Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH3:8])C.[H][H]>O1CCCC1.[Rh]>[C:12]([O:11][C:9]([N:6]([CH2:7][CH3:8])[C@H:5]([C:4]([OH:23])=[O:3])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)OC(C)(C)C
Agent: [Rh]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](CC1CCCCC1)C(=O)O
Yield: 82.6 %

Procedure:
To a mixture of 2.65 g (10 mmole) of Boc-Phe in 50 ml of cold (ca. -78°), dry tetrahydrofuran was added 12 ml (ca. 22 mmole) of 1.9M t-butyllithium. After thirty minutes, the mixture was allowed to warm to -20° and then to react with 4.2 g (22 mmole) of triethyloxonium tetrafluoroborate. After thirty minutes, the mixture was allowed to warm to 0° and was then poured into water and extracted with dichloromethane. The organic extract was washed sequentially with portions of 5% aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered, and concentrated to dryness. Distillation (ca. 130°-200°) afforded an oil that was further purified by column chromatography on silica gel to give t-butoxycarbonyl-N-ethylphenylalanine ethyl ester. To a stirred mixture of this ester intermediate in tetrahydrofuran was added a two-fold (molar) quantity of potassium hydroxide in water. After the mixture was stirred overnight, an equal volume of dichloromethane was added and acidified to pH 3 with 0.5M sodium bisulfate. The aqueous layer was separated and washed with dichloromethane, and all organic layers were recombined. This organic solution was further washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to dryness. Column chromatography on silica gel afforded de-esterified t-butoxycarbonyl-N-ethylphenylalanine. A solution of 2.6 g of this protected amino acid intermediate in about 100 ml of tetrahydrofuran was catalytically hydrogenated at 80° using 60 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate was concentrated to an oil which crystallized on standing to afford 2.0 g of the title compound. The title compound was used in subsequent reactions without further purification.
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][O:12][C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:22])C1C=CC=CC=1>[Ni]>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:22])[C:13]=1[O:12][CH2:11][C@H:10]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:9]([OH:31])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(Cl)cccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Ni]
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1Cl)C(=O)O
Yield: 91 %

Procedure:
In an analogous manner to that described in example 5b), the hydrogenation of (S)-2-tert-butoxycarbonylamino-3-(2-chloro-6-nitro-phenoxy)-propionic acid benzyl ester using Raney-nickel instead of palladium as the catalyst yielded (91%) the title compound as a light brown foam, MS m/e (%): 329.3 (M−H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:26])[C:21]=2[CH:20]=1>C1COCC1>[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[C:12]([O:14][CH3:15])=[O:13])(=[O:28])=[O:29])=[C:25]([CH3:26])[C:21]=2[CH:20]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.5 %

Procedure:
Into 8 mL of THF was dissolved 115 mg of dimethyl 4-aminoisophthalate, followed by addition of 22 mg of sodium hydride (oily, 60%). After 20 minutes of stirring at room temperature, 130 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at the same temperature, followed by 30 minutes of stirring at room temperature. Further, 26 mg of sodium hydride (oily, 60%) was added and the whole was heated under refluxing for 6 hours. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane 1/1) to obtain 62 mg of the title compound as light yellow amorphous.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=O)[C:6]([C:12]([NH:14][C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:16]=2[CH2:24][CH3:25])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([C:4]1[C:5]([Cl:29])=[C:6]([C:12]([NH:14][C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:16]=2[CH2:24][CH3:25])=[O:13])[C:7]([CH3:11])=[N:8][C:9]=1[CH3:10])[CH:2]=[CH2:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=CCc1c(C)[nH]c(C)c(C(=O)Nc2c(CC)cc(C)cc2CC)c1=O
Product: C=CCc1c(C)nc(C)c(C(=O)Nc2c(CC)cc(C)cc2CC)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.85 g (2.41 m mol) of 5-allyl-N-(2,6-diethyl-4-methylphenyl)-1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide and 5 ml of phosphorus oxychloride was heated under reflux for an hour. An excess of phosphorus oxychloxide was removed under vacuum, and the residue was dissolved in 100 ml of methylene chloride. Then the resulting solution was added into 150 ml of saturated sodium bicarbonate solution, followed by stirring for an hour at room temperature. The organic layer was washed with water, dried and concentrated by the conventional method. The resultant crystalline residue was recrystallized from ethyl acetate to give 0.84 g of the title compound, m.p. 192.5°-194° C.
Reaction SMILES: S(=O)(=O)(O)O.[C-]#[N:7].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([CH3:21])(O)[CH3:19])=[CH:12][CH:11]=1.[OH-].[Na+].[ClH:24]>C(Cl)(Cl)Cl>[ClH:24].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([CH3:21])([NH2:7])[CH3:19])=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: CC(C)(O)CCc1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(N)CCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
Sulphuric acid (d. 1.84, 18 ml) was added dropwise over 10 min. to an ice-cold stirred suspension of potassium cyanide (9.5 g) and 4-(4-fluorophenyl)-2-methyl-2-butanol (10.0 g) in chloroform (80 ml). The mixture was allowed to warm to room temperature and was stirred over 20 hr. The mixture was basified with 5 N sodium hydroxide solution and was extracted with chloroform. The solvent was removed to leave a pale yellow oil which was treated with hydrochloric acid (d. 1.18, 30 ml) at reflux for 1 hr. The product (9.0 g) crystallised from the acid solution as colourless plates, m.p. 200°-201°.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of isonipecotic acid (12.9 g, 100 mmol) in 2N NaOH (55 mL) was cooled to 0° C. in an ice-bath. Benzylchloroformate (15.7 mL, 110 mmol, 1.1 eq.) and 2N NaOH (55 mL) were then added in about 10 portions, alternatively. The reaction mixture remained distinctly alkaline. The temperature of the reaction mixture was kept between 5 and 10° C. by controlling the rate of addition of reactants (about 45 min). The ice-bath was removed and the mixture was stirred at room temperature for 30 min. TLC showed the reaction was completed. The alkaline solution was extracted with Et2O (4×50 mL). The aqueous layer was acidified using 6N HCl to pH ˜5, extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with saturated brine (100 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to give 1-benzyloxycarbonyl-piperidine-4-carboxylic acid as a white solid (17.3 g, 66 mmol, 66%). 1H NMR (300 MHz, CDCl3): δ 7.35 (m, 5H), 5.14 (s, 2H), 4.12 (m, 2H), 2.97 (t, 2H), 2.53 (m, 1H), 1.95 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[Na+].Cl>CCO>[CH2:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:18])=[O:2])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(CCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(CCc2ccccc2)c1
Temperature: 25 °C

Procedure:
75B (660 mg, 2.75 mmol) was suspended in EtOH (2 mL) and aqueous NaOH (1 M, 6 mL) and was heated to 80° C. for thirty minutes. Upon cooling to room temperature, the solution was acidified with HCl (concentrated), was cooled to 0° C., and was filtered. The white crystalline precipitate was dried under vacuum (356 mg, 57%). NMR 1H (ppm, CDCl3): 7.96-7.91 (m, 2H), 7.40-7.36 (m, 2H), 7.30-7.15 (n, 5H), 3.02-2.90 (m, 4H).
Reaction SMILES: [C@@:1]12(O)[CH2:9][C@@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10].CS(C)=[O:15].N1C=CC=CC=1>C(N(CC)CC)C>[OH:11][C:2]1([CH3:10])[C:3](=[O:15])[CH2:4][CH:5]2[CH2:9][CH:1]1[C:6]2([CH3:8])[CH3:7]
Reactant: CS(C)=O
Reactant: CC1(O)CC[C@H]2C[C@]1(O)C2(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(O)C(=O)CC2CC1C2(C)C

Procedure:
oxidizing cis-pinanediol with DMSO activated by pyridine.SO3 and triethylamine in an appropriate solvent to form 2-hydroxy-3-pinanone;
Reaction SMILES: [C:1]([O-:5])(=O)[CH2:2][OH:3].C=C.[Na+].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)([O-:11])=[O:10].O>C(O)CO>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:3][CH2:2][CH2:1][OH:5])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])CO
Agent: C=C
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
200 ml of ethylene glycol and 40 ml of a 14.4% strength mono-sodium ethylene glycolate solution were introduced initially under nitrogen and were heated to 65° C. in a 2 l reaction vessel fitted with a stirrer. Over the course of 5 h, 162 g of molten 2,4-dinitrochlorbenzene and a further 480 ml of a 14.4% strength mono-sodium ethylene glycolate solution in ethylene glycol were simultaneously metered in. The mixture was then stirred for one hour at 65° C., and then 600 ml of water were added. The precipitate which formed was filtered off and washed with 1000 ml of water and dried, giving 161.3 g of 2-(2′,4′-dinitrophenoxy)-ethanol in a purity of 97%. Hence, a yield of 92.2% is achieved based on 2,4-dinitrochloro-benzene.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:23]([C:24]2[CH:29]=[CH:28][C:27](OC)=[C:26]([C:32](=[O:44])[NH:33][C:34]3([C:38]4[N:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:37][O:36][CH2:35]3)[CH:25]=2)=[CH:22][C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>CN(C1C=CN=CC=1)C.O>[CH2:1]([N:3]([C:4]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:32](=[O:44])[NH:33][C:34]3([C:38]4[N:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:37][O:36][CH2:35]3)[CH:25]=2)=[CH:22][C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[S:52]([CH3:51])(=[O:54])=[O:53])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNc1cc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)COC2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC2(c3ncccn3)COC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(ethylamino)-2-(4-fluorophenyl)-5-(4-methoxy-3-((3-(pyrimidin-2-yl)oxetan-3-yl)carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (90 mg, 0.151 mmol), pyridine (5.0 mL), DMAP (18.46 mg, 0.151 mmol) and methanesulfonyl chloride (0.018 mL, 0.227 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (20 ml×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by prep HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=2)[N:27]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([C:28]([C:31]([F:32])([F:34])[F:33])=[N:29][N:30]=4)[N:27]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Product: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(6-bromonaphthalen-2-yl)sulfonylpiperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(6-bromonaphthalen-2-yl)sulfonylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[C:17]([Cl:20])[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:2].[CH:22](OCC)(OCC)OCC>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:22]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[Cl:20])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Nc2ncnc(Cl)c2N)cc1
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)Cc1ccc(-n2cnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(5-amino-6-chloro-pyrimidin-4-ylamino)-phenyl]-acetic acid ethyl ester (0.178 g, 0.58 mmol) and triethyl orthoformate (4 mL, 23.3 mmol, 40 equiv) is stirred for 1 h at reflux. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound as a red solid: ES-MS: 317.0 [M+H]+; tR=4.06 min (System 1).
Reaction SMILES: [O:1]([CH2:8][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C-:21]#[N:22].C([Al+]CC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[NH2:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:21]#[N:22]
Reactant: N#CCOc1ccccc1
Reactant: [C-]#N
Agent: CC(C)C[Al+]CC(C)C
Agent: CC[Al+]CC
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CC(N)COc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
5 millimoles (0.665 g) of phenoxy-acetonitrile are dissolved in 8 ml of anhydrous toluene at 0° C., under an argon atmosphere 7.5 millimoles of a toluenic solution 1.5 M of diisobutylaluminum hydride (5 ml) are added dropwise, at this temperature. The stirring is maintained for 1 hour at 0° C., then 5.9 ml (1.3 eq) of diethylaluminum cyanide are added. The reaction mixture is stirred for 3 hours at room temperature, then hydrolyzed with 4 ml of methanol and pasty sodium sulfate. After purification by high pressure liquid chromatography on silica, there are obtained 0.182 g of 2-amino-3-phenoxy-propionitrile, in form of a cream-colored solid-state product; M.P. 65° C., yield: 22%.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:30])[C:14]=2[C:18](=[O:29])[NH:19][CH2:20][C:21]2([OH:28])[CH2:26][CH:25]3[CH2:27][CH:22]2[CH2:23][CH2:24]3)[C:9]1=[O:31])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:30][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:31])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:19][CH2:20][C:21]1([OH:28])[CH2:26][CH:25]2[CH2:27][CH:22]1[CH2:23][CH2:24]2)=[O:29]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCC3(O)CC4CCC3C4)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCC3(O)CC4CCC3C4)c(Cl)ccc2c1=O

Procedure:
A mixture of (2R)-2-(6-chloro-5-((2-hydroxybicyclo[2.2.1]heptan-2-yl)methylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (31 mg, 0.000042 mol) and potassium carbonate (23 mg, 0.00017 mol) was stirred in methanol (3 mL, 0.07 mol) at room temperature for 1 hour and concentrated. The residue was purified by reverse phase preparative HPLC and then by flash chromatography to afford a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=O)[CH2:5][C:4]1([CH3:13])[CH3:12].[CH2:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:21][CH:6]2[CH2:7][C:8]([CH3:9])([CH3:10])[N:3]([O:2][CH3:1])[C:4]([CH3:13])([CH3:12])[CH2:5]2)[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: NCCCCCCN
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Product: CON1C(C)(C)CC(NCCCCCCNC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C

Procedure:
The product is prepared as described in Example II-1, by reaction of 185.3 g (1 mole) of 1-methoxy-2,2,6,6-tetramethyl-4-oxopiperidine and 60.4 g (0.52 moles) of 1,6-hexanediamine.
Reaction SMILES: [N:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22]CC)=[O:21].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:18]([CH2:25][CH2:26][CH3:27])=[C:19]([C:20]([OH:22])=[O:21])[N:3]=[N:2]2)=[CH:16][CH:15]=1)=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
4-Azido-N-butylbenzamide (2.3 g) obtained in Example 56a) and ethyl 3-oxohexanoate (1.06 ml, 6.33 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (479 mg, 6.33 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.62 g, 4.91 mmol, 97.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:30])=[C:11]([CH:15]([C:23]2[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=2)[NH:16][C:17]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=C(C(N)C2C(Cl)=NC=C[N:47]=2)C=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C1(C(Cl)=O)CCC1>C(Cl)Cl>[NH2:47][C:28]1[C:23]2[N:24]([C:17]([CH:19]3[CH2:22][CH2:21][CH2:20]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:30])[CH:25]=[CH:26][N:27]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl)C1CCC1
Reactant: NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl
Agent: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
N-[(3-benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl)methyl]cyclobutylcarboxamide: To a solution of C-(3-benzyloxy-2-fluoro-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine (1.1 g, 3.2 mmole) in methylene chloride (10 mL) was added diisopropylethylamine (1.1 mL, 6.4 mmole) under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and cyclobutanecarboxylic acid chloride (0.55 mL, 4.8 mmole) was added in one portion. The reaction mixture was stirred overnight at room temperature then quenched with water (10 mL). The organic layer separated and washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (60:40) as an eluant to give the title compound (911 mg, 67%). FAB-MS: m/z 426.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18]1([CH:24]=[CH:25][CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>>[C:18]1([CH:24]=[CH:25][CH2:26][C:27]([O:17][C@H:14]2[CH2:15][CH2:16][C@@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Reactant: O=C(Cl)CC=Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@@H](OC(=O)CC=Cc3ccccc3)CC2)cc1

Procedure:
from cis-4-(4-dimethylaminomethylphenyl)-cyclohexanol and 4-phenyl-3-butenoic acid chloride/triethylamine. White crystals.