Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][NH:2]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20](O)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:2]2[CH2:3][CH2:4][NH:5][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:1]23)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1CCC2NCCNC2C1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCCC21

Procedure:
The title compound of Example 15 base (0.49 g, 3.5 mmol) was coupled with 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol) as described in Example 5 to give the amide as a crystalline solid: mp 119-120° C. (2-propanol); 1H-NMR (CDCl3) σ 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 4.48 (m, 1H), 3.66 (br s, 2H), 3.64 (m, 1H), 3.29 and 2.87 (m, 1H), 2.64-2.85 (complex m, 2H), 2.41 and 2.09 (m, 1H), 1.93-2.06 (complex m, 2H), 1.40-1.87 (complex m, 5H), 1.12-1.36 (complex m, 2H); Anal (calcd for C16H20Cl2N2O): C 58.72, H 6.16, N 8.56. Found: C 58.80, H 6.17, N 8.52.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:21]([Li])[CH2:22][CH2:23]C.C(I)C=C.[Cl-].[NH4+]>O1CCCC1.O>[CH2:23]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:8]([O:17][CH2:18][O:19][CH3:20])([C:9]([F:12])([F:11])[F:10])[C:13]([F:14])([F:15])[F:16])[CH:6]=1)[CH:22]=[CH2:21]
Reactant: COCOC(c1ccc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: [Li]CCCC
Agent: C=CCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Cl
Yield: 63.9 %

Procedure:
To a solution of 2-chloro-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)pyridine (50 mg, 0.155 mmol) in tetrahydrofuran (2 mL), butyllithium (71 μL, 1.70 mmol) was added under −78° C. and the resultant mixture was stirred for 0.5 hour. Allyl iodide (71 μL, 0.773 mmol) was added under −78° C. and the resultant mixture was stirred at room temperature for 1 hour. The reaction solution was added with a saturated aqueous solution of ammonium chloride and water under room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (36 mg, yield 64%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[C:9]([NH:11][CH2:12][C@H:13]([CH:26]([CH3:28])[CH3:27])[CH2:14][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH2:17])=[O:10].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:37].[Mg+2]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[C:9]([NH:11][CH2:12][C@H:13]([CH:26]([CH3:27])[CH3:28])[CH2:14][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[C@@H:16]1[CH2:17][O:37]1)=[O:10]
Reactant: C=C[C@H](C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C)NC(=O)OC(C)(C)C
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1)C(C)C
Reaction time: 72 h

Procedure:
The solution of 1.48 g of tert-butyl (3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methyl-1(S)-vinylpentyl)carbamate in 30 ml of methanol is admixed with 7.81 g of magnesium monoperoxyphthalate and stirred over 72 hours. The reaction mixture is poured onto water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf=0.30 (1:1 EtOAc-heptane, run 2×); Rt=18.64 (gradient II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C=O.C([O-])(=O)C.[NH4+:13].[C:14](O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>C(O)(C)C>[NH2:13][CH:14]([C:5]1[CH:6]=[N:1][CH:2]=[CH:3][CH:4]=1)[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: NC(CC(=O)O)c1cccnc1

Procedure:
Scheme I describes a synthesis of a pyridyl β-amino acid which can be used to synthesize compounds of the present invention wherein R1 is pyridyl. The reaction can be modified using conventional methodology to prepare other aroma substituted or heterocyclic substituted β-amino acids by substitution of the pyridyl carboxaldehyde with any other appropriate aldehyde. Briefly, in Scheme I to pyridine-carboxaldehyde in isopropanol is added ammonium acetate followed by malonic acid. The reaction mixture is stirred at reflux, the resulting precipitate filtered and washed with hot isopropanol and dried to yield 3-amino-3-(3-pyridyl)propionic acid. The ethyl ester is synthesized by heating this acid in excess ethanol in the presence of excess HCl gas.
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[CH:44]1([NH:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[C:50]=2[Cl:56])[CH2:46][CH2:45]1>>[CH:7]([OH:8])=[O:6].[CH:44]1([N:47]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[C:50]=2[Cl:56])[C:36]([C:15]2[C@@H:14]3[NH:9][C@H:10]([CH2:17][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=2)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]3)=[O:37])[CH2:45][CH2:46]1
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: Clc1cccc(CNC2CC2)c1Cl
Product: CC(=O)N1C[C@H]2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)[C@@H](C1)N2
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and cyclopropyl-(2,3-dichlorobenzyl)amine. LC-MS: Rt=0.92; ES+: 672.22.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-nitrophenylhydrazine as described for compound 35. Crystallized from methanol. M.p. 179°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:20]2[N:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)[CH:26]=3)[N:21]=2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cc1nnc(-c2ccc3nc(Nc4ccc(OCc5cccc(F)c5)cc4)ncc3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 4-(3-fluoro-benzyloxy)aniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.71(1H, bs), 9.40(1H, s), 8.90(1H, s), 8.58(1H, d), 8.09(1H, d), 7.66(2H, d), 7.47(1H, m), 7.33(2H, m), 7.15(3H, m), 5.21(2H, s), 2.65(3H, s); m/z (M+1+) 428.
Reaction SMILES: [CH:1]1([NH:5][C@H:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[CH:1]1([N:5]([C@H:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:32](=[O:33])[C:31]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:30]=2[O:29][CH3:28])[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-(cyclobutylamino)cyclopentyl]carbamate (400 mg, 1.573 mmol) in dry DCM (5.3 ml) was added DIPEA (1.3 ml, 7.86 mmol) and 2,6-dimethoxybenzoyl chloride (CAS number 1989-53-3; 473 mg, 2.359 mmol). The reaction was stirred at room temperature for 1 hour and was then partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 4 h
Yield: 100.6 %

Procedure:
A solution of hydrochloric acid (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[(E)-2-phenylvinyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (40 mg, 0.084 mmol) in 5:1 dichloromethane-methanol (2.5 mL) at 0° C. After 4 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-diethyl ether, filtered, washed with pentane and dried under reduced pressure to provide a light yellow solid (33 mg, 76%). MS (LCMS) m/z 391.4 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3H) 2.30-2.42 (m, 1H) 2.56-2.69 (m, 1H) 3.08 (s, 3H) 3.93-4.06 (m, 1H) 4.32 (td, J=11.76, 4.98 Hz, 1H) 6.75 (s, 1H) 7.00 (d, J=6.24 Hz, 1H) 7.11 (d, J=16.39 Hz, 1H) 7.30-7.42 (m, 3H) 7.47 (d, J=16.39 Hz, 1H) 7.62 (d, J=7.02 Hz, 2H) 7.75 (s, 1H)
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH2:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.[C:22]1([C@H:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:1]([O:4][CH2:5][C@@H:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:11][CH:12]=1)[NH:20][C:29](=[O:30])[C@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:32])(=[O:3])[CH3:2]
Reactant: CCCC(C)COc1ccc([C@@H](N)COC(C)=O)cc1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)COc1ccc([C@H](COC(C)=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of (2R)-2-amino-2-(4-(2-methylpentyloxy)phenyl)ethyl acetate.HCl (400 mg, 1.432 mmol) and (S)-2-phenylpropanoic acid (323 mg, 2.15 mmol) in tetrahydrofuran (8 mL) at 0° C. was added N,N-diisopropylethylamine (0.875 mL, 5.01 mmol) followed by HATU (817 mg, 2.15 mmol). The cooling bath was removed and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (25 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30%→45% ethyl acetate in hexanes; 40 g column) and dried under vacuum to afford (2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethyl acetate (430 mg, 73.0% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.22-7.37 (m, 5H), 6.95 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 5.87 (d, J=8.1 Hz, 1H), 5.16 (td, J=7.7, 4.5 Hz, 1H), 4.25 (dd, J=11.5, 7.4 Hz, 1H), 4.14 (dd, J=11.3, 4.5 Hz, 1H), 3.74 (dd, J=8.8, 5.8 Hz, 1H), 3.65 (dd, J=8.8, 6.8 Hz, 1H), 3.59 (q, J=7.1 Hz, 1H), 1.95 (s, 3H), 1.85-1.95 (m, 1H), 1.49 (d, J=7.3 Hz, 3H), 1.24-1.47 (m, 3H), 1.13-1.23 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 412.2 [(M+H)+, calcd for C25H34NO4 412.3].
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:23][C:24]1([CH3:30])[CH2:29][O:28][CH2:27][CH2:26][NH:25]1.CCN(C(C)C)C(C)C>>[CH3:23][C:24]1([CH3:30])[N:25]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:27][O:28][CH2:29]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC1(C)COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 100 °C
Yield: 12 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 65 mg, 0.230 mmol), 3,3-dimethylmorpholine hydrochloride (69.8 mg, 0.461 mmol, Tyger Scientific, Ewing, N.J.), and DIPEA (201 μl, 1.151 mmol), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(3,3-dimethylmorpholino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (s, 6H) 2.92 (t, J=6.85 Hz, 2H) 3.46-3.50 (m, 2H) 3.51 (s, 2H) 3.74-3.79 (m, 2H) 3.90-3.94 (m, 2H) 7.00 (br. s., 1H) 7.12 (d, J=2.15 Hz, 1H) 7.59 (t, J=7.82 Hz, 1H) 7.81 (dd, J=8.12, 1.27 Hz, 1H) 7.96 (dd, J=7.53, 1.27 Hz, 1H) 8.91 (s, 1H) 11.69 (br. s., 1H). MS (ESI, pos. ion) m/z: 378.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)=[CH:12]\[C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH:27]([F:28])[F:29])=[CH:21][CH:20]=2)[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(OC(F)F)c(=O)[nH]2)cc1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(OC(F)F)c(=O)[nH]2)cc1

Procedure:
An (R,S) mixture of the title compound was obtained by performing substantially the same reaction as in Examples 4-207 and 4-208(2) except for using 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(difluoromethoxy)pyridin-2(1H)-one obtained in Example 4-165. This was preparatively isolated by a chiral HPLC column (CHIRALCEL OD-H, hexane:ethanol=50:50 v/v, 40° C., 7.0 mL/min, 210 nm) to give one diastereomer (A) of the title compound as a colorless amorphous (20 mg) and the other diastereomer (B) of the title compound as a colorless powder (24 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:15][CH2:16]Cl.[I-:18].[Na+].C.[IH:21]>CC(C)=O>[I:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:15][CH2:16][I:21]
Reactant: O=[N+]([O-])c1ccc(OCCCl)c(OCCCl)c1
Reactant: I
Reactant: [I-]
Agent: C
Agent: [Na+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCI)c(OCCI)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 2.8 g of the dichloride obtained in Example 15 and 3.8 g of anhydrous sodium iodide in 35 ml of anhydrous acetone are stirred under a nitrogen atmosphere and heated at reflux temperature for 2 days. After cooling to ambient temperature, the solution is evaporated to dryness. The solid residue is dissolved in ether and washed with a sodium thiosulfate solution to remove iodine. The organic layer is separated, dried (Na2SO4) and evaporated to dryness, and after recrystallization from hexane the title compound is produced. Yield 60%: IR 1503 cm-1 and 1349 (aromatic C--NO2); 1HNMR (CDCl3) δ7.83 (d,1H), 7.77 (s, 1H), 7.0 (d, 1H), 4.38 (t, 4H), 3.48 (t, 4H); MS (CI, methane), m/z 464 (M+H), 492 (M+29), 504 (M+41), 336 (MH-HI).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][CH:9]([CH:11]([OH:16])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:10].[N+]([C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[C:21]=1[C:28]#[N:29])([O-])=O>C1(C)C=CC=CC=1.O>[CH3:8][CH:9]([CH:11]([O:16][C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[C:21]=1[C:28]#[N:29])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:10]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: C=C(C)CC(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)CC(Oc1cccc(C#N)c1C#N)C(C)C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
9.6 g (0.24 mol) of 60% sodium hydride and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, a reflux condenser and a nitrogen-introducing tube, and the solution was then stirred under the feed of nitrogen. Afterward, 32 g (0.25 mol) of 2,5-dimethyl-5-hexene-3-ol was added dropwise thereto at 20°-30° C. over 1 hour, and the solution was then stirred at the same temperature for 3 hours to prepare a sodium alcoholate solution. Next, 34.6 g (0.2 mol) of 3-nitrophthalonitrile and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, and the above-mentioned sodium alcoholate solution was then added dropwise at 0° C. or less over 5 hours. After completion of the addition, the temperature of the solution was raised up to a level of 20°-30° C., and the solution was then stirred for 2 hours to bring reaction to an end. The thus obtained reaction solution was poured into 3 l of water and then stirred for 30 minutes, and 500 ml of toluene were added. After stirring for 30 minutes, the solution was allowed to stand to separate a toluene layer. After toluene was distilled off under reduced pressure, recrystallization was carried out from 500 ml of n-hexane to obtain 43.7 g of 3-(2,5-dimethyl-5-hexene-3-oxy)phthalonitrile (yield =86.0%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:31]1([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]=[CH:12]2)=[C:4]([NH:39][CH2:38][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:3]=1
Reactant: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2,6-Dichloro-9-[(1R,4S)-4-(5-ethyl-tetrazol-2-yl)-cyclopent-2-enyl]-9H-purine (step 1) (0.2 g, 0.57 mmol) is dissolved in THF (5 ml) under an atmosphere of argon. Diisopropylamine (0.088 g, 0.68 mmol) is added followed by 2,2-diphenylethylamine (0.123 g, 0.63 mmol) and the reaction mixture is stirred at 50° C. for 4 hours. The solvent is removed in vacuo and residue is partitioned between dichloromethane (20 mL) and 2M HCl (20 mL). The organic layer is washed with sat. NaHCO3 (20 mL), water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.20 (br s, 1H), 7.30-7.10 (m, 10H), 6.30 (m, 1H), 6.20 (m, 1H), 5.95 (m, 1H), 5.80 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2H), 3.35 (m, 1H), 2.85 (q, 2H), 2.20 (m, 1H), 1.30 (t, 3H), MS (ES+) m/e 512 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[C:29]([O:32][CH2:33][CH3:34])[CH:28]=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[CH:31]=[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH3:15])=[N:8][C:7]=1[OH:16])[CH:23]=[N:24]2)[CH3:34]
Reactant: CCOc1cccc2ncc(CCl)cc12
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1cccc2ncc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (51 mg, 233 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.22 mL, 0.44 mmol) at RT followed by CCH 29192 (50 mg, 194 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic layer was isolated and the aqueous layer was further extracted with CH2Cl2 (50 mL). Both organic layers were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 4-((5-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-((5-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 28 as a yellow solid (11 mg, 12% yield).