Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])[C:5](=[O:30])[CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:7][CH2:8]O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N-:54]=[N+:55]=[N-:56].[Na+]>C(Cl)Cl.O>[N:54]([CH2:8][CH2:7][CH:6]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:15][CH:16]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39])=[O:30])=[N+:55]=[N-:56]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CCO)C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CCN=[N+]=[N-])C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-4-hydroxybutanamide from the previous step (1 eq.) and Hunig's base (3.5 eq.) were combined in CH2Cl2 (0.024 M). At −78° C., methanesulfonyl chloride (1.5 eq) was added and the reaction mixture was stirred at −78° C. for 10 min and at 0° C. for 10 min. The resulting mixture was quenched with sat. aq. NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo. The resulting residue was taken up in DMF (0.06 M) and added sodium azide (5 eq). This mixture was then allowed to stir at RT for 24 h. The resulting mixture was poured into water and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C2[N:27]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:27][C:13](=[O:14])[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]([F:20])([F:19])[F:18]
Reactant: On1nnc2ccccc21
Reactant: O=C(NC(CC(F)(F)F)C(=O)O)OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: NC(=O)C(CC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A solution of 2-(benzyloxycarbonylamino)-4,4,4-trifluorobutanoic acid (200 mg, 0.687 mmol), HOBt monohydrate (137 mg, 0.895 mmol) and EDC (171 mg, 0.890 mmol) in DMF (5 mL) was stirred at room temperature for 15 min, conc. NH4OH (0.250 mL, ca. 3.50 mmol) was added. The mixture was stirred at room temperature for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give benzyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate (175 mg).
Reaction SMILES: CI.[CH2:3]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[OH:16])[CH:4]=[CH2:5].[C:17](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:3]([C:6]1[C:7]([O:16][CH3:17])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1[F:12])[CH:4]=[CH2:5]
Reactant: C=CCc1c(F)ccc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: C=CCc1c(F)ccc([N+](=O)[O-])c1OC
Yield: 75.8 %

Procedure:
Methyl iodide (5.3 g, 37.9 mmol, 5 eq) was added to a solution of 2-allyl-3-fluoro-6-nitro-phenol (1.5 g, 7.5 mmol) and potassium carbonate (2.1 g, 15.1 mmol, 2 eq) in anhydrous acetonitrile (20 ml) and the reaction mixture was heated to reflux for 6 hr. The reaction mixture was filtered and washed with acetonitrile and the filtrate was concentrated to dryness to yield 2-allyl-1-fluoro-3-methoxy-4-nitro-benzene (1.2 g, 75%). The crude compound was used in the next stage without purification.
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:15])([F:17])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(N)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (I79) (138 mg, 0.231 mmol) was dissolved in dry dichloromethane (10 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (1.0 mL, 13 mmol) was added to the solution and the reaction was stirred at room temperature overnight. The volatiles were removed in vacuo, EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL) were added to the residue and the layers were separated.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[H-].[Na+].C(O[C:13](=O)[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C.O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]1[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH3:6])[N:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: CCCC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Hydroxy-butyramidine (0.425 g, 4.16 mmol) in DMF (2 ml) is added to a stirred suspension of sodium hydride (0.183 g of a 60% dispersion in oil, 4.58 mmol) in the presence of molecular sieves (0.4 g). The reaction flask is then immersed in a pre-heated oil bath at 50° C. and stirring continued for 5 min. 3-tert-Butoxycarbonylamino-propionic acid ethyl ester (0.904 g, 4.16 mmol) in DMF (2 ml) is added over 5 min followed by more DMF (2 ml). After 3 h at 50° C. the mixture is cooled to 0° C. and water (3 ml) is added. The mixture is allowed to warm to room temperature then filtered through Celite™ filter material, washing with ethyl acetate, and the solvent is removed. Purification by chromatography, eluting with DCM:MeOH (95:5 increasing to 85:15) affords the titled compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCCCOc2cnc(C3CCNCC3OCc3ccc4ccccc4c3)nc2)cc1
Yield: 60 %

Procedure:
A solution of 40 mg (0.07 mmol) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 0.1 ml of trifluoroacetic acid in 1 ml of methylene chloride was stirred at room temperature for 2 hours. Thereafter, the solution was evaporated and the residue was taken up in 1 ml of ethyl acetate and crystallized by the addition of hexane. There were obtained 25 mg (60% of theory) of (3RS,4RS)-5-(3-benzyloxy-propoxy)-2-[3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine trifluoroacetate in the form of colourless crystals; MS: 484 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.C(O)C.O.[BH4-].[Na+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 16.2 g of 7α-(5-bromopentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 162 ml of tetrahydrofuran as well as 90 ml of ethanol and 36 ml of water are mixed in portions at 0° C. with 4.7 g of sodium borohydride and stirred for 2 hours at 0° C. Then, it is added to water, extracted four times with ethyl acetate, washed with water and common salt solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 17.1 g of crude product is obtained. After chromatography on silica gel with hexane/ethyl acetate, 15.6 g of pure 7α-(5-bromopentyl)-11β-fluoro-estra-1,3,5(10)-triene-3,17β-diol is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10]CC)=[O:9])=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:19][C:18]=1[CH3:26]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)COc1cccc(C=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2cccc(OCC(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ethyl 2-(3-formylphenoxy)acetate (20.8 g, 0.1 mol) and 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (21.0 g, 0.375 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained yellow oil was dried under high-vacuum, 20 g (64%) of yellowish solid was obtained. 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 8.40 (br, 1H), 7.80 (s, 1H), 7.65 (m, 2H), 7.22-7.55 (m, 5H), 6.85 (d, 1H), 4.75 (s, 2H), 2.22 (s, 3H). MS (EI): 313 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.Br[C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]1([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:37]3[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:33][CH2:32]1
Reactant: Cc1cccc(Br)c1
Reactant: COCCCOc1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)cc(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cccc(C)c3)C2)C2CC2)cc(OC)c1
Temperature: 110 °C

Procedure:
A mixture of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.081 mmol), 3-bromotoluene (16 mg, 0.094 mmol), (rac)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (3.8 mg, 0.006 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.8 mg, 0.004 mmol), and cesium carbonate (32 mg, 0.098 mmol) in toluene (0.6 mL) is heated at 110° C. for 36 h. The mixture is purified by RP-HPLC to give the desired amine, which is treated with 4 N HCl-1,4-dioxane (1 mL) at room temperature for 1 h. Concentration under vacuum gives the title compound as a white amorphous solid. MS: 481 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.07 min.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH2:22]1[O:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=3[C:6]([OH:8])=[O:7])=[CH:16][C:17]=2[O:23]1
Reactant: COC(=O)c1cccc(Nc2ccc3c(c2)OCO3)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Nc2ccc3c(c2)OCO3)c1C(=O)O
Yield: 87.4 %

Procedure:
A mixture of 3-(3,4-methylenedioxyphenylamino)phthalic acid dimethyl ester (0.63 g, 1.9 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 2 hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.50 g of the product in 88% yield: 1H NMR (DMSO-d6) δ 5.99 (s, 2H), 6.59 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 7.04 (dd, J=7.3 Hz, J=0.9 Hz, 1H), 7.13 (dd, J=8.5 Hz, J=0.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.95 (s, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=1.O>CN(C=O)C>[CH3:29][O:28][C:24]1[N:23]=[C:22]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(Cl)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2cccc(OC)n2)CC1
Yield: 10.9 %

Procedure:
Diisopropylethylamine (2.16 mL, 12.7 mmol) was added to a solution of ethyl piperidine-4-carboxylate (2.00 g, 12.7 mmol) and 2-chloro-6-methoxypyridine (1.48 mL, 12.7 mmol) in DMF (10 mL), and the mixture was stirred while irradiated with microwaves at 150° C. for 3 hours using Initiator® manufactured by Biotage Japan Ltd. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=90/10] to obtain the title compound (365 mg, yield: 11%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: O[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](O)CC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 43, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:37][CH3:38])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)=[CH:13][N:12]=[C:11]([C:30]#[C:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:10]=3[N:36]=2)=[N:4][O:5][N:6]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:37][CH3:38])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:30]#[C:31][C:32]([CH3:33])([OH:35])[CH3:34])[C:10]=3[N:36]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Temperature: 65 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a suspension of 1,1-Dimethylethyl (2S)-2-({[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-morpholinecarboxylate (14.2 g, 0.027 mol) in methylene chloride (150 mL) was added trifluoroacetic acid (40 mL). After 1 h, the solvent was removed in vacuo. The residue was evaporated from ethyl acetate (2×) to give a solid. The residue was suspended in water and treated with 1N NaOH in an ice bath until the mixture was basic (pH 8). The precipitate was isolated by filtration, washed with water, ethyl acetate and dried in a vacuum oven at 40° C. for 4 h. The resulting solid was treated with ethyl acetate (250 ml) and stirred at 65° C. then allowed to cool to RT and then placed in an ice bath and then filtered and the solid dried in a vacuum oven at 40° C. The resulting solid was suspended in 20% tetrahydrofuran/ethanol (1.2 L). Darco G60 activated charcoal (3.9 g) was added and the mixture heated at reflux for 90 min. and filtered while hot through celite. The solvent was removed and retreated with ethanol and removed in vacuo (2×). The resulting solid was dried under high vacuum for 24 hr at 40° C. to afford the title compound (7.24 g, 64%). MS (ES)+ m/e 428 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:17][CH:16]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: C[C@@H]1COC(=O)N1Cc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3C(=O)OC[C@H]3C)cc2)CC1
Yield: 34.9 %

Procedure:
Using (R)-4-(4-methyl-2-oxooxazolidin-3-ylmethyl)benzoic acid (141 mg) described in Preparation Example 64 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (91 mg) was obtained.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCC(=O)CC>[ClH:3].[CH2:8]([C:7]1([CH2:12][CH3:11])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:18]1)[CH3:9]
Reactant: CCCCCCCNC(=N)NC(=N)NCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCC(=O)CC
Product: CCCCCCCNC1=NC(CC)(CC)N=C(NCc2ccccc2)N1

Procedure:
100 ml of methanol, 150 ml of 3-pentanone, and 0.5 ml of concentrated hydrochloric acid were added to 6.0 g (15.6 mmol) of N1-benzyl-N5-heptyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of methanol, and to the solution were added 80 ml of water and 5 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water, and acidified with 6N hydrochloric acid, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1)) to obtain 4.7 g of a pale yellow resinous solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.[Li]CCCC.[C:26]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1.Cl>COCCOC>[C:1]1([S:7]([CH:10]([CH:28]2[CH2:29][CH2:30][CH2:31][C:26](=[O:32])[CH2:27]2)[C:11]#[N:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: COCCOC
Product: N#CC(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 57.2 %

Procedure:
To 9.4 g (0.052 mol) of benzenesulfonyl-acetonitrile in 200 mL of DME at −50° C., 7.8 mL (0.052 mol, 1 eq) of TMEDA and 32.4 mL (0.052 mL, 1 eq) of nBuLi (1.6M in hexane) were added and stirring was continued for 45 min. To the resulting white suspension, 4.98 g (0.052 mol, 1 eq) of cyclohex-2-enone were added and the temperature was raised to −10° C. within 4 hours. The reaction mixture was poured into 180 mL of 1M HCl, extracted with EtOAc, and the combined organic phases dried over Na2SO4. Evaporation of the solvent and recrystallisation from AcOEt/Et2O yielded 8.25 g (57%) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile as a racemic mixture of diastereomers, white crystals, MS: 278 (MH+) (in analogy to: E. Hatzigrigoriou, L. Wartski, Synth. Comm., 1983, 14(4), 319-235).
Reaction SMILES: COC1C=CC(C([NH:18][C:19]([C:21]2[N:26]=[CH:25][C:24]([NH:27][CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:23][C:22]=2[NH:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=2)=[O:20])C2C=CC(OC)=CC=2)=CC=1.C([SiH](CC)CC)C.[C:55]([OH:61])([C:57]([F:60])([F:59])[F:58])=[O:56]>ClCCl>[OH:61][C:55]([C:57]([F:60])([F:59])[F:58])=[O:56].[NH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:24]1[CH:23]=[C:22]([NH:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=2)[C:21]([C:19]([NH2:18])=[O:20])=[N:26][CH:25]=1
Reactant: COc1ccc(C(NC(=O)c2ncc(NCCCNC(=O)OC(C)(C)C)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(Nc2cc(NCCCN)cnc2C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl {3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propyl}carbamate (51 mg, 0.080 mmol) in dichloromethane (4 mL) was added triethylsilane (0.064 mL, 0.40 mmol) followed by TFA (0.8 mL) at ambient temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-[(3-aminopropyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.22-8.04 (br s, 1H), 7.92-7.76 (m, 4H), 7.58 (s, 1H), 7.37 (s, 1H), 6.74-6.66 (br s, 2H), 3.22-3.16 (m, 2H), 2.94-2.84 (m, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.90-1.82 (m, 2H).