Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(OS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-butyl-6-benzenesulphonyloxy-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[C:28](Cl)(=[O:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:28](=[O:30])[CH3:29])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[N:12]O)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[ClH:15].[H][H]>C(O)C.[Pd]>[ClH:15].[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH2:12])[C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[CH3:2]
Reactant: CCOC(=O)C(=NO)C(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)C(F)(F)F
Yield: 61.8 %

Procedure:
A stirred solution of 4,4,4-trifluoro-2-hydroxyimino-3-oxo-butyric acid ethyl ester (55 g, 0.258 mol) in ethanol (140 ml) was added with palladium on activated carbon and 4N hydrochloric acid (90 ml) accordingly. The reaction mixture was stirred in a Parr shaker under 0.3 MPa of hydrogen at room temperature for 2.5 hours. The reaction mixture was filtered, the filtrate was concentrated to give 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (37.56 g, 61.8%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:6]3[C:5]4[C:9](=[N:10][C:2]([Cl:1])=[N:3][C:4]=4[Cl:11])[N:8]=[CH:7]3)=[CH:27][CH:26]=2)=[O:24])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3nc(Cl)nc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
To a solution of 2,6-dichloropurine (3.25 g) in DMF (34 ml) was added potassium carbonate (2.85 g) as well as 4-(4-chlorobenzoyl)benzyl bromide (5.32 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1-1:3) to provide the title compound (1.37 g, 19%) as colorless (anhydrous) powder. 1H-NMR (CDCl3) δ5.76(2H,s), 7.21-7.85(8H,m), 8.33(1H,s).
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]([CH3:13])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:14][Mg]Cl.O>O1CCCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:13])[CH:10]2[CH3:14])[CH2:5][CH:4]=1
Reactant: C[Mg]Cl
Reactant: C[N+]1=Cc2cc(N)ccc2CC1
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CC1C2=CC(N)=CCC2CCN1C
Temperature: -78 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(±) 7-Amino-2-methyl-3,4-dihydroisoquinolinium iodide (0.50 g, 1.7 mmol) was suspended in anhydrous tetrahydrofuran (50 ml) and cooled to −78° C. The cooled solution was treated with methyl magnesium chloride (2.14 ml of a 3M solution in THF, 6.96 mmol), added as a single portion. The reaction was allowed to reach 25° C. over 18 h before being poured into water (50 ml). The organic solvent was removed in vacuo and the organic product extracted into dichloromethane. Drying over magnesium sulfate and evaporation in vacuo furnished the title compound as a pale yellow oil (0.3 g, 98%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:14]([CH3:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CN1C(=O)CCC1>[CH3:23][C:14]1[O:9][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[N:10][C:15]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Product: Cc1oc(-c2ccc([N+](=O)[O-])cc2)nc1-c1ccccc1
Temperature: 135 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
a mixture of 4-nitrobenzamide (6.1 g, 37 mmol) and 2-bromopropiophenone (5.233 g, 25 mmol) in 3 mL NMP was heated to 135° C. After 2 hours at 135° C., the reaction was removed from the oil bath and ca. 30 mL of toluene was added. The resulting mixture was equilibrated to room temperature. After 15 minutes the precipitate was removed by filtration, rinsing with toluene, and discarded. The filtrate was concentrated under reduced pressure and the concentrate taken up in 50 mL ethyl acetate. A precipitate developed and was collected by filtration, rinsing the solid with ethyl acetate and drying under vacuum to afford yellow crystals (1.5 g, 22%). ESI+ m/z=281.0 [MH]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1.C1(C(C2CCCCC2)N2CCNCC2)CCCCC1.C1[O:44]C1>>[OH:44][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1
Reactant: ClCCN1CCN(C(C2CCCCC2)C2CCCCC2)CC1
Reactant: C1CO1
Agent: C1CCC(C(C2CCCCC2)N2CCNCC2)CC1
Product: OCCN1CCN(C(C2CCCCC2)C2CCCCC2)CC1

Procedure:
For example, 1-(2-chloroethyl)-4-dicyclohexylmethylpiperazine can be prepared by reacting N-dicyclohexylmethylpiperazine with ethylene oxide, to form 1-(2-hydroxyethyl)-4-dicyclohexylmethylpiperazine, which is subsequently treated with a chlorinating agent, such as thionyl chloride, to produce the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](OC)=[O:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(CO)c2ccccc21
Reaction time: 2 h
Yield: 102.4 %

Procedure:
To a solution of methyl 1-(tert-butoxycarbonyl)-1H-indole-3-carboxylate (2.5 g, 9.08 mmol) in anhydrous tetrahydrofuran (40 ml) was added 1.5 M diisobutylaluminum hydride-toluene solution (14 ml, 21 mmol) under ice-cooling, and the mixture was stirred for 2 hrs. An aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.3 g, 100%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cc(Cl)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(Br)c(OCc2ccccc2)c1
Yield: 97.8 %

Procedure:
A mixture of 2-bromo-5-chlorophenol (3.93 g, 18.94 mmol), benzyl bromide (3.42 g, 20 mmol) and potassium carbonate (10 g, 72.46 mmol) in acetone (80 ml) was stirred and refluxed for 3 hours then cooled, evaporated and dissolved in ether/water. The organic phase was dried (magnesium sulphate) evaporated and purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:99) to give 5.51 g of white solid.
Reaction SMILES: [CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH3:6])[OH:4].C[O-].[Na+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO.Cl>[CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH3:6])([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])=[O:4]
Reactant: COP(O)C(C)NC(=O)OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCP(=O)(OC)C(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a stirred solution of 0.36 gm (0.0014 mol) of 1-benzyloxycarbonylaminoethylphosphonous acid methyl ester in 3 ml of methanol at 0° C. was added a solution of sodium methoxide in methanol (0.77 ml of a 2N solution) dropwise over 10 minutes whereupon was then added methyl acrylate 0.126 ml (0.0014 mol). The reaction mixture was stirred 30 minutes at 0° C. and 4 hours at room temperature whereupon it was diluted with 1N HCl. The mixture was extracted twice with ethyl acetate. The organic fractions were dried over sodium sulfate, filtered through magnesium sulfate and evaporated in vacuo. The product mixture was purified by chromatography (silica, 9:1, ethylacetate:acetonitrile) to give 0.34 gm of methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-1-ethyl]phosphinate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].C(O)(=O)C.[CH3:20][C:21]([CH3:23])=O>>[C:1]([O:5][C:6]([NH:7][N:8]=[C:21]([CH3:23])[CH3:20])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Product: CC(C)=NNC(=O)OC(C)(C)C

Procedure:
To a solution of tert-butylcarbazate (50.0 g, 378 mmol) in 40 mL acetone is added 10 g MgSO4 and 5 mL acetic acid and the reaction mixture is stirred at reflux temperature for 1 h. The reaction mixture is filtered and concentrated in vacuo. The residue is crystallized from diethyl ether/cyclohexane. Yield: 49.4 g.
Reaction SMILES: C[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[CH2:25](Cl)Cl.CCOC(C)=O.CCCC(C)C>>[CH3:25][C:7]1[CH:2]=[N:3][C:4]2[N:5]([C:8]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[N:6]=1
Reactant: Cc1cnn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Reactant: ClCCl
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: Cc1cnc2ncc(-c3cccc(-c4ccccc4C#N)c3)n2n1

Procedure:
1H NMR (400 MHz, CDCl3) δ 2.72 (3H, s), 7.50 (1H, td, J 7.6, 1.3 Hz), 7.59-7.67 (3H, m), 7.70 (1H, td, J 7.7, 1.4 Hz), 7.82 (1H, dd, J 7.8, 1.0 Hz), 8.14 (1H, dt, J 7.6, 1.6 Hz), 8.29 (2H, m), 8.37 (1H, s); MS (ES+) m/z 312 [M+H]+. 3′-(3-Methylimidazo[1,2-b][1,2,4]triazin-7-yl)biphenyl-2-carbonitrile: mp 211-216° C. (CH2Cl2-EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 2.73 (3H, s), 7.50 (1H, td, J 7.6, 1.3 Hz), 7.59-7.66 (3H, m), 7.70 (1H, td, J 7.7, 1.4 Hz), 7.82 (1H, dd, J 7.8, 1.4 Hz), 8.10 (1H, dt, J 7.6, 1.5 Hz), 8.29 (2H, t, J 1.4 Hz), 8.26 (1H, s), 8.36 (1H, s); MS (ES+) m/z 312 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:41])(=[O:40])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH:37]1[CH2:39][CH2:38]1)[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:40])(=[O:41])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH:37]1[CH2:39][CH2:38]1)[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 31).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][N:21]=[CH:22]3)[CH:6]=1.C(O)(=O)C>CO.[Pt](=O)=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)[CH:6]=1
Reactant: Cc1cn(-c2cc(C(F)(F)F)ccc2-c2cccc3cnccc23)cn1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C(F)(F)F)ccc2-c2cccc3c2CCNC3)cn1
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A solution of 5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)isoquinoline (1.435 g, 4.06 mmol) in 15 mL MeOH was treated with platinum(IV) oxide (0.092 g, 0.406 mmol) and acetic acid (0.697 ml, 12.18 mmol) and was placed under 45 psi (4559.6 kpa) H2 for 3 hours. The reaction mixture was filtered through a plug of diatomaceous earth eluting with EtOAc. The filtrate was concentrated then purified directly be reverse phase column chromatography [RediSep Gold C18 150 g, 5 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding 5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.808 g, 2.261 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.C(=O)(O)[O-].[Na+].[C:26]1(B2OCCCO2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[C:13]3[N:12]=2)[N:3]=1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: c1ccc(B2OCCCO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)c1
Temperature: 110 °C
Yield: 80.4 %

Procedure:
350 mg of 2-[2-(amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine (compound 4) are dissolved in 5.6 ml of anoxic dioxane under a nitrogen atmosphere. Subsequently, 3.15 ml of an aqueous sodium bicarbonate solution (2.0 M), 193 mg of 2-phenyl-1,3,2-dioxaborinane, and 49 mg of trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 46 hours. Thereafter, the volatile components are removed in vacuo and the remaining residue is redissolved in 200 ml of a mixture of water/dichloromethane (1:1). The aqueous phase is extracted twice each with 125 ml of dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield a colorless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 8:1) to afford 279 mg of the title compound as a colorless solid of m.p. 230° C. MS: 330.3 (MH+). TLC: Rf=0.34 (dichloromethane/methanol 8:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10.0 g of 1-(2,4-dimethoxy-benzyl)-2,3-dioxopiperazine, 1.66 g of sodium hydride (60%, oil) and 100 ml of N,N-dimethylformamide was stirred at 50° C. for 30 minutes and then cooled to room temperature. To the reaction mixture was added 3.6 ml of methyl bromoacetate, after which the resulting mixture was stirred at the same temperature for 30 minutes and added to a mixed solvent of 200 ml of ethyl acetate and 200 ml of ice water, and the pH was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with five 50-ml portions of ethyl acetate. The combined organic layer was washed with 50 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=10:1) to obtain 10.7 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].CS(C)=O.[H-].[Na+].S(OCC1CCC=CC1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=O)=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:22][CH:21]1[CH2:23][CH2:24][CH2:18][CH:19]=[CH:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Reactant: CCCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOCCOCC1C=CCCC1
Reaction time: 8 h

Procedure:
A 500 niL round bottom flask equipped with a mechanical stirrer was charged with 16.7g (0.15 mol) 2-butoxyethanol, and 150 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 3 hrs, 39.9 g (0.15 mol) of 3-cyclohexene-1-methanol tosylate was slowly added to the above mixture over 20 min. The reaction was carried at room temperature overnight, then 80° C. for 3 hrs. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 mL), washed with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)cc1
Yield: 44.4 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 4.42 g (25.8 mmol) p-bromoaniline was heated to reflux under N2 for 3 hours. Removed heat and added saturated sodium bicarbonate until basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, and air dried. Washed with water and dried in vacuo. Boiled in 1.4 liters ethyl acetate, and without completely dissolving all solids, stirred with Darco, and filtered. Stripped solvent and dried in vacuo, giving 3.524 g of yellow solid: mass spectrum (electrospray m/e): M+H=369, 370.9.
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[ClH:10].N1C=CC([C:16]([NH2:18])=[NH:17])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:10].[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:16]([NH2:18])=[NH:17])[CH2:3]2
Reactant: N=C(N)c1cc[nH]n1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)N[C@H]1CN2CCC1CC2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)-3-aminoquinuclidine (5.85 g, 46.4 mmol) and pyrazole carbox-amidine hydrochloride (6.80 g, 46.4 mmol) is added Hunig's base (8.07 ml, 46.4 mmol) and DMF (30 ml). The reaction is heated at 70° C. for 40 hours. The reaction is then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separates out as a white solid, which is filtered, washed and dried (8.94 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:2].[C:16]12([NH:26][C:27](=[O:35])[NH:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.CCN=C=NCCCN(C)C.CN(C1C=CN=CC=1)C>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][NH:28][C:27]([NH:26][C:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:24]3)[CH2:23]1)[CH2:25]2)=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCCCCCCCO
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCOC(=O)CCCCCCCCCOC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 60 %

Procedure:
A mixture of 10-hydroxydecanoic acid (0.25 g, 1.33 mmol; 11-hydroxyundecanoic acid for compound 881 and 12-hydroxydodecanoic acid for compound 882), ethyl bromide (0.16 g, 1.46 mmol), and lithium carbonate (0.11 g, 1.46 mmol) in DMF (25 mL) was stirred at 70 C for 6 h. Then the product was extracted with ether (30 mL), and the ether solution was washed with 1 N NaOH aqueous solution (20 mL) and water (30 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to give 10-hydroxydecanoic acid ethyl ester (80 mg, 28%). This alcohol was coupled with 4-(3-adamantan-1-yl-ureido)butyric acid 822 by using EDCI/DMAP coupling reagent to give 880 (0.11 g, 60%) as a solid: 1H NMR (CDCl3) 1.24-1.32 (13H, m), 1.62-1.68 (10H, m), 1.80 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J=6.9 Hz), 2.36 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05-4.14 (5H, m), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C27H46N2O5 [M+H]+ 479.34. found [M+H]+ 479.29; mp 60-61 C. Anal. Calcd for C27H46N2O5: C, 67.75; H, 9.69; N, 5.85. Found: C, 68.33; H, 9.92; N, 5.97.