Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:4].[CH2:25]([NH:32][CH2:33][CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:32]([CH2:33][CH3:34])[C:16](=[O:18])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
(4-{2-[2-(methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.150 g, 0.454 mmol) was dissolved in DMF (10 ml), N-benzyl-N-ethylamine (0.061 g, 0.454 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.160 g, 0.499 mmol) and N-ethyl-N,N-diisopropylamine (0.123 g, 0.954 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.138 g of methyl 2-[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 67.9%).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[CH3:23][O:24]C1C=C(C=CC=1)N>CO>[Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:24][CH3:23])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3]
Reactant: COc1cccc(N)c1
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CO
Product: COc1cccc(-[n+]2ccc(C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)-pyridinium chloride (43.2 g, prepared in a similar manner to that described in Example 2), 3-methoxyaniline (34 g) and methanol (1500 ml) was stirred at ambient temperature for 16 hours. The mixture was then warmed at 40° C. for 30 minutes, and stirring was continued for 2 hours at ambient temperature, then the solvent was removed in vacuo. Ether was added to the resulting oily solid and the solid collected by filtration. The solid was triturated in hot 2-propanol (11), collected by filtration and dried. The solid was triturated in hot acetone, collected by filtration and dried to give 4-carbamoyl-1-(3-methoxyphenyl)pyridinium chloride as a beige solid (32.4 g), m.p. 272° C. (dec).
Reaction SMILES: NC1SC(CC2C=CC=CC=2)=CC=1[C:7]([NH2:9])=[O:8].[NH2:17][C:18]1[S:19][C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[C:28]1([CH:26]([C:20]2[S:19][C:18]([NH:17][C:7]([NH2:9])=[O:8])=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=2)[CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=O)c1cc(Cc2ccccc2)sc1N
Reactant: CC(c1ccccc1)c1cc(C(N)=O)c(N)s1
Product: CC(c1ccccc1)c1cc(C(N)=O)c(NC(N)=O)s1
Yield: 87 %

Procedure:
5-(1-Phenyl-ethyl)-2-ureido-thiophene-3-carboxylic acid amide was prepared by the same procedure as Example 6b except that 2-amino-5-benzyl-thiophene-3-carboxylic acid amide was replaced with 2-amino-5-(1-phenyl-ethyl)-thiophene-3-carboxylic acid amide to give the above titled compound as a light brown solid (87% yield). LC-MS [M+H]+ m/z 290.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]1([SH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CS(C)=O>[CH:7]1([S:13][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: SC1CCCCC1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccccc1SC1CCCCC1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
To a stirred suspension of K2CO3 (4.5 g, 32.6 mmol) and cyclohexylmercaptan (2.0 mL, 16.4 mmol) in DMSO (20 mL) was added 2-fluorobenzaldehyde (1.7 mL, 16.2 mmol) dropwise over 10 minutes at room temperature, and the reaction mixture was heated at 100° C. for 5 hours with stirring. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous phase extracted with ethyl acetate (×3). The combined organic extracts were washed successively with sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 2-(cyclohexylthio)benzaldehyde (3.22 g, 14.6 mmol, 90%) which was used directly without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=3[F:38])[N:26]=[CH:27][C:20]=12.O>C1COCC1>[F:38][C:29]1[CH:30]=[C:31]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:32]=[CH:33][C:28]=1[N:25]1[C:21]2=[N:22][CH:23]=[N:24][C:19]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)=[C:20]2[CH:27]=[N:26]1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1noc(N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (338 mg, 1.6 mmol) and sodium hydride (87 mg, 3.66 mmol) were stirred together in dry THF (2 mL) at room temperature for 30 minutes. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine was then added and the reaction continued to stir at room temperature for 45 minutes. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted with ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided the desired Compound A198 as a white solid (600 mg, 98%). Exact mass calculated for C22H24FN7O4S 501.53, found 502.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:23])[O:22][C:14]2(C(OC)=O)[C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1.[OH-].[K+].Cl>CO>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:23])[C:14](=[O:22])[C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1
Reactant: COC(=O)C1(C(N)=O)OC1(C)c1ccc(-c2sccc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccsc1-c1ccc(C(C)C(=O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In 5 ml of methanol was dissolved 3.32 g (0.010 mole) of 3-[4-(3-methyl-2-thienyl)phenyl]-2,3-epoxy-2-methoxycarbonylbutyramide, followed by gradual addition of 15 ml (0.015 mole) of 1 N methanol solution of potassium hydroxide. The mixture was stirred at room temperature for one hour and freed from methanol by distillation under reduced pressure, and 40 ml of water was added thereto and 20 ml of benzene was then added to remove impurities, and the mixture was shaken thoroughly. The aqueous layer was separated, and 17 ml (0.017 mole) of 1 N hydrochloric acid was gradually added thereto, after which the mixture was heated with stirring to 90° C. to effect decarboxylation. After one hour of heating, the aqueous mixture was cooled and extracted with 70 ml of diethyl ether. The ether extract solution was dried over anhydrous magnesium sulfate and freed from diethyl ether by distillation under reduced pressure to obtain 2.10 g (77% yield) of 3 -[4-(3-methyl-2-thienyl)phenyl]-2-oxobutyramide.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].O=[CH:15][CH2:16][N:17]1[C:21]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@H:4]([NH:3][CH2:15][CH2:16][N:17]1[C:21]3[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]1)[CH2:5]2
Reactant: COC(=O)c1cccc2ncn(CC=O)c12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of (S)-(−)-3-aminoquinuclidine dihydrochloride (0.2 g, 0.8 mmol) in methylene chloride (2 mL) was added sodium hydride (0.1 g, 1.6 mmol) and the mixture was stirred for 2 h. A solution of methyl 1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, 0.7 mmol) from Step E above in methylene chloride (3 mL) was added followed by acetic acid (0.7 mL) and the mixture was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (0.4 g, 2.1 mmol) was then added in portions and the reaction was stirred at room temperature overnight. The crude reaction was quenched with methanol, concentrated under reduced pressure, and purified by preparative thin layer chromatography (90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, quantitative yield): MS (ESI+) m/z 329 (M+H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5](=[N:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6].CN(C)C1CCCCC1.Cl.CN(C)C1CCCCC1>O.C(Cl)Cl>[CH:5]([N:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:1]([Cl:4])=[O:2])=[CH2:6]
Reactant: CC=NC(C)(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CN(C)C1CCCCC1
Solvent: O
Solvent: ClCCl
Product: C=CN(C(=O)Cl)C(C)(C)C
Yield: 80 %

Procedure:
60 parts of phosgene are introduced into 224 parts of methylene chloride. 39.6 parts of ethylidene-tert.-butylamine, 51 parts of dimethylcyclohexylamine and 210 parts of methylene chloride are added to this solution in the course of one hour at from 0° to 5° C., whilst stirring. The mixture is then stirred for 30 minutes, after which the reaction solution is freed from excess phosgene. The mixture is now thoroughly mixed with 250 parts of water at 0° C., whereupon the dimethylcyclohexylamine hydrochloride passes into the aqueous phase. This aqueous phase is separated off and neutralized with sodium hydroxide solution, and the dimethylcyclohexylamine is recovered by distillation. The organic phase is distilled. 52 parts of N-vinyl-N-tert.-butylcarbamoyl chloride (80% of theory) boiling at 85° C./14 mm Hg are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH:20]3[CH2:21][CH2:22][CH2:23][CH:16]2[CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:20]3[CH2:21][CH2:22][CH2:23][CH:16]2[CH2:17][CH2:18][CH2:19]3)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(OCc3ccccc3)cc2)C2CCCC1CCC2
Agent: Cl
Solvent: CCO
Product: c1ccc(COc2ccc(C3C4CCCC3CCC4)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
9-(4-Benzyloxy-phenyl)-bicyclo[3.3.1]nonan-9-ol (4.7 g, 14.57 mmol) (prepared in accordance with the procedures set forth in Step 2 of Example 18) was dissolved in EtOH (150 mL) after which concentrated hydrochloric acid (15 mL) was added. This mixture was stirred at 50° C. overnight. The solvent was removed under reduced pressure. Water (50 mL) was added. The mixture was basified with aqueous ammonia and extracted three times with EtOAc. The organic phase was dried and concentrated to provide the title compound (5.5 g).
Reaction SMILES: C([O:8][C:9]1[C:18]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13](C(OCC1C=CC=CC=1)=O)[CH2:14]2)C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C:9]1[C:18]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH2:14]2
Reactant: CN(C)c1ccc2c(c1OCc1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc2c(c1O)CCNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methanol (40 mL), Palladium carbon (400 mg) and benzyl 5-(benzyloxy)-6-(dimethylamino)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.6 g, 3.84 mmol, 1.00 equiv). To the above H2 gas was introduced in. The resulting solution was stirred overnight at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1 g (crude) of 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline as brown oil. MS (ESI) m/z 193 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][C:3]2[CH2:7][N:8](C(OCC)=O)[CH2:9][C:2]1=2.[ClH:15]>>[ClH:15].[ClH:15].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][NH:8][CH2:9][C:2]=12
Reactant: CCOC(=O)N1CC2=C(C1)NCC=C2
Agent: Cl
Product: c1cnc2c(c1)CNC2

Procedure:
8.5 g (44 mmol) of ethyl 5,7-dihydro-1H-pyrrolo-[3,4-b]pyridine-6-carboxylate are refluxed overnight in 90 ml of concentrated hydrochloric acid. The solution is concentrated, the residue is stirred with acetone, and the salt is filtered off with suction and dried in the air.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[CH2:23]([O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O.O>[CH2:23]([O:25][C:26]1[C:31]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[N:7][C:6]=23)=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:24]
Reactant: CCOc1ncccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOc1ncccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Temperature: 85 °C
Yield: 68.1 %

Procedure:
To a 1 liter round bottom flask was added 15.00 g (40.76 mmol) of isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate, 8.85 g (52.99 mmol) of (2-ethoxypyridin-3-yl)boronic acid, 14.06 g (101.90 mmol) of K2CO3, 1.41 g (1.22 mmol) of P(PPh3)4, and a stirring rod. After adding all the solids, 200 ml of MeCN was added, followed by the addition of 100 mL of water. The reaction flask was plunged into an oil bath pre-heated to 85° C., and stirred vigorously. This reaction was setup to reflux. After stirring at 85° C. for about 16 hr, it was allowed to cool to RT and diluted with 200 mL of EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with 80 mL portions of EtOAc. The combined organic layers was washed with brine, dried over MgSO4, and concentrated. A small volume of DCM was used to dissolve the crude mixture, and then loaded directly onto a 750 g silica gel column for separation on the ISCO-XL. A gradient of 50% EtOAc/hex to 100% EtOAc was run for the first 35 minutes. The desired product did not elute, only some impurities eluted. However, about 10 minutes into running with 100% EtOAc, the desbromo side product starts eluting together with the desired product. Even though the desbromo compound is spread through all the fractions containing the desired product, the percentage of the desbromo compound seem to decrease with time. Therefore, the initial fractions containing the highest percentages of the desbromo were discarded, and the remaining fractions were concentrated to obtain 13.46 g of about 86% purity at 254 nm. (with about 14% desbromo compound). This material was recrystallized twice, using IPAC and heptanes, to obtain 11.4 g (68%) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 1.53 (t, J=7.07 Hz, 3 H) 3.59-3.70 (m, 4H) 3.70-3.81 (m, 4 H) 4.53 (q, J=7.07 Hz, 2 H) 5.00 (dt, J=12.44, 6.28 Hz, 1 H) 6.38 (d, J=7.83 Hz, 1 H) 6.98 (dd, J=7.45, 4.93 Hz, 1 H) 8.01 (dd, J=4.93, 1.89 Hz, 1H) 8.37 (d, J=7.83 Hz, 1 H) 8.70 (s, 1 H) 8.76 (dd, J=7.45, 1.89 Hz, 1 H). LRMS (ESI) m/e 411 [(M+H)+, calcd for C21H26N6O3 410].
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]([CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17](=[O:28])[C:12]([C:13]([O:15]C)=[O:14])=[CH:11]2)=[CH:6][CH:5]=1.C(O)(=O)C>C(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]([CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][C:17](=[O:28])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c(C=Cc2cccnc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(C=Cc2cccnc2)cc1=O
Yield: 82.6 %

Procedure:
In a mixture of 9 ml of ethanol and 9 ml of a 10% by weight aqueous sodium hydroxide solution was suspended 0.45 g of methyl 1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinate and the suspension was subjected to reaction at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration and dried to obtain 0.357 g of 1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinic acid having a melting point of 250° C. or more.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:25][CH2:24]3)[CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:25][CH2:24]3)[CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (525 mg, 1.28 mmol) and 0.15 mL of 70% HClO4 in DCM (10 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes) using an Isolera chromatography station gave (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 264 mg (44%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.92/5.87 (s, 1H), 4.91-4.85 (m, 1H), 3.47/3.27 (br. s, 1H), 3.17-3.10 (m, 2H), 2.94-2.91 (m, 1H), 2.52 (s, 3H), 2.41 (s, 3H), 2.16/2.07 (br. s., 1H), 1.86-1.77 (m, 2H), 1.15-1.12 (m, 12H), 1.06-1.03 (m, 3H), 0.92-0.87/0.80-0.78 (m, 1H), 0.47-0.37 (m, 2H), 0.19-0.10 (m, 2H). UPLC (M+H)=469.3.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(OC(C)C)(=O)C.[F:13][C:14]1([F:65])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C@@H:28](O)[CH2:27][C:26]([CH3:32])([CH3:31])[CH2:25][C:24]=3[N:23]=[C:22]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]4[N:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:41][N:40]=4)[CH2:35][CH2:34]3)[C:21]=2[C@@H:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:16][CH2:15]1>>[CH3:1][S:2]([O:5][C@H:28]1[CH2:27][C:26]([CH3:31])([CH3:32])[CH2:25][C:24]2[N:23]=[C:22]([CH:33]3[CH2:34][CH2:35][N:36]([C:39]4[N:40]=[CH:41][C:42]([O:45][CH2:46][CH2:47][CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:43][N:44]=4)[CH2:37][CH2:38]3)[C:21]([C@@H:53]([F:64])[C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:61])[F:63])=[CH:58][CH:59]=3)=[C:20]([CH:17]3[CH2:18][CH2:19][C:14]([F:65])([F:13])[CH2:15][CH2:16]3)[C:29]1=2)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: CS(=O)(=O)O
Solvent: CC(=O)OC(C)C
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](OS(C)(=O)=O)C1
Yield: 80.2 %

Procedure:
Reactions similar to those of Example 13 were performed except for using 3.8 μl (57 μmol) of methanesulfonic acid instead of 35% hydrochloric acid and using 1.5 ml of isopropyl acetate instead of acetone, and from 40.0 mg (52.0 μmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 28, 35.3 mg of the title compound was obtained as a white powder (yield: 78%).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:16][C:17]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14].[C:26](=[O:28])=[O:27]>C(OCC)C>[CH2:12]([O:16][C:17]1[C:25]2[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C=O
Reactant: CC(C)COc1cccc2sccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)COc1cccc2sc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.6 M solution of n-butyl lithium in hexane (18 ml, 28.8 mmol) is dissolved under an argon atmosphere in 100 ml of dry diethyl ether, followed by dropwise addition of a solution of 4-Isobutoxy-benzo[b]thiophene (201, 5.4 g, 26.1 mmol) in 40 ml of diethyl ether. The reaction mixture is refluxed for 45 min, then cooled down and transferred via syringe to a mixture of excess dry ice (115 g, 2.61 mol) in diethyl ether (the dry ice is washed before twice with diethyl ether). The mixture is allowed to stir overnight at room temperature, then distributed between diethyl ether and water. The ether layers are reextracted with water. The aqueous layers are acidified with 2M aqueous HCl solution, and the precipitate is filtered off, washed with water and dried under high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C@@H:28]([OH:34])[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:19][C@H:20]([C@@H:28]([OH:34])[CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:18])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of N-t-butoxycarbonyl-L-histidine (363 mg) and 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (294 mg) in dry N,N-dimethylformamide (30 ml) which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (390 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (144 mg). The mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 10% citric acid solution, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (chloroform as eluent) to give 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (384 mg) as an amorphous powder.