Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:28][CH3:29])[CH:8]=[C:9]([C:12]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([O:28][CH3:29])[CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3[Br:1])=[CH:26][CH:25]=1
Reactant: COc1cc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(Br)ccnc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(Br)ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed (4-bromo-8-methoxyquinolin-6-yl)bis(4-chlorophenyl)methanol (6 g, 12.27 mmol, 1.00 equip), dichloromethane (200 mL), triethylsilane (8 mL), and trifluoroacetic acid (24 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with saturated sodium bicarbonate (3×100 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:1) to yield 6-[bis(4-chlorophenyl)methyl]-4-bromo-8-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 474 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[Br:13][CH2:10][C@@H:9]([CH3:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](CO)Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](CBr)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of (2S)-3-(4-chlorophenyl)-2-methylpropan-1-ol (300 mg) in DCM (20 mL) were added N-bromosuccinimide (347 mg) and triphenylphosphine (511 mg) under ice-cooling. The reaction liquid was stirred at room temperature for 2 hours, and then the reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over MgSO4, and then vehicle was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain 1-[(2S)-3-bromo-2-methylpropyl]-4-chlorobenzene (373 mg) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23].Cl.C(N1CCCCC1)C>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: CCN1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
11.0 grams of N,N-dicyclohexylbodiimide was added to a solution of 12.45 grams of benzyloxycarbonyl proline and alanine methyl ester released from 7.0 grams of the corresponding hydrochloride using 7 ml of N-ethyl piperidine in 40 ml of methylene chloride cooled to -5 degrees C. The resultant reaction suspension was stirred for 1 hour at 0 degree C. N,N-dicyclohexylurea separated from the suspension and was filtered off after it was allowed to stand for 12 hours at 3 degrees C. Then, the filtrate was successively washed with 1M hydrochloric acid, water, 5% sodium hydrogen carbonate, with water, dried with anhydrous sodium sulfate and evaporated. A solid evaporation residue was crystallized from 100 ml of ethyl acetate and 500 ml of petroleum ether. 12.2 g of a product having a melting point of 45 to 49 degrees C. was obtained.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1)=[O:3].CS(C1N2C(=O)C3NC=NC=3N(CCCCC)C2=NN=1)(=O)=O.[Br:44]N1C(=O)CCC1=O>C1COCC1.O>[Br:44][C:12]1[NH:11][C:10]2[C:9](=[O:21])[N:8]3[C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(S(C)=O)nnc12
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCn1c2nc[nH]c2c(=O)n2c(S(C)(=O)=O)nnc12
Solvent: O
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(S(C)=O)nnc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one and 3-(methylsulfonyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (3:2, 125 mg, 0.40 mmol) in THF (3 mL) was added N-bromosuccinimide (82.3 mg, 0.462 mmol). The mixture was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H15BrN6O2S (M+H) 387.0. found: 387.0, 389.0.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-methylphenyl isocyanate (0.152 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 120 mg (38.8%) of the desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:21])([F:22])[F:23])[CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Temperature: 80 °C

Procedure:
To a stirred solution of 6-hydroxyindan-1-one (1.48 g, 10 mmol) in 30 ml of DMF was added 3-chloro-4-fluorobenzotrifluoride (2.46 g, 12 mmol) and cesium carbonate (8.40 g, 25 mmol). The reaction mixture was heated at 80° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with ethyl acetate (2-40%) in hexane. The final product was collected as brownish yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[C:19]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)(=[O:21])[CH3:20].C(N(CC)CC)C>C(O)C>[C:19]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][N:26]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:25]1)(=[O:21])[CH3:20]
Reactant: CC(=O)CNC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NCC(C)=O)C3)nc21
Yield: 98.4 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (5.41 g), 3-(N-acetylmethylamino)pyrrolidine (4.26 g), triethylamine (6.06 g), and ethanol (100 ml) was heated under reflux for 2 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water (70 ml) and acetic acid (15 ml). After cooling the mixture, the precipitate was collected, washed with water, and recrystallized from dimethylformamide. There were obtained 7.4 g of 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 287°-289° C.
Reaction SMILES: Cl.[BH4-].[Na+].[Br:4][C:5]1[C:6]([O:26][CH3:27])=[CH:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[N:13][N:12]=[C:11]([CH3:24])[CH2:10][C:9]=2[CH:25]=1>CO.O>[Br:4][C:5]1[C:6]([O:26][CH3:27])=[CH:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[N:13][NH:12][CH:11]([CH3:24])[CH2:10][C:9]=2[CH:25]=1
Reactant: COc1cc2c(cc1Br)CC(C)=NN=C2c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
3.5 ml (43.2 mmol) of concentrated hydrochloric acid is first added, and then over about 10 minutes, 1.80 g (47.5 mmol) of sodium borohydride is added in portions to a suspension of 1.4 g (3.6 mmol) of 7-bromo-4-methyl-8-methoxy-1-(4-nitrophenyl)-5H-2,3-benzodiazepine (Example 3, Step C) in 60 ml of methanol. The suspension is stirred for another hour, and then diluted with water (60 ml). The crystalline material is suctioned off and washed with 50% aqueous methanol (3×50 ml). The 7-bromo-4-methyl-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine that is obtained as a crude product is further purified by suspension in 8 ml of hot ethanol. After suctioning-off, 1.23 g (88%) of chrome yellow crystals with a melting point of 172-174° C. is obtained.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH2:18])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5].[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH:18][C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC(=O)Cl
Reactant: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Product: CCCCCOc1ccc2c(c1)C=C(CNC(=O)CCC)CO2

Procedure:
0.37 g (1.5 mmol) of the amine obtained in Step F of Example 55 is condensed with butanoyl chloride according to the same procedure as in Example 54. Purification on a silica column (eluant: ethyl acetate/petroleum ether 50/50) allows isolation of the title amide in the form of a yellowish solid.
Reaction SMILES: [NH2:1]C1C=CN=CC=1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[C:16](=[O:17])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:1]
Reactant: Nc1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a solution of 4-aminopyridine (2.00 g, 21.2 mmol) in CH2Cl2 (30 mL) at 0° C. was added triethylamine (3.50 mL, 25.0 mmol) and benzyl chloroformate (3.10 mL, 22.0 mmol). The ice bath was removed and the resulting mixture was allowed to warm to rt overnight before being poured into saturated aqueous NaHCO3. The product was extracted with CH2Cl2, dried (Na2SO4) and concentrated. The crude product was recrystallized from EtOAc to give 2.90 g (60% yield) of pure benzyl carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]([CH:14]([CH3:16])[CH3:15])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccc(Br)cc1)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromobenzylbromide (5.0 g), N,N-diisopropylamine (7.85 ml) and potassium carbonate (2.76 g) in dimethylformamide (50 ml) was stirred at 80° C. for 2 hours. To the mixture was added water, and the mixture was extracted with ether. The extract was washed with water, dried (MgSO4) and concentrated to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CSc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(N)nc(N)c1N=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-Methylthio-pyrimidine-2,4-diamine (50.0 g; 321 mmol) in water (1000 mL) was added 500 mL of 2N acetic acid. The mixture was warmed to 50° C. and NaNO2 solution was added (24.0 g; 353 mmol in 200 mL H2O) rapidly. After 1 hr at 50° C., the deep Blue/purple mixture was allowed to cool to room temperature and filtered. The blue/purple solid was washed several times with water and finally washed with ether. The solid was allowed to air dry to give 51.0 g of 6-Methylthio-5-nitroso-pyrimidine-2,4-diamine 2 as blue/purple solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([OH:45])=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54]O)[CH:47]=1>C(Cl)Cl>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:45][CH2:54][CH2:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1
Reactant: OCCCc1cccnc1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Diethyl azodicarboxylate (340 mg, 2 mmol) was added dropwise to a solution of triphenylphosphine (520 mg, 2 mmol), 4-chloro-7-hydroxy-6-methoxyquinoline (265 mg, 1.26mmol), (prepared as described for the starting material in Example 3), and 3-(3-pyridyl)-1-propanol (170 mg, 1.24 mmol) in methylene chloride (10 ml). The mixture was stirred for 1 hour at ambient temperature. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (50/45/5 increasing to 50/40/10). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(3-(3-pyridyl)propoxy)quinoline (300 mg, 72%).
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#[N:2].F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C>[C:37]([CH2:36][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:4]2[CH2:3][C:1]#[N:2])[CH2:35][CH2:34]1)#[N:38]
Reactant: N#CCC(N)=O
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-Cyanoacetamide (11 mg, 0.13 mmol) and triethyloxonium tetrafluoroborate (21 mg, 0.11 mmol) in THF (0.13 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (55 μL) and added to a suspension of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (8.9 mg, 0.031 mmol) in ethanol (0.20 mL). The mixture was stirred at 85° C. for 2 h. The mixture was purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the desired product (2.7 mg, 26%) as TFA salt. LCMS calculated for C18H18N5S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: I[CH2:2][C:3]([O:5][CH:6]=[CH2:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[C:29]1([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)C>[CH:6]([O:5][C:3](=[O:4])[CH:2]=[CH:40][C:39]1[CH:38]=[CH:37][C:36]([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:43][CH:42]=1)=[CH2:7]
Reactant: C=COC(=O)CI
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=COC(=O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 6 °C
Reaction time: 16 h

Procedure:
A 100 mL round bottom flask equipped with a nitrogen inlet-outlet, magnetic stirrer and addition funnel was charged with vinyl iodoacetate (5.6 g, 26 mmol) and triphenylphosphine (6.9 g, 26 mmol) in 50 mL anhydrous tetrahydrofuran. The reaction mixture was blanketed with nitrogen and allowed to stir for 16 h and then cooled to 6° C. on an ice-water bath. Sodium hydride (1.0 g, 25 mmol) was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for 4 h, 4-diphenylaminobenzaldehyde (5.4 g, 20 mmol) dissolved in 40 mL anhydrous THF was added dropwise to the stirring reaction mixture over 30 minutes. After stirring at room temperature for five days, the reaction mixture was diluted with 50 mL diethyl ether and transferred to a separatory funnel. An additional 300 mL diethyl ether was added to the separatory funnel and the combined ether solution was washed three times with 100 mL water and one time with 100 mL saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated on a rotary evaporator. The residue was further dried on a high vacuum line to yield the crude product as a brown oil. After purification by flash column chromatography (silica gel; 3:7 dichloromethane:hexanes) 5.5 g of the pure product was obtained as a light yellow oil. The product yield was 81%.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:35][C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(c1)CCCC2N(Cc1ccncc1)Cc1nc2ccccc2[nH]1
Reaction time: 18 h
Yield: 70.2 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (120 mg, 0.32 mmol) and 4-pyridinecarboxaldehyde (30 μL, 0.32 mmol) in CH2Cl2 (5 mL) was added sodium triacetoxyborohydride (136 mg, 0.64 mmol) and the reaction stirred for 18 h. The resulting crude material was taken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture was extracted with CH2Cl2 (3×10 mL) then the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) afforded the title compound (83 mg, 70%) as a white solid. 1H NMR (CDCl3) δ 1.68-1.72 (m, 1H), 1.97-2.06 (m, 2H), 2.26-2.30 (m, 1H), 2.74-2.77 (m, 1H), 2.80-2.86 (m, 1H), 3.77 (s, 2H), 3.92 (d, 1H, J=16 Hz), 4.09 (dd, 1H, J=9.7 Hz), 4.17 (d, 1H, J=16 Hz), 7.18-7.22 (m, 3H), 7.36 (d, 2H, J=6 Hz), 7.44 (dd, 1H, J=7.1 Hz), 7.52 (br d, 1H, J=7 Hz), 7.66 (br d, 1H, J=7 Hz), 8.46 (dd, 2H, J=5.2 Hz), 8.70 (dd, 1H, J=5.1 Hz); 13C NMR (CDCl3) δ 21.2, 23.8, 29.0, 49.1, 53.0, 60.5, 110.9, 118.8, 121.4, 121.9, 122.5, 123.3, 133.7, 134.7, 137.4, 144.2, 146.9, 148.7, 149.8, 155.4, 156.9. ES-MS m/z 370 (M+H). Anal. Calcd. for C23H23N5.0.2H2O.0.2CH2Cl2: C, 71.44; H, 6.15; N, 17.95. Found: C, 71.63; H, 6.30; N, 17.77.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CC(C)=O.[SH2]=N.[C:11]1([NH:17][C:18](C2C=CC=CC=2C(O)=O)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:11]1([NH:17][C:18]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)NC(=O)Nc1ccccc1
Yield: 81.4 %

Procedure:
A solution of 0.75 g i-propylamine with 5 ml aceton was added dropwise to a suspension of 1,5 g phenylcarbamoyl-benzoic acid sulfimide with 10 ml acetone, under stirring. The reaction mixture was stirred for 30 minutes at ambient temperature, then diluted with 50 ml water and cooled. The 0.75 g crystalline 1-phenyl-3-i-propylurea was isolated by filtration (melting point: 158°-160° C.).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]([O:47][CH3:48])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]=1[O:49][CH3:50]>>[CH3:50][O:49][C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([O:47][CH3:48])=[CH:46][C:37]=1[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1

Procedure:
(ff) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow syrup; MS: 689 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:12]=1.C(N(CC)CC)C.[H][H]>[Pd].CO>[N:12]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Clc1ccc2c(n1)CCNCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: c1cnc2c(c1)CCNCC2

Procedure:
Under a hydrogen atmosphere 0.125 g (0.49 mmol) 2-chloro-6,7,8,9-tetrahydro-5H-pyri do[2,3-d]azepine, 30 mg palladium on charcoal (10%) and 0.28 mL triethylamine in 4 mL methanol were hydrogenated at RT under 50 psi hydrogen pressure for 6 h. The catalyst was removed and the filtrate was concentrated to dryness. The residue was used without further purification. Yield: 72 mg (99% of theory). ESI-MS: m/z=149 (M+H)+; Rt(HPLC): 0.52 min (Method J).