Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].C(Cl)(Cl)Cl.C(Cl)Cl.I[Si](C)(C)C>C(#N)C>[CH3:1][N:2]([C:3]([C:4]([F:7])([F:6])[F:5])=[O:8])[C:3]([C:4]([F:7])([F:6])[F:5])=[O:8]
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN(C(=O)C(F)(F)F)C(=O)C(F)(F)F

Procedure:
The compound of formula III is initially protected by reaction with a trimethylsilating agent such as N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in an inert solvent such as chloroform or methylene chloride. The resulting trimethylsilyl ester, in which all potentially reactive sites, such as amino, hydroxy, and carboxylic acid functions, are protected by trimethylsilyl groups, is then subjected to a reaction with iodotrimethylsilane at about 0° C. to room temperature, over a period of about twenty minutes to about two hours. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is dissolved in a suitable non-hydroxylic solvent such as acetonitrile. A small amount of tetrahydrofuran (THF) is introduced to decompose any residual traces of iodotrimethylsilane. The resulting protected iodo intermediate is then further reacted in situ with a protected form of the pipefarine derivative IV which is obtained from IV by treatment with a trimethylsilating agent such as MBTFA in a compatible solvent such as acetonitrile. The quaternization reaction is conducted at about room temperature over a period of about 30 minutes to 24 hours, preferably about 2 hours. Addition of a hydroxylic solvent such as methanol, with ice-cooling, then causes solvolysis of the trimethylsilyl protecting groups, and the quaternary iodide of formula IA precipitates. Further treatment under aqueous conditions with a base such as sodium bicarbonate or sodium hydroxide, or with sodium phosphate buffer, converts IA to the zwitterionic form I in which, depending upon the amount of base added, or the pH of the buffer, other acidic functions in the R3 and Q substituents can be converted to salts. ##STR29##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:15]12[O:20][CH:18]([CH2:17][CH2:16]1)[CH2:19][N:13]([C:4]1[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=[C:6]3[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]=13)[CH2:14]2
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 25 °C

Procedure:
3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (3.08 g, 10.5 mmol) was dissolved in toluene (95 mL) and ethanol (55 mL). 4-Aminophenylboronic acid, pinacol ester (2.53 g, 11.55 mmol) was added followed by the addition of a 2M aqueous solution of Na2CO3 (21 mL). The mixture was degassed by bubbling a stream of nitrogen through the solution and tetrakis(triphenylphosphine)palladium (606 mg) was added. The mixture was heated under reflux for 16 h, cooled to room temperature and concentrated. The mixture was dissolved in ethyl acetate and washed with brine. The organic phase was dried over MgSO4 and filtered over magnesol. The aqueous phase was extracted with ethyl acetate, which was dried over MgSO4. The combined organic phases were concentrated. The crude product was applied to a silica gel column and eluted with ethyl acetate in hexanes (30-100%) to give 3.6 g of the title compound. HRMS: 351.1925 [M+H]. For [M+H]+ mass error=−0.3 mDa or −0.92 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5](=[O:20])[N:6]([CH:8]([CH2:16][CH2:17][O:18][CH3:19])[C:9]([O:11]C(C)(C)C)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5](=[O:20])[N:6]([CH:8]([CH2:16][CH2:17][O:18][CH3:19])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COCCC(C(=O)OC(C)(C)C)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
455 mg (purity 80%, 0.83 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 417 mg (purity 76%, quant.)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[CH:28]=3)[CH:20]=2)[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[K].[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][B-](F)(F)F)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCCC1>[C:1]([C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([O:15][CH3:16])=[C:7]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:49][N:46]3[CH2:47][CH2:48][N:43]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:44][CH2:45]3)[CH:28]=2)=[O:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)c3)c2)c1OC
Reactant: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 414 mg methyl 5-tert-butyl-3-[3-(2-chloro-pyridin-4-yloxy)-4-methyl-benzoylamino]-2-methoxy-benzoate, 370 mg potassium-(4-tert-butyloxycarbonyl-piperazin-1-ylmethyl)-trifluoroborate, 0.84 g Cs2CO3, 0.80 ml of water and 8 ml of tetrahydrofuran is flushed for 10 min with argon. Then 200 mg of 2-dicyclohexylphosphinyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos) and 20 mg palladium(II)acetate are added, and the mixture is heated to 80° C. The reaction mixture is stirred overnight at 80° C. in an argon atmosphere. After cooling to ambient temperature the mixture is evaporated down and the residue is taken up in ethyl acetate and water. The organic phase is separated off, washed with water and aqueous saturated saline solution and dried (MgSO4). The solvent is removed, and the residue is chromatographed on silica gel with dichloromethane/methanol (99:1→90:10) and then chromatographed by reversed phase (HPLC, Xbridge C18) with methanol/water/ammonia.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:10]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: Cc1nc(Cl)c(N)c(NCC(N)=O)n1
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(N)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
Heat a mixture of 2-[(5-amino-6-chloro-2-methyl-pyrimidin-4-yl)amino]acetamide (2.2 g, 0.01 mol), 2-chlorobenzaldehyde (2.86 g, 0.02 mol), p-toluene sulfonic acid (0.2 g) and molecular sieves (1.0 g) in toluene (50 mL) to reflux for 16 h. Cool and remove the sieves by filtration through diatomaceous earth. Concentrate the filtrate under reduced pressure to afford a residue. Dissolve the residue in dry dichloromethane (50 mL) and add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.3 g, 0.01 mol) at 0° C. Allow to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N aqueous sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with dichloromethane:methanol (98:2) to provide the title compound (0.3 g). ES/MS m/z 336 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[N:8][C:7]2=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[CH:5]=1)([O-])=O>CCOC(C)=O.CO.[Pd]>[C:13]1([N:11]2[CH:12]=[C:6]3[C:7]([N:8]=[CH:9][C:4]([NH2:1])=[CH:5]3)=[N:10]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cnc2nn(-c3ccccc3)cc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc2nn(-c3ccccc3)cc2c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A suspension of 3B (350 mg, 1.458 mmol) and palladium (5% wt) on activated carbon (300 mg) in EtOAc(100 mL) and MeOH (200 mL) was stirred under a hydrogen balloon for 1 hour. The reaction mixture was filtered via a pad of Celite. The filtrate was concentrated under reduced pressure to give the title compound as a light brown solid (305 mg, 99% yield). LC/MS (method A): retention time=1.60 min, (M+H)+=211.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][N:17]3[CH3:16])[C:11]=1[CH3:12]
Reactant: Cn1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2ccn3C)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.016 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.57 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.557 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 44 h to give 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinoline as a light yellow solid. Mass Spectrum (ESI) m/e=343.0 (M+1).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][N:7]([CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][CH3:29])[CH:22]=1)[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].S(Cl)([C:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:38]([N:39]([CH3:41])[CH3:40])[C:37]=2[CH:36]=[CH:35][CH:34]=1)(=O)=O>O.C(#N)C>[CH3:40][N:39]([CH3:41])[C:38]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:37]=1[CH:36]=[CH:35][CH:34]=[C:33]2[N:28]([CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH2:18][CH2:17][N:7]([CH3:6])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH3:29]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CNCc1cccc(OCCCN(C)CCC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(CCCOc1cccc(CN(C)c2cccc3c(N(C)C)cccc23)c1)CCC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The NaHCO3 solution (133 mg, 1.58 mmol) in water (2 mL) is added at RT to the solution of crude tert-butyl 3-(methyl(3-(3-((methylamino)methyl)phenoxy)propyl)amino)propanoate (455 mg, 1.35 mmol) and of dansyl chloride (364 mg, 1.35 mmol) in acetonitrile (35 mL). This mixture is stirred for 1 h 30 at the same temperature under argon. And the solvent is then evaporated under reduced pressure and the obtained oil is purified by chromatography on silica gel (eluent—DCM followed by the mixture DCM:MeOH=100:1). The final product is obtained as a fluorescent pale green amorphous gum (522 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1C=CC=CC=1>[Cl:20][CH2:21][C:22]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:23]
Reactant: Cc1cccc(C)c1NCC=O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde (12.2 grams; 0.058 mole), triethylamine (8.1 ml) and benzene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture was cooled in an ice bath and chloroacetyl chloride (6.6 grams; 0.058 mole) was added dropwise with stirring. After the addition was completed stirring was continued and the reaction was allowed to warm up to room temperature. After this time the mixture was filtered and the filtrate washed with dilute aqueous hydrochloric acid. The washed filtrate was dried over anhydrous magnesium sulphate and was stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[N-(α-chloroacetyl)-2,6-dimethylanilino]acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccco1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.062 mMol) 2-furoyl chloride, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:20])[S:5][CH:6]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:20])[S:5][CH:6]=1
Reactant: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccc3ncccc32)n1

Procedure:
To a solution of N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide (0.047, 0.12 mmol) in DMF (0.4 mL) was added potassium carbonate (0.041 g, 0.30 mmol) and iodomethane (17 uL, 0.27 mmol). After 2 h the reaction mixture was partitioned between H2O and ethyl acetate. The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product was submitted to prep HPLC for further purification. Retention time (min)=4.407, method [8], MS(ESI) 403.1 (M+H). 1H NMR (CDCl3) δ 12.40 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.07 (s, 1H), 7.56 (d, J=8.1 Hz, 1H) 7.41 (d, J=5.1 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H) 6.81 (s, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.47-3.42 (m, 2H), 3.03-2.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10](Cl)[CH3:11].[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][N:26]1[CH2:25][CH2:24][CH:23]([C:20]2[C:19]3[CH:29]=[CH:30][C:16]([F:15])=[CH:17][C:18]=3[O:22][N:21]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(Cl)CNc1cnn(C)c(=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ncc(NCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
2.4 g (10 millimoles) of 4-chloro-5-(2-chloropropylamino)-2-methyl-2H-pyridazine-3-one, 40 ml of acetonitrile, 2.46 g (11 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 2.8 g of potassium carbonate and 0.18 g potassium iodide are admixed. The reaction mixture is heated to boiling under stirring for 24 hours, cooled to room temperature and filtered. The filtered product is suspended in 100 ml of water under stirring and refiltered. The crude product is recrystallized from acetonitrile. Thus 2.4 g of the desired compound are obtained. Yield 57.3%. Mp.: 200–202° C.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]2ON=[C:36]([CH2:39][O:40]C3C=CC(OC)=CC=3)[N:35]=2)=[CH:29][CH:28]=1)[CH3:24].[Na].C(OCC)(=O)C>C(#N)C.O>[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]2[O:4][N:1]=[C:36]([CH2:39][OH:40])[N:35]=2)=[CH:29][CH:28]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cc2nc(CO)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 528 %

Procedure:
Add half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol) to a solution of 4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester (193 mg, 0.52 mmol) in acetonitrile (9 mL) and water (2.3 mL) at room temperature. Stir the reaction mixture at room temperature for one hour and add the second half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol). Stir at room temperature for an additional hour, dilute the reaction is with saturated aqueous sodium hydrideCO3, stir for 5 minutes, dilute with water, and extracte with ethyl acetate (3×). Wash the combined organic layers with brine, dry over MgSO4, and concentrate. Purify the residue by flash column chromatography using 50% ethyl acetate/hexane to give the title compound (720 mg, 81%). LC-MS (m/e): 263 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=[NH:12])[NH:10][OH:11])[CH:6]=[CH:5][C:4]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:2].[CH2:17]([N:19]([CH2:30][CH3:31])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([CH3:29])[N:28]=1)[C:23](O)=O)[CH3:18]>>[CH2:30]([N:19]([CH2:17][CH3:18])[C:20]1[CH:21]=[C:22]([C:23]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[CH:5][C:4]([NH:13][C:14](=[O:16])[CH3:15])=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:12]=2)[CH:26]=[C:27]([CH3:29])[N:28]=1)[CH3:31]
Reactant: CCc1cc(C(=N)NO)ccc1NC(C)=O
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)ccc1NC(C)=O

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-[2-ethyl-4-(N-hydroxycarbamimidoyl)-phenyl]-acetamide and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.81 min, [M+1]+=394.15; 1H NMR (CDCl3): δ 1.25 (t, J=7.0 Hz, 6H), 1.36 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 2.50 (s, 3H), 2.73 (q, J=7.3 Hz, 2H), 3.63 (q, J=6.8 Hz, 4H), 7.01 (s, 1H), 7.08-7.16 (m, 2H), 8.03-8.09 (m, 2H), 8.13-8.21 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([C:9](OCC)=[O:10])=[CH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:15][C:2]([F:1])([F:14])[C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cnc(C(F)(F)F)nc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 138.1 %

Procedure:
To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (25.5 g, 116.0 mmol) in dichloromethane (580 mL) at −78° C. was slowly added diisobutylaluminium hydride (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at −78° C. After 2 h, the mixture was quenched via slow addition of hydrochloric acid (2.0 M). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3×). The combined organic extracts was dried over sodium sulfate, filtered and concentrated to give the title compound (28.2 g).
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].BrC1[CH:11]=[C:10](C)[C:9](/[CH:13]=[CH:14]/[CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:8]([CH3:28])[CH:7]=1.[C-]#N.[Na+]>[Cu](I)I.O>[C:1]([C:2]1[CH:7]=[C:8]([CH3:28])[C:9](/[CH:13]=[CH:14]/[CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:10]([CH3:11])[CH:3]=1)#[N:4]
Reactant: CCC#N
Reactant: Cc1cc(Br)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: I[Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C#N)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Under argon atmosphere, 3 ml of propionitrile was added to a mixture of 339 mg of tert-butyl 4-[(E)-2-(4-bromo-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate, 89 mg of sodium cyanide, 53 mg of tetrakistriphenylphosphine palladium and 17 mg of copper iodide, followed by heating under reflux for 7 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 299 mg of tert-butyl 4-[(E)-2-(4-cyano-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22]([O:24]C)=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22]([OH:24])=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 3.30 g (9.50 mmol) 4-[4-(1-methoxycarbonyl-ethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (VIII.1) in 20 mL MeOH are added 10.5 mL (10.5 mmol) 1N NaOH solution and the mixture is stirred at 70° C. for 1 h. After that time, the solvent is evaporated and the residue is washed with DCM. The residue is taken up in 1N HCl and the precipitate is filtered off and dried in vacuo to yield the desired product.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[O:21][C:20]=2[CH2:34][O:35][CH3:36])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[O:21][C:20]=2[CH2:34][O:35][CH3:36])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methanol (553 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate as an amorphous compound. The obtained methyl 4-(cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (195 mg, 27%) as an amorphous compound.