)OC(C)(C)C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (339.0 mg) obtained in Example 84-1 was dissolved in chloroform (5.1 ml) and added with triethylamine (0.41 ml). Ethyl bromoacetate (0.20 ml) was dropped to the solution and the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (273.9 mg) as a colorless oily substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(#N)C>[OH:10][CH2:9][CH2:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: OCCCC1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCCC1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
3-(2-Piperidinyl)-1-propanol (8.69 g, 60.7 mmol) was stirred in acetonitrile (90 ml) with triethylamine (10.40 mL, 74.6 mmol) under N2 and cooled in an ice bath. Benzyl chloroformate (9.53 ml, 66.7 mmol) was added dropwise. After complete addition the reaction was allowed to warm to ambient temperature and stirring then continued overnight. The suspension was filtered and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, passed through a hydrophobic frit and evaporated to dryness. The residue was purified by chromatography on silica (330 g silica RediSep column, loaded in DCM) using a 0-50% ethyl acetate in cyclohexane gradient over 40 mins. with a 50-100% flush of ethyl acetate on an ISCO Companion. No peaks were detected (254 nm, 280 nm) so the waste was evaporated in vacuo to recover the material. The material was re-columned using identical conditions as before but detecting at 220 nm and collecting all the eluent. The main product peak was collected and evaporated in vacuo to give the title compound as a yellow oil (6.15 g).