Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH2:20]>C1CCCCC1>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:20]
Reactant: BrCCCCCCCCCCCCCCCCBr
Reactant: O
Agent: Br
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCCCCCBr

Procedure:
The diol 14 (1.047 g, 4.05 mmol) was dissolved in cyclohexane (30 mL) and vigorously stirred with 48% HBr (0.5 mL, 4.46 mmol, 1.1 eq.). The mixture was refluxed for 6 h, diluted with water (50 mL) and the phases were separated. The aqueous phase was extracted with a mixture of dichloromethane and methanol (v/v, 4:1 3×20 mL). The combined organic layer was dried over MgSO4. The product was purified by column chromatography with silica gel (6×6 cm, cyclohexane/ethyl acetate, 8:1) and isolated as a white solid. Yield: 4.598 g (96%). Traces of 1,16-dibromohexadecane were also found.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (1.50 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.10 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.87 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (1.30 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: CN1CCN=C1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][N:39](C2C=CC(N)=CC=2)[CH2:38][CH2:37]1.C(Cl)CCl>CN(C=O)C.O>[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][N:39]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])=[CH:11][CH:12]=2)[CH2:38][CH2:37]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C2=NCCN2C)cc1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N2CCCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 84, 40 mg, 0.13 mmol) and 4-(4-methyl-homopiperazinyl)phenylamine (61 mg, 0.25 mmol) in DMF (3 mL) and H2O (1 mL), EDC (96 mg, 0.50 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (25 mg). MS 506.2 and 508.2 (M+H, Cl pattern).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[N:18]=[C:19]([NH2:28])[S:20][C:21]=1[CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([NH:28][C:19]2[S:20][C:21]([CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=[C:17]([CH3:16])[N:18]=2)=[O:14])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Product: Cc1nc(NC(=O)C(C)c2ccc(CC(C)C)cc2)sc1CCO[N+](=O)[O-]
Yield: 63 %

Procedure:
Pet-152 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 2-(4-isobutyl-phenyl)-propionic acid (Ibuprofen) and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 63%.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[S:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:27][NH2:28]>C(O)(C)C>[N+:1]([C:4]1[C:5]([NH:28][CH2:27][C:19]2[S:18][C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:20]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1nc2cnccc2s1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-2,6-dichloropyridine (106 mg, 0.55 mmol) in isopropanol (3 mL) was sequentially added Na2CO3 (116 mg, 1.1 mmol) and intermediate R (100 mg, 0.61 mmol). The reaction mixture was stirred at room temperature overnight, and then concentrated. The residue was extracted with EtOAc. The organic layer was separated, concentrated, and purified by chromatography on silica gel to afford the title compound. MS (m/z): 322 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1ccc(F)cc1Cl

Procedure:
From 2-chloro-4-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=401.0, tR (minutes, Method D)=0.79
Reaction SMILES: [N:1]([C:4]1([C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][NH:11][CH2:9][C:4]1([NH2:1])[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=NC1(C(=O)NCCOCc2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1(CNCCOCc2ccccc2)CCCC1
Temperature: 0 °C

Procedure:
A solution of the crude 1-azido-N-(2-benzyloxyethyl)cyclopentan-1-carboxamide 12a (22.3 g) in tetrahydrofuran (100 ml) was added to a suspension of LiAlH4 (6 g) in tetrahydrofuran (100 ml). After reflux for 2 h the mixture was cooled to 0° C. and subsequently treated with water (6 ml), 15% aqueous NaOH (6 ml) and water (6 ml). The mixture was filtered and the precipitate extracted with dichloromethane (200 ml). Drying of the combined organic phases (MgSO4) and evaporation of the solvents in vacuo afforded the title compound as an oil: 18.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[N:12][N:11](COCC[Si](C)(C)C)[C:10]=2[C:23]2[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.COC.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[N:12][NH:11][C:10]=2[C:23]2[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c(C)nn(COCC[Si](C)(C)C)c2-c2cc(C)nc(N)n2)cc1
Agent: COC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(-c2c(C)n[nH]c2-c2cc(C)nc(N)n2)cc1
Reaction time: 2 h

Procedure:
4-[4-(4-Methoxy-phenyl)-5-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-6-methyl-pyrimidin-2-ylamine was dissolved in anhydrous dichloromethane under nitrogen. 2M borontrichloride.dimethylether in dichloromethane (7 eq) was added dropwise, and all was stirred for 2 hours. The reaction mixture was added dropwise to sat. NaHCO3(aq) and extracted into dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC/MS to give 4-[4-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-6-methyl-pyrimidin-2-ylamine as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)cc1

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and p-anisaldehyde (77 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (75 mg, 27.3%). 1H NMR (CDCl3): 7.66 (d, J=15.9 Hz, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.32 (d, J=15.6 Hz, 1H), 7.28 (d, J=3.3 Hz, 2H), 7.11 (dd, J=3.3, 9.0 Hz, 1H), 6.94 (t, J=8.7 Hz, 2H), 4.44-4.33 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:13]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.2 %

Procedure:
To a solution of piperazine (25.9 g, 0.30 mol) in tetrahydrofuran (300 ml) at 0° C. was added triphenylmethyl chloride (27.9 g, 0.10 mol). The reaction was stirred for 48 hours at room temperature. The product was extracted from aqueous sodium carbonate with three portions of ether. The combined organic layers were washed with three portions of water, dried with sodium sulfate, and the volatiles were then evaporated. The residue was subjected to chromatography on silica (LPS-1) (eluting with 90:10:4 ether/acetonitrile/triethylamine) to yield 7.62 g of N-tritylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:59]([CH3:61])[CH3:60])[C:7]([N:9]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:35]2[NH:39][C:38]([CH:40]4[CH2:44][CH2:43][CH2:42][N:41]4[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]([CH3:49])[CH3:48])=[N:37][CH:36]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[CH2:56][CH2:57][CH2:58][C@H:10]12)=[O:8])=[O:4].[CH3:62][O:63][C:64](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:59]([CH3:61])[CH3:60])[C:7]([N:9]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:35]2[NH:39][C:38]([CH:40]4[CH2:44][CH2:43][CH2:42][N:41]4[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]4[CH2:49][CH2:64][O:63][CH2:62][CH2:48]4)=[N:37][CH:36]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[CH2:56][CH2:57][CH2:58][C@H:10]12)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@@H]7CCC[C@@H]7N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc(C4CCCN4C(=O)[C@@H](NC(=O)OC)C4CCOCC4)[nH]3)ccc2-5)C[C@@H]2CCC[C@@H]21)C(C)C
Yield: 56 %

Procedure:
This compound was made in an analogous manner to methyl {(2S)-1-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid to give methyl [(1S)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate (0.039 g, 56%). MS (ESI) m/z 874.34 [M+H]+. 1H NMR (400 MHz, cd3od) δ 8.58 (s, 2H), 8.26-8.08 (m, 2H), 7.96-7.75 (m, 4H), 7.65-7.54 (m, 5H), 5.36-5.11 (m, 4H), 4.34-4.04 (m, 4H), 3.97-3.79 (m, 4H), 3.65 (s, 4H), 3.53-3.44 (m, 2H), 2.68-2.47 (m, 4H), 2.32-2.02 (m, 7H), 1.95-1.82 (m, 3H), 1.77-1.54 (m, 4H), 1.49-1.24 (m, 5H), 1.10-0.99 (m, 3H), 0.92-0.85 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccnc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-[(1-benzyloxycarbonyl-piperidin-4-ylmethyl)-amino]-pyridine-2-carboxylic acid (0.59 gm, 0.0016 mol) in THF (2 mL) under nitrogen was added a solution of 1.0M borane-tetrahydrofuran (6 mL) and the mixture allowed to stir at room temperature for 1 h. The reaction was cooled to 0° C., quenched with 1N HCl (10 mL), concentrated and diluted with 10% aqueous sodium bicarbonate. Extraction with dichloromethane (2×50 mL)and concentration of the organic layer gave 540 mg of crude material. Column chromatography using dichloromethane/methanol/ammonium hydroxide-90/10/2 and crystallization from diethyl ether gave 4-[(2-hydroxymethyl-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][O:33][CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][O:33][CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCCC1CCCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCCOC1

Procedure:
Prepared similarly to Intermediate 243 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
A mixture of N-{5-bromo-2-[(cyclopropylmethyl)amino]phenyl}-3,3-dimethylbutanamide (Step C, 11.2 g, 33.0 mmol), p-toluenesulfonic acid monohydrate (6.29 g, 33.0 mmol) and toluene (240 mL) was stirred at reflux temperature for 20 h with Dean-Stark apparatus. The mixture was cooled to 0° C. The resulting precipitate was collected by filtration and washing with small amount of ethyl acetate. The residue was dissolved in ethyl acetate (200 mL). The whole was extracted with saturated sodium hydrogen carbonate aqueous solution (100 mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 as eluent) to give the title compound (10.1 g, 95%) as a white solid.
Reaction SMILES: [CH2:1]1[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:9]([NH:18][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCCCCCCCCN
Reactant: CCCCCC1CO1
Solvent: CO
Product: CCCCCC(O)CNCCCCCCCCNCC(O)CCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-heptene oxide (52 g.) and 1,8-octanediamine (32.8 g.) and two recrystallizations of the resulting product from methanol gave N,N'-(1,8-octylene)-bis[2-hydroxyheptylamine] (I: R= CH3 (CH2)4, R' = H, X= (CH2)8, Z= H) (17.2 g., m.p. 128.0°-132.8° C.).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1)=[O:15])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccc(F)cc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccc(F)cc1

Procedure:
Coupling of (R)-1-(4-fluoro-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: Cl[C:2]1[C:3]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[S].N1C2SC3CCCCC=3C=2C=NC=1.P(Cl)(Cl)(Cl)=O.CNC.[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH2:52]>CN1CCCC1=O>[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH:52][C:2]1[C:3]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(n2)sc2ccccc23)cc1
Reactant: COc1ccc(CN)cc1Cl
Agent: CNC
Agent: [S]
Agent: c1ncc2c3c(sc2n1)CCCC3
Solvent: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(Cl)c3)c3c(n2)sc2ccccc23)cc1
Yield: 125.5 %

Procedure:
A mixture of 1.5 g of methyl 4-(4-chlorobenzothieno[2, 3-d]pyrimidin-2-yl)phenylcarboxylate (“B”), prepared by dehydrogenation of the corresponding 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine compound with sulfur and subsequent chlorination with phosphorus oxychloride/dimethylamine, and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone is heated at 110° for 4 hours. After cooling, the mixture is worked up in the customary manner. 2.6 g of methyl 4-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]-benzoate, m.p. 203-204°, are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:21][CH3:22])[CH:5]=[C:4]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:3]=1.CN.[CH3:35][N:36]1C(=O)CCC1.O>CCCCCC>[CH2:31]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][CH3:30])[C:23]=1[C:4]1[N:3]=[C:2]([NH:36][CH3:35])[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:21][CH3:22])[CH:5]=1)[CH3:32]
Reactant: CN1CCCC1=O
Reactant: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Agent: CN
Solvent: CCCCCC
Solvent: O
Product: CCc1cc(-c2c(CC)cccc2CC)nc(NC)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of (S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (50 mg), anhydrous MeNH2 (2 mL) and NMP (3 mL) is heated in a sealed tube at 110° C. overnight. On cooling, water (10 mL) and hexane (20 mL) are added and the organic layer is separated. The organic layer is washed with brine, dried and concentrated. The residue is purified by PTLC (8:1 Hexane/EtOAc) to give the desired product. 1H NMR (CDCl3) 7.45 (d, 1H), 7.10-7.26 (m, 6H), 6.82 (br, 1H), 6.32 (s, 1H), 3.95 (m, 1H), 3.77 (m, 2H), 2.30 (s, 3H), 2.75 (m, 2H, 2.65 (m, 2H), 2.42 (m, 4H), 2.11 (s, 3H), 1.80-2.10 (m, 2H), 1.07-1.27 (m, 9H).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27][CH:26]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)=[CH:26][N:27]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1cncc2ccccc12
Product: OC1(c2cncc3ccccc23)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 53 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 4-bromo-isoquinoline, the title compound was formed in 53% yield as a white solid, mp 256°-259° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 9.10 (s, 1H), 8.82 (d, J=7.5 Hz, 1H), 8.50 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.67 (m, 1H), 7.58 (m, 1H), 7.26 (m, 4H), 6.94 (m, 4H), 4.29 (s, 1H), 3.53 (s, 2H), 2.91 (m, 4H), 2.64 (d, J=l.3 Hz, 2H), 2.28 (m, 4H) MS (CI, CH4) m/z 433 (M+1,100), 461 (M+29,14), 415 (26), 123 (12) hydrochloride salt:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][NH:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[N+:28]([O-])=O)[CH:10]=1>CO.ClCCl.[Pd]>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][NH:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH2:28])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCOCC3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(OC2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(tetrahydro-2H-pyran-4-yloxy)phenyl)isonicotinamide (400 mg, 0.76 mmol, 1.00 equiv, 95%) in methanol/dichloromethane (10/5 mL). The solution was treated with Pd/C (400 mg), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 270 mg (68%) of product as a brown oil.