Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:28]>ClCCl.FC(F)(F)C(O)=O.C(OCC)C>[ClH:28].[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:15][C:16]=1[C:23]([F:26])([F:24])[F:25])([O-:22])=[O:21].[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: NC1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (400 mg; 2.0 mmol), 5-fluoro-2-nitrobenzotrifluoride (418 g; 2.0 mmol) and potassium carbonate (1.11 g; 8.0 mmol) in dimethylsulfoxide (5 mL) is heated at 100° C. for 5 hours. The mixture is allowed to reach room temperature, is diluted with ethyl acetate (50 mL) and filtered. The filtrate is washed with aq. sat. sodium hydrogencarbonate (2×10 mL) and with water (10 mL). The organic layer is then dried over magnesium sulfate and evaporated under reduced pressure to afford the desired product (797 mg; 2.0 mmol). The [1-(4-Nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester obtained (797 mg; 2.0 mmol) is dissolved in a 2 to 1 mixture of dichloromethane and trifluoroacetic acid (5 mL) and the resulting solution is stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue obtained is co-evaporated with dichloromethane (2×10 mL), is then dissolved in diethylether (2 mL) and a molar solution of hydrochloric acid in diethylether (5 mL) is added. The precipitate formed is triturated in ethylacetate (5 mL), filtered and is dried under high vacuum to yield the desired product as hydrochloride (624 mg; 1.6 mmol).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH:27]1([CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(OCc1ccccc1)N1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(OCC2CCCCC2)c(CCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
554 mg of 1-(benzyloxycarbonyl)-4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine was dissolved in 10 ml of ethanol, 250 mg of 10% palladium-carbon powder (water-containing product) was added thereto, and the mixture was stirred at room temperature under normal pressure overnight under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was evaporated, to give 379 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42][CH2:43][CH2:44]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:44][CH2:43][Cl:42])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: OCCCl
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.30 g), triphenylphosphine (0.25 g) and 2-chloroethanol (0.07 ml) in tetrahydrofuran (4 ml) was added diethyl azodicarboxylate (0.15 ml) and the reaction mixture stirred at room temperature for 18 h. Further triphenylphosphine (0.12 g) and diethyl azodicarboxylate (0.08 ml) were added and the reaction stirred for an additional 4 h. Silica was added and the reaction mixture concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 20% ethyl acetate in isohexanes) to deliver the sub-title compound as a lightly coloured oil (0.31 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:19].[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1csc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
4-(2-Thienyl)piperazine-1-carboxylic acid tert-butyl ester (700 mg) was dissolved in ethyl acetate (4 ml), a 4N hydrochloric acid-ethyl acetate solution (4 ml) was added, and the mixture was stirred at room temperature for 1.5 hr. The precipitated solid was collected by filtration, washed with ethyl acetate and dried to give 1-(2-thienyl)piperazine hydrochloride (532 mg, yield 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cccc(F)c1
Temperature: 25 °C

Procedure:
(3-Fluorophenyl)magnesium bromide (1 M in THF, 9.3 mL, 9.3 mmol) was added dropwise by syringe to a solution of nicotinaldehyde (0.88 mL, 9.3 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was stirred while warming to room temperature for 30 minutes, then quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate once and the organic layer was washed with water three times. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-60% EtOAc-hexanes) to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[S:12](=O)(=[O:15])([OH:14])[OH:13]>O>[OH:15][S:12]([O:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)(=[O:14])=[O:13]
Reactant: OCC1Cc2ccccc2N1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)OCC1Cc2ccccc2N1
Temperature: 160 °C

Procedure:
(RS)-2-Hydroxymethylindoline (29.8 g) is dissolved in a mixture of 34 N sulphuric acid (11.5 cc) and water (60 cc). The mixture is heated whilst distilling the water under reduced pressure (10 mm Hg), the heating bath being raised gradually to 160° C., which temperature is maintained for 2 hours. (RS)-2-Hydroxysulphonyloxymethylindoline (45.8 g) is thus obtained in the form of white crystals.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[K+]>C(O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc2c(-c3ccc(Br)cc3)ccnc12
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(-c3ccc(Br)cc3)ccnc12
Temperature: 25 °C

Procedure:
A solution of tin (II) chloride dihydrate (9.50 g) and 4-(4-bromophenyl)-8-nitroquinoline (4.60 g) in 50 mL absolute ethanol was refluxed for 6 hours. The reaction mixture was cooled to room temperature and then made alkaline with 30% KOH solution. The precipitated solid was filtered off, and dissolved in chloroform. The filtrate was extracted with ether. The ether extract and chloroform solution were combined and dried over MgSO4. Evaporation gave a solid with 1H-NMR spectral signals consistent with 8-amino-4-(4-bromophenyl)quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:24]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (391 mg., 0.001 mole) in tetrahydrofuran (15 ml.) is cooled in an ice bath and treated with a saturated solution of ammonia in methanol (12.5 ml.). The resulting solution is allowed to warm to ambient temperature and stand for 24 hours. It is then concentrated in vacuo. The residue is suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give 0.229 g. of crude product of melting point 227°-228.5° C. Recrystallization of this material from ethyl acetate gives three crops of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: 0.142 g. of melting point 228°-229.5°, 0.053 g. of melting point 228.5°-229.5° C. and 0.021 g. of melting point 228°-229.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC(S(O[CH2:24][CH2:25][CH2:26][Cl:27])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OC)c(OCCCCl)c1

Procedure:
The aforementioned J. Med. Chem., 44, 3965 (2001) further describes a process for preparing a 4-alkoxy-5-halogenoalkoxy-2-nitrobenzoic acid compound from a 4-alkoxy-3-hydroxybenzoic acid compound. For example, methyl 3-hydroxy-4-methoxybenzoate is reacted with 3-chloropropyl p-toluenesulfonate in an aqueous potassium carbonate solution in the presence of tricaprylmethyl ammonium chloride to produce methyl 3-(3-chloropropoxy)-4-methoxybenzoate, and the methyl 3-(3-chloropropoxy)-4-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate in 61% yield (based on the amount of methyl 3-hydroxy-4-methoxybenzoate).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCOc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCCCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 53 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-pentyloxybenzaldehyde 1.77 g were dissolved in methanol 60 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 2.5 hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.25 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C-:23]#[N:24].[Na+]>CS(C)=O>[C:23]([CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:24]
Reactant: CCCN(CCC)C(=O)c1cc(CBr)cc(C(=O)OCC)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20–25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20–25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CC(C)=O>[CH:18]1([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCC2CC2)cc1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (2.00 g), potassium carbonate (4.53 g) and acetone (50.0 mL), (bromomethyl)cyclopropane (3.32 g) was added and the mixture was refluxed for 9 hours. After cooling the reaction mixture to room temperature, the resulting precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and, thereafter, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the titled compound as a colorless oil (2.63 g).
Reaction SMILES: [N-]=[N+]=[N-].[N:4]([C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH3:17])[CH:11]=1)([CH3:9])[CH3:8])=[N+]=[N-]>CO.O.[Pt](=O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([NH2:4])([CH3:8])[CH3:9])=[CH:11][C:12]=1[CH3:17]
Reactant: Cc1cc(C(C)(C)N=[N+]=[N-])ccc1Cl
Agent: O=[Pt]=O
Agent: [N-]=[N+]=[N-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)(C)N)ccc1Cl

Procedure:
A solution of azide INT 21 (4.58 g, 21.84 mmol) in MeOH (100 mL) was hydrogenated at room temperature under atmospheric pressure for 6 hours in the presence of platinum dioxide hydrate (268 mg, 1.1 mmol). The mixture was filtered through Celite and concentrated. The crude was used without further purification.
Reaction SMILES: C(=O)(OC1C=CC=CC=1)N.[Br:11][C:12]1[S:16][C:15](N)=[N:14][CH:13]=1.F[B-](F)(F)F.[H+].[N:24]([O-:26])=[O:25].[Na+]>[Cu]>[Br:11][C:12]1[S:16][C:15]([N+:24]([O-:26])=[O:25])=[N:14][CH:13]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)s1
Agent: [Cu]
Agent: F[B-](F)(F)F
Agent: NC(=O)Oc1ccccc1
Product: O=[N+]([O-])c1ncc(Br)s1
Temperature: 23 °C

Procedure:
Scheme 3 depicts a method for preparing compounds of formula 1 wherein R1 is ABN-. An aqueous solution consisting of 5-bromo-2-aminothiazole (6) and 20% tetrafluoroboric acid are added to an aqueous slurry of copper powder and sodium nitrite at about 0° C., followed by warming to about 23° C. Standard work-up and purification by radial chromatography afford 5-bromo-2-nitrothiazole 7. Treatment of 7 with triethylamine and ABNH hydrochloride in dimethylsulfoxide at about 60° C. affords 8. Dissolution of 8 in a solvent such as ethyl acetate and treatment with palladium on carbon and hydrogen gas (3 atmospheres) affords aminothiazole 4. The aminothiazoles thus obtained can be treated with a carboxylic acid (HO(═O)C(CR10R11)nR4), propanephosphonic acid cyclic anhydride, and triethylamine in a solvent such as ethyl acetate or dichloromethane to afford compounds of formula 1.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[CH:8]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].C(N(CC)CC)C>C1COCC1>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCC(F)(F)F
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCC(C(=O)NCC(F)(F)F)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
2-(4-Nitro-1H-imidazol-1-yl)octanoic acid (7.8 mmoles,2.0 g) was treated with 25 ml oxalyl chloride, concentrated and added to a solution of trifluoroethylamine hydrochloride (7.8 mmoles, 1.06 g) and triethylamine (2 ml) in 50 ml THF. After stirring at room temperature for 16 hours, the mixture was added to ice, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel to yield 0.6 g of N-(2,2,2-trifluoro)ethyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.N.[C:38](P(=O)(OCC)OCC)#[N:39]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:39][CH3:38])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12
Agent: N
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2n[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indazol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and ammonia using diethyl cyanophosphonate as a coupling reagent. Mass: 521.15 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@H:35]3[CH2:38][C@H:37]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:47][CH3:48])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@H:35]3[CH2:36][C@H:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:38]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:47][CH3:48])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cooled TFA (2 mL) was added to tert-butyl 2-(trans-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (60 mg, 0.10 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The pH of the reaction mixture was adjusted to 6 to 7 with cooled aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (36.0 mg, 0.068 mmol, 66.3%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C(O)(=O)C>O1CCCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C@@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](CO)C1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To (S)-1-(benzyloxycarbonyl)4-(tert-butyloxycarbonyl)-piperazine-2-carboxylic acid (15.2 g, 0.04 mol) in tetrahydrofuran (200 ml) at 0° C. under argon was added borane (1M soln. in THF; 111 ml, 0.11 mol) dropwise over 15 min. The resulting mixture was stirred for 1 h, maintaining the temperature between 0° C. and 5° C., and then allowed to reach room temperature and stirred a further 18 h. The mixture was then carefully added, with stirring, to 5% g. acetic acid in water (1 l). After 1 h, the organics were evaporated in vacuo and the residual aqueous extracted with ethyl acetate (300 ml×4). The combined extracts were dried (Na2SO4), and evaporated in vacuo to a colourless oil. Chromatography on silica gel eluting with ethyl acetate-hexane mixtures afforded the title product (11 g, 75%) as a colourless oil.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[CH:17][NH:16]2)[CH:10]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[N:21]1([C:18]2[C:19](=[O:20])[N:15]([C:11]3[CH:10]=[C:9]([N:5]4[CH2:6][CH:3]([CH3:2])[CH2:4]4)[N:14]=[CH:13][N:12]=3)[NH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC1CNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1CN(c2cc(-n3[nH]cc(-n4ccnc4)c3=O)ncn2)C1

Procedure:
43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory)