Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=2)=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (4.89 g, 12.66 mmol), 3-chlorophenylboronic acid (2.97 g, 18.99 mmol), Pd(PPh3)4 (1.463 g, 1.266 mmol) and 2 M aqueous Na2CO3 (12.66 ml, 25.3 mmol) in 1,2-dimethoxyethane (100 ml) is allowed to stir at 95° C. under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and quenched with brine. The two phases are separated. The mixture is extracted twice with ethyl acetate from the aqueous layer. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 70:30) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (3.33 g); HPLC retention time=1.44 minutes (condition B); MS (ES+)=318.26 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.2 Hz, 3 H) 1.41 (s, 9 H) 2.47 (A of ABX, Jab=15.8 Hz, Jax=5.9 Hz, 1 H) 2.52 (B of ABX, Jab=15.8 Hz, Jbx=5.4 Hz, 1 H) 2.83-2.89 (m, 1 H) 2.95-3.00 (m, 1 H) 4.17 (q, J=7.2 Hz, 2 H) 4.18 (br s, 1 H) 5.07 (br s, 1 H) 7.26-7.37 (m, 4 H) 7.43-7.51 (m, 3 H) 7.55 (br t, J=1.8 Hz, 1 H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].O.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[NH2:7][C:1]1[C:2]2[C:3]3[CH:4]=[CH:5][CH:20]=[CH:21][C:22]=3[C:23](=[O:19])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[S:9][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: C1CCOC1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 17.5 g of methyl 2-cyanomethyl benzoate and 16.2 g of phenyl isothiocyanate in 300 ml of tetrahydrofuran was added 4.8 g of a 60% sodium hydride for 20 minutes under an ice-cooling in a stream of nitrogen, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 18.4 g of methyl bromoacetate for 15 minutes, and then the mixture was stirred for 1 hour. To the reaction mixture was added 4.8 g of a 60% sodium hydride, and the mixture was stirred for 14 hours. The reaction mixture was poured into 3 l of water, and the precipitates were collected by a filtration. The precipitates were successively washed with water and acetone, and air-dried, and dried over phosphorus pentaoxide to obtain 25.3 g of the desired product as brown crystals.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C@@:2]1([C:18]([F:21])([F:19])[F:20])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:9]=[C:4]2[N:3]1[CH2:23][CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCSc1ccccc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCSc1ccccc1

Procedure:
The product is prepared according to the procedure described in Example 1, using 100 mg of (S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (Example 1j) and 143 mg of 2-bromoethylphenyl sulphide, replacing the sodium hydride with caesium carbonate. After purification by silica column chromatography (eluent: dichloromethane/methanol 97/03), 96 mg of (S)-2-methyl-7-morpholin-4-yl-1-(2-phenylsulfanylethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are the following:
Reaction SMILES: [OH-].[K+].CC1C=C(C=CC=1)C([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[CH2:13][CH2:12]1)=O>C(O)C.O>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][OH:9])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cc1cccc(C(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)N2CCC(CO)CC2)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 12.76 g (0.23 mol) of potassium hydroxide in 75 ml of ethanol and 75 ml of water is added to a solution of 80 g (0.23 mol) of [1-(3-methylbenzoyl)-4-piperidyl]methyl 3-methylbenzoate in 400 ml of ethanol. The mixture is stirred at 20° C. for 3 h, the solvent evaporated off under reduced pressure and the aqueous phase extracted with ethyl acetate. The organic phase is washed with water and then with saturated aqueous sodium hydroxide solution, and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure and 53 g of alcohol are obtained, this being used without further treatment in the following stage.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])[CH2:3]1.[C:14]([N:21]1[CH2:24][CH2:23][C:22]1=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][CH:23]2[CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:24]2)[CH2:3]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC1=O
Reactant: N[C@H]1CCN(C(=O)c2nccs2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3nccs3)C2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of compound 1d (diHCl salt, 2.7 g, 10 mmol) and N-Boc azetidinone 1e (2.4 g, 14 mmol) in 1,2-DCE (50 mL) was added slowly Et3N (20 mmol) followed by acetic acid (3.5 mL). To this mixture was added Na(OAc)3BH (3.39 g, 16 mmol). The reaction was stirred at room temperature for 5 h. To the reaction mixture was added aq. NaHCO3, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 80% EtOAc/heptane) gave compound 1f (2.96 g). 1H NMR (300 MHz, CDCl3): δ 7.91 (m, 1H), 7.53 (m, 1H), 4.28 (m, 1H), 4.22-4.11 (m, 2.5; H), 3.91 (m, 0.5; H), 3.83 (m, 1H), 3.73-3.60 (m, 3.5; H), 3.49 (m, 0.5; H), 3.41 (m, 1H), 2.11 (m, 1H), 1.89-1.73 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH3:26][N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C(Cl)Cl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([NH:27][CH3:26])=[O:10])=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a solution of (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (300 mg, 0.88 mmol) in DMF (1.5 mL) and DCM (1.5 mL) was added HATU (401 mg, 1.05 mmol) and triethylamine (0.37 mL, 2.64 mmol) followed by methylamine (0.46 mL, 0.91 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sat NaHCO3 and extracted with EtOAc. The organic layer was washed with water (8 times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 3% 2N Ammonia in MeOH in DCM to give (S)-tert-butyl 3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-ylcarbamate (111 mg). HPLC retention time=1.66 minutes (condition B); MS (m+1)=355.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9H) 2.66 (d, J=4.8 Hz, 3H) 3.01 (d, J=6.3 Hz, 2H) 4.18-4.41 (m, 1H) 5.08 (br. s., 1H) 5.93 (d, J=4.3 Hz, 1H) 7.19 (d, J=8.1 Hz, 2H) 7.22-7.29 (m, 1H) 7.35 (t, J=7.6 Hz, 2H) 7.44 (d, J=8.1 Hz, 2H) 7.48 (d, J=7.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH3:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[NH:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCC(N)CC
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC(CC)CC)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and pentan-3-amine as a pale-yellow solid (78%). 1H NMR (400 MHz, DMSO-d6) δ 0.68 (t, J=8.0 Hz, 6H), 1.27 (s, 6H), 1.31 (t, J=8.0 Hz, 3H), 1.37-1.42 (m, 4H), 2.54 (s, 3H), 3.56-3.61 (m, 1H), 4.16 (s, 2H), 4.30 (q, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.06 (s, 2H). MS 416 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:33][CH:34]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Yield: 90.8 %

Procedure:
Trifluoromethanesulphonic anhydride (4 ml, 23 mmol) was added to a mixture of N-Boc tyrosine methyl ester (5.9 g, 20 mmol) and pyridine (8 ml, 100 mmol) in DCM (30 ml) at 0°. After 30 min the reaction mixture was diluted with water (60 ml) and DCM (100 ml) and washed with aqueous NaOH (0.5M, 50 ml), water (60 ml), citric acid (10% solution, 2×75 ml) and water (60 ml), dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography (SiO2; EtOAc/hexane, 2:1) gave the title compound (7.76 g, 91%) as a colourless oil which solidified on standing. δH (CDCl3) 7.25-7.18 (4 H, m, ArH), 5.01 (1 H, brd, CONH), 4.60 (1 H, brq, CHα), 3.71 (3 H, s, CO2Me), 3.17 (1 H, dd, J 13.8, 5.8 Hz, CHAHBAr), 3.03 (1 H, dd, J 13.6, 6.3 Hz, CHAHBAr) and 1.41 (9 H, s, tBu); m/z (ESI, 15 V) 428 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: OB(O)c1cncnc1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 182.1) and pyrimidin-5-ylboronic acid to afford a light yellow foam. HPLC (Condition 4) tR=5.23 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=464.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (t, J=6.84 Hz, 3H) 3.14 (m, J=7.00 Hz, 2H) 3.32-3.54 (m, 4H) 4.61 (t, J=5.28 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.84 (d, J=1.00 Hz, 2H) 8.10 (dd, J=2.35, 1.17 Hz, 1H) 8.77 (dd, J=2.35, 1.17 Hz, 1H) 9.01 (d, J=0.78 Hz, 2H) 9.19 (d, J=1.17 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[NH2:37])[CH2:21][CH2:20]1.Cl.O1CCOCC1>CO>[N:22]1([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[NH:37][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=2[CH3:18])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-3-methyl-2-phenylquinoline (150 mg, 591 μmol), 2,5-dimorpholinobenzenamine (156 mg, 591 μmol) and 4N hydrochloric acid solution in dioxane (0.15 mL, 591 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.18 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.6, 1.2 Hz), 7.69 (1H, td, J=7.6, 1.2 Hz), 7.59-7.66 (2H, m), 7.41-7.57 (4H, m), 7.23 (1H, s), 7.12 (1H, d, J=8.6 Hz), 6.44 (1H, dd, J=8.6, 2.7 Hz), 6.04 (1H, d, J=2.7 Hz), 3.88-4.01 (4H, m), 3.69-3.80 (4H, m), 3.02-3.16 (4H, m), 2.88-3.00 (4H, m), 2.32 (3H, s). Mass Spectrum (ESI) m/e=481.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=2[NH2:15])=[CH:7][CH:6]=1)=[O:4].C=O.[C:23]([BH3-])#N>CO.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][C:13]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=2[NH:15][CH3:23])=[CH:9][CH:10]=1)=[O:4]
Reactant: [BH3-]C#N
Reactant: COC(=O)c1ccc(COc2cc(C)ccc2N)cc1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccc(C)cc1OCc1ccc(C(=O)OC)cc1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a mixture of 2-(4-methoxycarbonylphenyl)methoxy-4-methylaniline (420 mg) and 37% formaldeyde solution (69.7 mg) in a mixture of methanol (10 ml) and actic acid (0.1 ml) was added soduim cyanoborohydride (146 mg) and the mixture was stirred at amibient temperature for 3 hours. The solution was diluted with ethyl acetate (30 ml) and washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column (chloroform) to give 2-(4-methoxycarbonylphenyl)methoxy-4-methyl-N-methylaniline (356 mg).
Reaction SMILES: C([O:5][C:6](=[O:57])[CH2:7][N:8]([CH2:49][C:50](=[O:56])[O:51]C(C)(C)C)[CH:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:23][C:24](=[O:30])[O:25]C(C)(C)C)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:7][N:8]([CH2:49][C:50]([OH:56])=[O:51])[CH:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:23][C:24]([OH:30])=[O:25])[CH2:31][C:32]([OH:34])=[O:33])[CH2:12][C:13]([OH:15])=[O:14])([OH:57])=[O:5]
Reactant: CC(C)(C)OC(=O)CN(CCN(CC(=O)OC(C)(C)C)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)CN(CCN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 122.5 %

Procedure:
To a flask containing compound 4a (50 mg, 0.0618 mmol) at 0-5° C. was added dropwise 4M HCl (g) in 1,4-dioxane (3 mL) over 10 min. The resulting mixture was gradually warmed to room temperature and continuously stirred for 40 h. Ether (20 mL) was added to the reaction mixture which was then stirred for 10 min. The resulting precipitate was filtered and washed with ether. The solid product was quickly dissolved in deionized water. The aqueous solution was concentrated in vacuo to provide 5a (40 mg, 100%) as an off-white solid. 1H NMR (D2O, 300 MHz) δ 2.63-2.82 (m, 1H), 2.96-3.40 (m, 7H), 3.40-4.05 (m, 11H), 7.39 (d, J=8.1 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H); 13C NMR (D2O, 300 MHz) δ 32.7 (t), 50.2 (t), 50.7 (t), 52.5 (t), 54.0 (t), 54.9 (t), 55.3 (t), 61.1 (d), 124.1 (d), 130.3 (d), 144.5 (s), 146.8 (s), 170.4 (s), 170.9 (s), 173.5 (s).
Reaction SMILES: [CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:25]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:1]([CH:4]1[N:9]([C:22]2[N:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[C:25]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (5.0 mg, 0.02 mmol, prepared according to example 1) in DMSO (1 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (8.7 mg, 0.03 mmol), DIEA (6.6 mg, 0.05 mmol) under N2. The mixture was stirred at 100° C. for 2 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative TLC to afford a racemic mixture of ethyl 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (5.6 mg, 64% yield) as a white solid. LC-m/z 512.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.98 (s, 1H), 8.07-7.98 (m, 1H), 7.93-7.83 (m, 2H), 6.16 (d, J=6.4 Hz, 1H), 5.53-5.41 (m, 1H), 4.43-4.32 (m, 3H), 4.28-4.16 (m, 1H), 3.92-3.79 (m, 1H), 3.09 (s, 3H), 2.61-2.46 (m, 1H), 1.40 (s, 3H), 1.38-1.32 (m, 3H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[Cl:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:19][CH:18]=1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: Clc1ccc(OCCCCCCBr)cc1
Product: CCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(Cl)cc1)c(=O)n2C
Yield: 51 %

Procedure:
3-Methyl-7-propylxanthine and 6-(4-chlorophenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9(a) to give 1-[6-(4-chlorophenoxy)hexyl]-3-methyl-7-propylxanthine (51%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=[CH:8][CH:7]=1.[CH2:12]([O:14]CC)[CH3:13].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>ClCCl>[CH2:7]([O:29][CH:28]([O:14][CH2:12][CH3:13])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH3:8]
Reactant: OCCCCCCCCCCCBr
Reactant: c1cc[nH+]cc1
Reactant: CCOCC
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CCOC(CCCCCCCCCCBr)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 250 ml round bottomed flask, 12.5 g of 11-bromoundecanol was dissolved in 50 ml of dichloromethane. A slurry of 16.2 g pyridiniumchlorochromate (PCC) in 100 ml of dichloromethane was added. The mixture was stirred at room temperature for 2 hours and then poured into 300 ml of diethylether. A brown solid was filtered off and the liquid phase was passed through a short column of silica gel using diethylether as eluent. The organic solvent was evaporated under reduced pressure and the residue was dissolved in absolute ethanol (EtOH) and anhydrous calcium chloride was added together with a small amount of p-toluene sulphonic acid (not shown in Scheme IV). This reaction mixture was left at room temperature over night. The solvent was removed under vacuum and the residue was taken up in diethyl ether and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulphate, filtered, and evaporated until no more solvent came off. The residue was dissolved in 15 ml of ethyl acetate/petroleum ether 1:4 mixture (v/v) and purified using column chromatography with said solvent mixture as eluent. 9.5 g of 11-bromoundecanal diethyl acetal was isolated. The 1H-NMP spectrum of the compound was found to be in accordance with the structure in Scheme IV.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)/[CH:42]=[CH:43]/[C:44](O)=[O:45]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:44](=[O:45])[CH:43]=[CH:42][C:41]1[CH:47]=[CH:48][CH:49]=[C:39]([O:38][CH3:37])[CH:40]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2cccc(OC)c2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 54 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-3-methoxy-cinnamic acid (17.6 mg, 0.099 mmol) gave 31.3 mg (54%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(3-methoxy-phenyl)-N-(4-pentyl-benzyl)-acrylamide. LC-MS: tR=1.01 min; [M+H]+=644.50.