Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]#[N:14])[CH2:10][CH:9]2[CH2:11][OH:12])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C1COCC1>[NH2:14][CH2:13][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:10][CH:9]1[CH2:11][OH:12]
Reactant: N#CC1(c2ccc(Br)cc2)CC1CO
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCC1(c2ccc(Br)cc2)CC1CO
Temperature: 80 °C
Yield: 72.6 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-2-hydroxymethyl-cyclopropanecarbonitrile (12.8 g, 51.0 mmol) in anhydrous THF (150 mL) was added BF3.OEt2 (10.15 mL, 0.2 mL per mmol) and the reaction mixture was heated at 80° C. Borondimethylsulphide complex (63.4 mL, 126.9 mmol, 2M in THF) was added to the reaction mixture and heated 80° C. for 4 h. Reaction mixture was quenched by 10% hydrochloric acid at 0° C. till effervescence vanishes. The reaction mixture was washed with diethyl ether (2×70 mL) and the aqueous layer was neutralized with solid sodium bicarbonate till pH 8. The neutralized aqueous layer was extracted with ethyl acetate (3×200 mL), dried over anhydrous sodium sulphate and concentrated to yield the title compound (9.49 g, 73%) as brown oil which was used as such in the next step.
Reaction SMILES: [C:1]([O-])(=[O:3])C.[NH4+].[NH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]>C(O)=O>[CH:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])=[O:3]
Reactant: COC(=O)c1sccc1N
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Product: COC(=O)c1sccc1NC=O
Yield: 98.5 %

Procedure:
Formic acid 125 ml, and ammonium acetate (15.9 g, 207 mmol) were added to methyl 3-amino-2-thiophene carboxylate (25 g, 159.04 mmol) and the mixture was refluxed for 4 hours. After lowering the temperature to room temperature, the synthesized solid was washed with water and the title compound (29 g, 98%) was obtained.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([CH:6]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][NH:8][C:7]1=S)[CH:4]=[CH2:5]>C(O)C>[CH2:3]([CH:6]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][NH:8]/[C:7]/1=[N:1]\[NH2:2])[CH:4]=[CH2:5]
Reactant: C=CCC1CCC(c2cccc(F)c2F)CNC1=S
Reactant: NN
Solvent: CCO
Product: C=CCC1CCC(c2cccc(F)c2F)CN/C1=N\N
Reaction time: 4 h

Procedure:
Hydrazine (anhydrous; 1.11 mL, 35.40 mmol) was added to a solution of 3-allyl-6-(2,3-difluorophenyl)azepane-2-thione (249 mg, 0.885 mmol) in ethanol (8 mL). After 4 h, the reaction mixture was concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×). The organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound. (MS 280.2 (M+1).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:12][C:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]1)=[O:13]
Reactant: CC(C)C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC[C@H](CC(C)C)CC1

Procedure:
To a solution of cis/trans-4-isobutyl-cyclohexanecarboxylic acid (7:3) (1.0 g, 5.4 mmol) in methanol (54 ml) was added a catalytic amount of sulfuric acid (2 drops). The reaction mixture was heated at reflux for 16 h. The solvent was evaporated. The residue was diluted with tert-butyl methyl ether (100 ml) and washed with aqueous saturated sodium hydrogen carbonate solution (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound ((7:3) cis/trans mixture) as a light yellow oil. MS m/e: 198 (M+)
Reaction SMILES: [N:1]1([C:6]2[C:7]([C:12]#[N:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1>[Pd].C(O)C>[N:1]1([C:6]2[C:7]([CH2:12][NH2:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#Cc1ncccc1-n1cnnn1
Agent: [Pd]
Solvent: CCO
Product: NCc1ncccc1-n1cnnn1

Procedure:
A solution of 3-(tetrazol-1-yl)cyanopyridine (250 mg, 1.45 mmol) and 45% by weight of palladium on carbon, 10% catalyst (110 mg) in ethanol (75 ml) was placed on a PARR Hydrogenation Apparatus under a hydrogen atmosphere at 55 psi. overnight. The mixture was filtered through celite and concentrated to give 3-(tetrazol-1-yl)-2-aminomethylpyridine; 1H NMR (CD3OD) δ 9.60 (s, 1H), 8.83–8.81 (m, 1H), 7.99–7.97 (m, 1H), 7.59–7.56 (m, 1H), 3.77 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](C2C=CC=CC=2)[N:4]=1)#[N:2].[Na].[C:16](O)(=[O:18])C>C[O-].[Na+].CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:18][CH3:16]
Reactant: CC(=O)O
Reactant: N#Cc1cccc(-c2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h

Procedure:
2-Cyano-6-phenylpyridine (20 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (200 ml) and metallic sodium (0.77 g). After the solution was left to stand overnight, acetic acid (2.0 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline imidate.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH2:4].C([Li])CCC.CCCCCC.[CH:22](=[O:24])[CH3:23].Cl>C1COCC1>[NH2:4][C:3]1[C:5]([Br:10])=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[CH:22]([OH:24])[CH3:23]
Reactant: CC=O
Reactant: Nc1c(Br)cc(Cl)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)c1cc(Cl)cc(Br)c1N
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
At −78° C. under nitrogen 1.8 M phenyl magnesium chloride solution in THF (3.06 ml, 5.5 mmol) were added dropwise to 2,6-dibromo-4-chloroaniline (1.426 g, 5.0 mmol) in THF (25 ml). The clear solution was warmed to −20° C. and stirred at this temperature for 5 minutes. The clear yellow solution was cooled to −78° C. and 1.6 M n-butyllithium solution in hexane (6.25 ml, 10 mmol) was added dropwise. The reaction was warmed to −10° C. and again cooled to −78° C. at which temperature acetaldehyde (440 mg, 10 mmol) dissolved in THF (5 ml) was added. After stirring for 10 minutes at −78° C. 1N aqueous hydrogen chloride solution was added and the reaction was allowed to warm to room temperature. The reaction was extracted twice with diethyl ether, dried over sodium sulfate, filtered and the solvent was evaporated to yield the product as a mixture of the corresponding amine, imine and aminal. The crude product was used directly in the next step.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:16]([CH3:32])[C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH3:32])[C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CN[C@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 69 %

Procedure:
Condensation of BocProOH (4.63 g.) and MeDTrpOMe (5.00 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MeDTrpOMe in 69% yield. Demethylation of BocPro-MeDTrpOMe (6.33 g.) using aqueous sodium hydroxide gave BocPro-MeDTrpOH in 77% yield. Condensation of BocPro-MeDTrpOH (3.60 g.) and HPheOBz (3.70 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-PheOBz in 83% yield. Debenzylation of BocPro-MeDTrp-PheOBz (4.60 g.) by hydrogenation with palladium catalyst gave BocPro-MeDTrp-PheOH in 100% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:20])[C:12]([CH:15]1[O:19][CH2:18][CH2:17][O:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:12]([CH3:14])([CH3:13])[C:11](=[O:20])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C(=O)CCl)C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C(=O)COc1ccc(F)cc1)C1OCCO1
Yield: 72.1 %

Procedure:
A mixture of 16.7 g (0.15 mol) of 4-fluorophenol, 29 g (0.15 mol) of 1-chloro-3-(1,3-dioxolan-2-yl)-3-methylbutan-2-one and 23.4 g (0.17 mol) of powdered potassium carbonate in 300 ml of methyl ethyl ketone is heated under reflux for 16 hours. The mixture is allowed to cool and filtered. The filtrate is evaporated down, the residue is taken up with dichloromethane, the solution is washed once with 5% strength sodium hydroxide solution and once with water, dried over sodium sulphate and evaporated down, and the residue is distilled. 29 g (72% of theory) of 3-(1,3-dioxolan-2-yl)-1-(4-fluorophenoxy)-3-methylbutan-2-one of boiling point 143° C. to 145° C./0.1 mbar are obtained. ##STR93##
Reaction SMILES: Cl[CH2:2][N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])=[CH:5][C:4]1=[O:31].[C:32]([O:36][P:37]([O:44][K])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[P:37]([O:44][CH2:2][N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])=[CH:5][C:4]1=[O:31])([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38]
Reactant: CC(C)(C)OP(=O)(O[K])OC(C)(C)C
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
The crude N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide from the previous step was taken up in N,N-dimethylformamide (5 mL). Di-tert-butoxyphosphoryloxypotassium (496.6 mg, 2.0 mmol) and tetrabutylammonium iodide (36.94 mg, 0.10 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate and washed with water then brine, dried with Na2SO4, filtered and evaporated to dryness. The material was purified by column chromatography (40 g silica, 50-100% EtOAc in Hexanes), fractions with the product were pooled and evaporated to give di-tert-butyl [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (20) (280 mg, 45%) as a yellow oil that was used in the next step without further purification. ESI-MS m/z calc. 628.20, found 629 (M+1)+; Retention time: 0.76 minutes (1 minute run).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH3:33])=[CH:4][C:5]([C:10]2[CH:11]=[N:12][C:13]([O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:35]([O-])=O.[Na+]>O.O1CCOCC1>[C:8]([C:7]1[C:2]2[N:1]=[N:35][N:32]([CH3:33])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]([O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:12][CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2cnc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOc1ncc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a suspension of tert-butyl 2-(5-amino-6-cyano-4-(methylamino)-5′-(trifluoromethyl)-2,3′-bipyridin-6′-yloxy)ethyl(methyl)carbamate (160 mg) in water (3 ml) and 1,4-dioxane (3 ml), 2N hydrochloric acid (192 mg) was added at 0° C. and sodium nitrite (34.2 mg) in water (1 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 20 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 140 mg light yellow solid as tert-butyl 2-(5-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yloxy)ethyl(methyl)-carbamate (85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:23])([CH3:22])[CH:3]1[CH3:24].S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([O:17][CH2:31][CH3:32])=[O:16])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:23])([CH3:22])[CH:3]1[CH3:24]
Reactant: CC1C(C)(C)c2ccc(C(=O)c3ccccc3C(=O)O)cc2C1(C)C
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)C(C)C2(C)C

Procedure:
A solution of 2.4 g (7.1 mmoles) of 2-[(1,1,2,3,3-pentamethyl-5-indanyl)carbonyl]benzoic acid, described in Example II, in 80 cm3 of ethyl alcohol containing 0.1 cm3 of 98% sulfuric acid, is heated for 12 hours at reflux. The solution is then concentrated under reduced pressure. The crude ester is dissolved in 100 cm3 of ethyl ether. The etherified solution is washed with sodium bicarbonate and then with water, dried on sodium sulfate and finally evaporated to dryness. After drying, 2.5 g of ethyl 2-[(1,1,2,3,3-pentamethyl-5-indanyl)carbonyl]benzoate in the form of a colorless oil are obtained which slowly crystallizes at ambient temperature to give a white solid whose melting point is 56-57° C. The NMR1H 80 MHz and IR spectra conform to the expected structure.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1>C(O)C.[Pd]>[NH:10]1[CH2:9][CH2:8][CH:7]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNC2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1NCCN1C1CCNCC1

Procedure:
A solution of benzyl 4-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (3.2 g) in ethanol (200 ml) was hydrogenated under a hydrogen filled balloon with 20% palladium on charcoal as catalyst. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound as a white solid, yield 1.6 g.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: Clc1cnccn1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3cnccn3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=564.3 (M+H+), was prepared in accordance with the general method of example 59 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 2-chloropyrazine.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][C:15]2=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].Cl>CCOCC>[N+:23]([CH:16]1[C:15](=[O:22])[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=2)[C:17]1=[O:21])([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC(=O)c2cc(OCCCOc3ccccc3)ccc21
Agent: Cl
Solvent: CCOCC
Product: O=C1c2ccc(OCCCOc3ccccc3)cc2C(=O)C1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(3-phenoxypropoxy)-indan-1,3-dione (0.296 gm, 0.001 mole) was suspended in dry ether (10 ml) and cooled to 0° C. The stirred mixture was treated with fuming nitric acid (1 ml) added dropwise over 15 mins and stirred in the ice bath for 1 hr. The mixture was then stirred at r.t. for a further 11/2 hrs. During this time all the solid dissolved leaving a deep yellow solution. Dilute hydrochloric acid (20 ml) was added and the ether evaporated in vacuo. A yellow gum formed which solidified on scratching to give 0.25 gm of yellow solid which had mp 77°-79° C.(d). (73%) (Found; C, 60.71; H, 4.58; N, 3.66; C18H15NO6.0.75H2O requires; C, 60.92; H, 4.69; N, 3.95%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][C@@H:3]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][C:10]=1[O:24]CC1C=CC=CC=1>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][C@@H:3]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][C:10]=1[OH:24]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C)c(OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C)c(O)c1
Yield: 84.1 %

Procedure:
Using the procedure of Example 4, 1.13 g (2.68 mmole) of N-methyl-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol and 452 mg of 5% palladium on carbon (50% wet) affords 0.752 g (84%) of the title compound as an oil.
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1C=CC=C(C#N)C=1O>>[C:15]([C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:14]
Reactant: N#Cc1cccc(N)c1O
Reactant: NCC1CNc2cccc(F)c2O1
Product: N#Cc1cccc2c1OC(CN)CN2

Procedure:
This compound is obtained using the same reaction sequence and the same experimental conditions as those used for the synthesis of intermediate 2b but replacing 2-amino-6-fluorophenol with 2-amino-6-cyanophenol. The title compound of formula (2f) is obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[C:3]([C:2]([NH:1][C:23](=[S:24])[C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=1)([CH3:16])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1ccc2nn(CC(C)(N)C#N)nc2c1
Product: Cc1ccc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2c1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-methyl-2H-benzotriazol-2-yl)propionitrile, described in Example 7, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.12 g, 57%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=420. 1H NMR: (400 MHz, DMSO-d6): 1.73 (s, 3H), 2.45 (s, 3H), 5.34-5.44 (m, 2H), 7.30 (dd, J=8.8, 1.4 Hz, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.84-7.94 (m, 4H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.94 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[Br:35][C:36]1[C:37]([OH:46])=[N:38][CH:39]=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:44][O:43][C:41](=[O:42])[C:40]1[CH:45]=[C:36]([Br:35])[C:37]([O:46][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:38][CH:39]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1cnc(O)c(Br)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Br)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), methyl 5-bromo-6-hydroxynicotinate (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The residue obtained after work-up was crystallized from acetonitrile. Colorless solid (86%). MS (Turbo Spray): m/z=604.3 [M+H].
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:8]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:7][C@@H:6]1[O:36][C@H:37]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C@@H:38]1[S:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)C.[Na]>C1(C)C=CC=CC=1.CO>[CH2:12]([O:11][C@H:10]1[C@H:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:8]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:7][C@H:6]([O:36][C@H:37]2[C@@H:49]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@H:48]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[O:46][C@@H:38]2[S:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:5]1[OH:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)O[C@@H]1[C@@H](O[C@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2Sc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: O[C@@H]1[C@@H](O[C@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2Sc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Compound 14 (6 g, 5.9 mmol) was dissolved in 40 ml of a toluene/methanol (1/1) mixture). We then added sodium (cat.). After 15 min, the solution was neutralized with Amberlite resin IR 120 (H+), filtered and concentrated. Silica gel chromatography (elution: cyclohexane/ethyl acetate=3/1) of the crude product yielded 16 (5.45 g, 95%) in the form of a colorless syrup.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)[CH3:2].[ClH:20].[CH:21](O)=O>C=O.CCOCC>[ClH:20].[ClH:20].[CH2:1]([N:3]([CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:10]1)[CH3:21])[CH3:2]
Reactant: CCNCC1CCN(CCOc2ccccc2)CC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Solvent: CCOCC
Product: CCN(C)CC1CCN(CCOc2ccccc2)CC1

Procedure:
A solution of 4-(ethylaminomethyl)-1-(2-phenoxyethyl)piperidine (3.0 g) in 98% formic acid (2.2 ml) and 37% aqueous formaldehyde (2.06 ml) was heated on a steam bath for 5 hours. Work up as described in Example 10 gave an oil which was dissolved in ether and treated with ethereal hydrogen chloride solution to give a solid which was collected by filtration and recrystallised from absolute ethanol to give 4-(N-ethyl-N-methylaminomethyl)-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 248°-250° C.