Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][C@@H:12]2[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]2[CH2:10]1.[C:20]([O:24][C:25]([N:27]([CH3:36])[C@H:28]([C:33](O)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:36][N:27]([C@@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:33](=[O:34])[NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:18])[F:19])[CH2:13]2)[CH2:16][CH2:15]1)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 4 mL vial was added (3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Step 2 (21.6 mg, 0.080 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-leucine (21.56 mg, 0.088 mmol), and 1-hydroxybenzotriazole hydrate (13.46 mg, 0.088 mmol) in dichloromethane (1 mL) to give a colorless solution. After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.016 mL, 0.088 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was diluted with 1 mL of dichloromethane and quenched with 2 mL of water. The aqueous layer was extracted with more dichloromethane (2×2 mL), the solvent was removed in vacuo, and the crude material was applied to a 24 g silica gel cartridge and purified with 1-50% ethyl acetate/hexanes to give tert-butyl methyl((S)-4-methyl-1-oxo-1-((3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=6.8, 1H), 7.69-7.62 (m, 1H), 7.45 (t, J=7.4, 1H), 7.26 (d, J=8.2, 1H), 7.11 (t, J=7.6, 1H), 5.17 (s, 1H), 4.46 (s, 1H), 3.45 (d, J=8.8, 1H), 3.08 (d, J=24.1, 4H), 2.98-2.87 (m, 2H), 2.63 (s, 2H), 2.09 (s, 1H), 1.86 (ddd, J=23.7, 16.2, 10.4, 3H), 1.70-1.51 (m, 3H), 1.48 (s, 9H), 0.90 (d, J=6.5, 3H), 0.86 (d, J=6.5, 3H); MS (ESI+) m/z 498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:20])[CH:15](Br)[CH2:16][CH2:17][CH3:18])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:20])[CH:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 mL) was heated at 140° C. for 1 h. After cooled to room temperature, the mixture was poured into water and the water phase was extracted with EtOAc thrice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:16][C:12]=3[CH:11]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccc(F)cc3)ccc2[nH]1
Temperature: 40 °C
Yield: 93.4 %

Procedure:
The product from Example 99B (0.65 g, 1.58 mmol), 1-(bromomethyl)-4-nitrobenzene (0.479 g, 2.22 mmol), and potassium carbonate (0.547 g, 3.96 mmol) were combined in dimethyl formamide (15 mL) and heated at 40° C. for 3 hours then diluted with water and filtered. The product was purified by combi-flash 24 g silica column, eluting with 0-5% methanol in dichloromethane to give 0.805 g (93%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14]CC(C)C)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.CCOCC.Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)COC(=O)c1cccc2c(Br)cccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1H, d, J=8.6 Hz), 7.95 (1H, d, J=8.6 Hz), 7.86-7.93 (3H, m), 7.74 (1H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1H, m), 7.40 (1H, dd, J=8.5, 7.6 Hz), 7.25 (2H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](=[S:21])[NH:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[CH3:22]C([O-])(C)C.[K+].CI.O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:14]([S:21][CH3:22])=[N:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2]
Reactant: C[Si](C)(C)CNC(=S)c1ccc(-n2cncn2)c(C#N)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzene-carbothioamide (1.5 g) in THF was added t-BuOK (0.64 g) under cooling (0° C.). After stirring for 15 minutes, methyl iodide (0.81 g) was added dropwise to the mixture under cooling (0° C.). The reaction liquor was returned to room temperature and stirred for 2 hours. Water was added to the reaction mixture, and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate at a yield of 64%.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[CH:6]=[N:5][CH:4]=1
Reactant: COCCn1cncc1CO
Reactant: O=S(Cl)Cl
Product: COCCn1cncc1CCl
Product: Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5-hydroxymethyl-1-(2-methoxyethyl)imidazole (2.8 g) was added to thionyl chloride (8.4 ml), and the mixture was stirred for 1 hour at 80° C. The solvent was removed under reduced pressure, and the obtained residue was washed with ethyl acetate, to give 5-chloromethyl-1-(2-methoxyethyl)imidazole hydrochloride (3.2 g).
Reaction SMILES: [NH2:1][C:2](=[O:31])[C@@H:3]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:29])[CH:17]([NH:21][C:22]1[S:23][C:24]([CH:27]=[O:28])=[CH:25][N:26]=1)[CH:18]([CH3:20])[CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:31])[C@@H:3]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:29])[CH:17]([NH:21][C:22]1[S:23][C:24]([CH2:27][OH:28])=[CH:25][N:26]=1)[CH:18]([CH3:19])[CH3:20])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)C(Nc1ncc(CO)s1)C(=O)NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of material from Example 31 in EtOH/H2O (4:1) (2.5 mL) is added sodium borohydride (25.5 mg, 0.674 mmol) in 2 equal portions over 5 min. The resulting light suspension is stirred at room temp for 2 h, quenched with MeOH (3 mL), stirred at room temp for 30 min, quenched with acetone (5 mL), and stirred at room temp for 45 min. All volatiles were evaporated off under a gentle stream of N2 to give the title compound (quantitative yield) that is used in its entirety in the macrocyclization step. LC/MS (Condition A): ret. T=1.45 min, (M+H)+ 450.20.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH3:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.CO>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH3:7])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(=O)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccco1
Reaction time: 48 h
Yield: 60.8 %

Procedure:
To an equimolar solution of 1-furan-2-yl-ethanone (250 mg, 2.27 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (454 mg, 2.27 mmol) in dichloromethane (14 mL) 1M titanium(IV) chloride in dichloromethane (1.13 mL, 1.13 mmol) and triethylamine (0.31 mL, 2.27 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere for 2 days. Then sodium cyanoborohydride (430 mg, 6.8 mmol) in methanol (7 mL) was added dropwise with stirring and the solution was allowed to stir overnight at room temperature. 35% sodium hydroxide was added and the product was extracted with ethyl acetate. The solvent was removed under reduce pressure and the crude was purified by flash chromatography (dichloromethane/methanol:95/5) to give the final compound as a red oil (406 mg, 61%).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
To tetrahydrofuran (120 mL) were added 4-bromobenzoyl chloride (25 g), 1-(2,4-dimethylphenyl)piperazine (22 g) and 1N aqueous sodium hydroxide solution (120 mL), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (31 g) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH:3]1[CH3:16].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:19]=1[C:20]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH:3]1[CH3:16])=[O:21]
Reactant: CC1CC(CNc2ccccc2)CCC1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: C1CCOC1
Product: CC1CC(CNc2ccccc2)CCC1NC(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Amino-3-methyl-cyclohexylmethyl)-phenyl-amine (113 mg, 0.52 mmol) in dry THF (5 mL) and TEA (105 mg, 1.04 mmol) is treated with 2-chloro-5-(trifluoromethyl)benzoyl chloride (139 mg, 0.57 mmol). After stirring at RT for 2 hours, the solvent is removed in vacuo and the residue is partitioned between water and DCM. The mixture is passed through a phase separator and the organic portion is concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with iso-hexane: EtOAc (9:1 increasing to 2:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (1H, d), 7.82 (1H, d), 7.73 (2H, m), 7.07 (2H, t), 6.56 (2H, d), 6.49 (1H, t), 5.55 (1H, m), 3.93 (1H, m), 2.86 (2H, m), 2.23 (1H, m), 1.88 (1H, m), 1.78 (1H, m), 1.70 (1H, m), 1.59 (2H, m), 1.31 (1H, m), 1.11 (1H, m), 0.92 (3H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CNC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-{N-[(1R)-1[(4-chlorophenyl)methyl]-2-(4-{2-[(methylamino)carbonylamino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (397 mg, 0.59 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (266 mg). MS (ESI, pos. ion) m/z: 574 (M+1); (ESI, neg. ion) in/z: 572 (M−1). Calc'd for C32H36ClN5O3: 573.25. Anal. Calcd for C32H36ClN5O3.1.8C2HF3O2: C, 54.86; H. 4.89; N, 8.99. Found: C, 55.11; H, 5.04; N, 9.11.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][N:27]([CH3:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([N:27]([CH3:26])[CH3:37])=[CH:36][CH:35]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)NCC(=O)N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (13.8 mg, 0.052 mmol) in CHCl3 (2 mL) was treated with Et3N (0.021 mL, 0.15 mmol), 4-(dimethylamino)benzoic acid (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution was washed with 2 N aqueous NaOH solution (2 mL×2) and brine (2 mL), and dried by filtration through a PTFE membrane using CH2Cl2 (3 mL). Concentration afforded the desired material (compound No. 952) (24.9 mg, quant): The purity was determined by RPLC/MS (91%); ESI/MS m/e 415.0 (M++H, C22H27ClN4O2).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1.[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24]Br)(=[O:19])[CH3:18]>CC#N>[Cl:3][C:4]1[N:5]([CH2:24][O:23][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1
Reactant: CC(=O)OCCOCBr
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
NaH (0.12 g, 3.0 mmole, 60% oil disperson) was added to a stirred suspension of 2,4,5,6,7-pentachlorobenzimidazole (14) (1.0 g, 3.4 mmole) in dry CH3CN (120 mL) under a N2 atmosphere. The solution was stirred until H2 evolution has ceased and a clear solution was obtained (20 min.). (2-Acetoxyethoxy) methyl bromide (0.68 g, 10.66 mmole) in CH3CN (34 mL) was then added dropwise. The reaction mixture was stirred for an additional 3 hr. The resulting mixture was concentrated under reduced pressure, diluted with H2O (50 mL), extracted with EtOAc (100 mL), washed with H2O (100 mL), dried (anhyd. Na2SO4) and the solvent was removed under reduced pressure to yield an oil (165). The resulting oil was purified by flash column chromatography (2×24 cm) (230-400 mesh). Elution of the column with hexane:EtOAc (6:4, v/v) and evaporation of the appropriate fractions gave a solid which was recrystallized from MeOH to afford 1.39 g (72%) of 165: m.p. 119° C. 1H NMR (CDCl3): d 5.93 (s, 2, H, C-1'), 4.143.92 (m, 4, H, C-3' and C-4'), 1.83 (s, 3 H, Ac). Anal. Calcd. for C12H9N2Cl5O3 : C,35.45; H, 2.23; N, 6.89. Found: C,35.57; H, 2.17; N, 16.91.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].[Cl:15][C:16]1[C:21]([CH3:22])=[C:20](Cl)[N:19]=[CH:18][N:17]=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: NCCCc1ccc2c(n1)NCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1c(Cl)ncnc1NCCCc1ccc2c(n1)NCCC2
Reaction time: 9 h
Yield: 58 %

Procedure:
A mixture of 774.3 mg (4.05 mmoles) of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylpropylamine (prepared according to J. Org. Chem, 2004, 69, 1959-1966) and 600 mg (3.68 mmoles) of 4,6-dichloro-5-methyl-pyrimidine in 6 ml of dimethylacetamide and 1.2 ml of diisopropylethylamine is taken to 120° C. for 9 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on Alumina then on silica eluting with a gradient of 100% heptane to 100% ethyl acetate. 680 mg (Yield=58%) of expected product is obtained.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:20]=1[NH2:21])=[O:16])[CH3:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNC1CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 70 °C
Yield: 92.9 %

Procedure:
Cyclohexylhydrazine hydrochloride (3.057 g, 20.29 mmol, CAS #24214-73-1, purchased from Aldrich) was combined with ethyl (ethoxymethylene)-cyanoacetate (3.390 g, 20.04 mmol) and anhydrous sodium acetate (2.080 g, 25.36 mmol) in 30 mL ethanol. The mixture was heated at 70° C. for 16 hours then cooled to room temperature and concentrated. The residue was partitioned between methylene chloride and water. The separated aqueous phase was extracted with a second portion of methylene chloride. The organic phases were successively washed with water and brine and then combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with a gradient of 25-70% ethyl acetate/hexanes to give 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.42 g, 92%). Mass spectrum: m/z: 238.1 (M+H).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](C)=[CH2:3].[C:7]([O:12]C)(=O)[C:8]([CH3:10])=C.[CH2:14]([OH:16])C>>[CH3:14][O:16][CH:8]([CH2:7][O:12][CH:2]([CH2:1][OH:6])[CH3:3])[CH3:10]
Reactant: CCO
Reactant: C=C(C)C(=O)OC
Reactant: C=C(C)C(=O)O
Product: COC(C)COC(C)CO

Procedure:
A slurry obtained by mixing 37.3 g of borosilicate glass powder, 24.9 g of alumina powder, 6.2 g of copolymer (weight average molecular weight=50,000) having a methacrylic acid/methyl methacrylate copolymerization ratio of 25/75 by weight, 3.1 g of ethanol and 0.5 g of dipropylene glycol monomethyl ether was formed in a sheet by the doctor blade method, and then dried at 100° C. for 1 hour to obtain a ceramic green sheet having a thickness of 30 μm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][CH:11]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH2:14][CH2:13][NH:12]1>>[CH3:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:13][CH2:14][C:15]3[CH:19]=[CH:18][S:17][C:16]=3[CH:11]2[CH3:10])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(Cl)n1
Reactant: CC1NCCc2ccsc21
Product: Cc1cc(O)nc(N2CCc3ccsc3C2C)n1
Yield: 70.4 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 6-methyl-2-chloro-4-hydroxypyrimidine(6 g, 37.5 mmol) prepared in Step 1 of Example 57, and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (12.07 g, 78.75 mmol) prepared in preparation 1 were used as starting materials, 6.9 g of the titled compound was prepared.