Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].C([C@@H]1CC[C@@H](C)C[C@H]1OC([N:17]1[CH:22]=[CH:21][C:20](=[O:23])[CH2:19][C@@H:18]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH3:31])=O)(C)C>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C@H:18]2[CH2:19][C:20](=[O:23])[CH:21]=[CH:22][NH:17]2)=[C:25]([CH3:31])[CH:26]=1
Reactant: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1
Yield: 161 %

Procedure:
Sodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture was refluxed for two hours and the solvent was removed in vacuo. The residue was partitioned between water (10 mL) and AcOEt (15 mL). The layers were separated, and the aqueous phase was extracted with further AcOEt (4×10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([OH:3])=[O:2]>S(=O)(=O)(O)O>[O:13]=[C:11]1[C:6]2[C:7](=[CH:14][CH:15]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[O:8][CH2:9][CH2:10]1
Reactant: O=C(O)CCOc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)C(=O)CCO2
Yield: 70 %

Procedure:
3-(4-Carboxyphenoxy)propionic acid (2.5 g) [prepared according to the procedure of J. Lichtenberger and R. Geyer. Bull. Soc. Chim. Fr., 1963 275] in conc. sulfuric acid (20 ml) was heated to 100° C. for 4 h and then poured onto crushed ice. The resultant precipitate was filtered and dried in vacuo to give the title compound (1.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][C:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:34])[C:31](O)=[O:32].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:31](=[O:32])[C:30]([CH3:29])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:34])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)C(C)(C)c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4′-(4-Aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.038 g, 0.1 mmol), α,α-dimethylphenylacetic acid (0.020 g, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.023 g, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (0.016 g, 0.12 mmol), and triethylamine (0.56 mL, 0.4 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10].[OH-].[K+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(C)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccccc1Cl
Yield: 84.3 %

Procedure:
A solution of ethyl 2-(2-chlorophenyl)-2-methylpropanoate (3.48 g, 15.4 mmol) and KOH (8.61 g, 154 mmol) in EtOH/water (1:1, 200 mL) was heated at 150° C. in a sealed vessel for 2 hours. The solution was concentrated in vacuo, suspended in diethyl ether (200 mL), and extracted with 1N NaOH(aq) (3×100 mL). The aqueous solution was made acidic with concentrated HCl and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, concentrated, and dried in vacuo to give to give 2-(2-chlorophenyl)-2-methylpropanoic acid (2.578 g). MS m/e=199 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:13])=[N-]>CCOCC>[CH:1]1([CH2:7][C:8]([O:10][CH3:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CC1CCCCC1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
To an ice-cooled and stirred solution of cyclohexylacetic acid (9.34 g, 0.066 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl cyclohexylacetate (7.45 g, 0.048 mol, yield 72.4%, b.p. 86°-88° C./12 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([N:21]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]1=[O:27])(=[O:20])[NH2:19].O>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[C:25]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:26])/[CH:24]=[CH:23]\[C:22](=[O:27])[NH:21][C:18](=[O:20])[NH2:19]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 49 g of hexadecanol (0.202 moles), 28 g of N-carbamylmaleimide (0.2 moles) and 270 mg of zinc chloride (0.002 moles) in 300 mL of p-dioxane was heated to reflux. After 24 hours, the mixture was cooled to room temperature and 200 mL of H2O was added. The resulting solid was filtered, washed with additional H2O and dried to afford 75 g (97% yield) of hexadecyl maleurate. M.P.: 106°-09° C. (dec.); 1H NMR (CDCl3): δ10.5 (br s, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.4 (br s, 1H), 4.2 (t, 2H), 1.6 (m, 2 H), 1.2 (m, 26H), 0.9 (t, 3H); HPLC (80% CH3CN/H2O, C18): Rt=6.9 minutes.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH:6]2[CH2:12][CH2:13][C:14]([NH:16][C:17]1C=CC(C(F)(F)F)=C[N:18]=1)=[O:15].NC1[S:38][CH:39]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])N=1>>[CH2:45]([O:44][C:42]([C:40]1[N:18]=[C:17]([NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH:6]2[C:7]3[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[F:11])[C:4](=[O:35])[N:5]2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[S:38][CH:39]=1)=[O:43])[CH3:46]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(CCC1c2c(F)ccc(F)c2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(F)(F)F)cn1
Product: CCOC(=O)c1csc(NC(=O)CCC2c3c(F)ccc(F)c3C(=O)N2Cc2ccc(F)cc2)n1

Procedure:
The product from Example 18, Part A (100 mg, 0.29 mmol) and ethyl 2-amino-1,3-thiazole-4-carboxylate were converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (80 mg, 55%). 1H (300 MHz, CDCl3) δ 10.31 (s, 1H), 7.77 (s, 1H), 7.28 (m, 2H), 7.12 (m, 1H), 6.99 (m, 3H), 5.21 (d, J=15 Hz, 1H), 4.65 (m, 1H), 4.32 (q, J=7 Hz, 2H), 4.12 (d, J=15 Hz, 1H), 2.57 (m, 2H), 2.14 (m, 1H), 2.08 (m, 1H), 1.35 (t, J=7 Hz, 3H). MS: m/z (MH+) 504.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C@@H:3]1[OH:14].[ClH:16]>CO.[Pd]>[ClH:16].[CH3:1][C:2]1([CH3:15])[CH2:6][NH:5][CH2:4][C@@H:3]1[OH:14]
Reactant: CC1(C)CN(Cc2ccccc2)C[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)CNC[C@@H]1O
Reaction time: 48 h
Yield: 91.9 %

Procedure:
To a solution of (3R)-4,4-dimethyl-1-(phenylmethyl)-3-pyrrolidinol (J. Med. Chem. 1992, 35, 4205-4213) (1.8634 g, 9.076 mmol) in MeOH (45 mL) was added 1 N aq. HCl (9.1 mL, 9.1 mmol) and 10% Pd/C (50% water, 375 mg). The mixture was hydrogenated under balloon pressure for 2 days, and was then filtered. The solution was concentrated in vacuo and azeotroped with MeOH (4×20 mL) to give (3R)-4,4-dimethyl-3-pyrrolidinol hydrochloride (1.2654 g, 93% yield) as an amber solid. LCMS: (M+H)+: 116.1.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=2)[CH:10]=1)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)[CH:10]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2ccc(CCC#N)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
A stirring mixture of ethyl 6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxylate (74) (100 mg, 0.411 mmol) and 2N LiOH (0.2 mL) in THF:MeOH (4:1, 3 mL) was heated at 50° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (75) was dried and used in the next step without further purification. MS m/z 416.07 (M+1)+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CC(O)CN
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reaction time: 0.75 h
Yield: 61.5 %

Procedure:
A solution of 2.08 g of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 3:7). 1.52 g (61%) of (RS)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CON(C)[C:16]([C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)=[O:17]>>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CON(C)C(=O)c1cnccn1
Reactant: Cc1c(F)ccc(C(=O)O)c1F
Product: Cc1c(F)c(C(=O)O)cc(C(=O)c2cnccn2)c1F

Procedure:
Starting materials: 2,4-difluoro-3-methylbenzoic acid (Intermediate 46) and N-methoxy-N-methylpyrazine-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[OH:18]O.[NH4+].[OH-]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]([NH2:17])=[O:18])[CH2:9][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:11]2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: N#CC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Compound [XXXIII] (13.0 g, 44.2 mmol, 1.0 eq.) in MeOH (520 mL) was added H2O2 (13.7 mL, 33% in water, 133 mmol, 3.00 eq.), and NH4OH (52 mL). The resulting mixture was stirred for 16 hours at room temperature, then diluted with additional water and extracted with ethyl acetate (×3). The combined organics were washed with Na2S2O3 (10% in water), dried, and concentrated. The residue was purified by silica gel chromatography by eluting with heptane and ethyl acetate (gradient of 0% to 100% EtOAc) to give Compound [XXXIV]: LCMS (m/e) 312, 314 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.78-2.87 (m, 2H) 3.22-3.29 (m, 2H) 3.84-3.91 (m, 2H) 3.91-3.99 (m, 2H) 5.42 (br. s., 2H) 7.19-7.25 (m, 2H) 7.48-7.55 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:17])[CH3:16]>C(OCC)(=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([CH3:16])=[O:17])=[CH:3][CH:4]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(C)cc1
Reaction time: 2 h
Yield: 77801.2 %

Procedure:
100 g (933.3 mmol) of p-toluidine and 154.8 g (1.120 mmol) of potassium carbonate were dissolved in a mixed solvent of 1,000 ml of ethyl acetate and 500 ml of water. Thereinto was dropped 87.9 g (1.120 mmol) of acetyl chloride with ice-cooling, followed by stirring for 2 hours. Extraction with ethyl acetate was carried out. The organic phase obtained was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crude crystal obtained was washed with hexane to obtain 130 g (yield: 93%) of p-acetotoluidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13](O)[CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[Cl:18][CH:13]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)[CH3:14]
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Temperature: 70 °C
Yield: 93 %

Procedure:
5 drops of DMF was added to 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol (12.3 g, 54.9 mmol) in SOCl2 (150 mL) and the reaction was heated at 70° C. for 5 h. The excess SOCl2 was evaporated and the residue was purified by column chromatography (Hep to Hep-EA 5:1) to give 12.4 g (93%) of the title compound. 1H NMR: 1.96 (d, 3H) 5.20 (q, 1H) 7.46 (t, 1H) 7.59 (m, 1H) 8.04 (m, 1H) 8.17 (t, 1H)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][OH:17]>>[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][O:17][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CC(C)CCO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOc1ccc(C(=O)O)cn1

Procedure:
6-(3-Methylbutoxy)nicotinic acid was prepared from 6-chloronicotinic acid (0.50 g), 3-methyl-1-butanol (0.36 ml) and sodium hydride (60%, 0.32 g) according to the method described in Example 54 to give the product as a white solid (0.25 g, 38%): δH (400 MHz, DMSO-d6) 12.97 (1H, m), 8.71 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.87 (1H, d, J 8.5 Hz), 4.36 (2H, t, J 7 Hz), 1.75 (1H, nonet, J 6.5 Hz), 1.62 (2H, q, J 6.5 Hz) and 0.93 (6H, d, J 6.5 Hz); HPLC (XTERRA, 20/50, 220 nm) 99% (3.90 min).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=2[C:17](O)=[O:18])=[CH:10][CH:9]=1>C(OCC)C.C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=2[CH2:17][OH:18])=[CH:12][CH:13]=1
Reactant: O=C(O)c1c(F)cccc1Sc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1c(F)cccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiAlH4 (0.77 g, 20.4 mmol) is suspended in 30 ml of dry diethyl ether with cooling in an ice bath. 2-(4--fluorophenylthio)-6-fluorobenzoic acid (4.53 g, 17.0 mmol) in 6 ml of diethyl ether and 6 ml of THF is then added and the reaction mixture stirred at room temperature overnight. The reaction mixture is quenched sequentially with 0.8 ml of water, 0.8 ml of 15% NaOH aqueous solution, and 2.4 ml of water. The resulting white precipitate is filtered off and washed thoroughly with diethyl ether. The filtrate and washings are combined and concentrated to afford the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]O)([CH3:16])([CH3:15])[CH3:14].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:13]([O:17][C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[Cl:1])=[O:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cccc2c(Cl)nccc12
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 1-chloro-5-hydroxyisoquinoline (539 mg, synthesized according to the method described in a reference (Georgian, V. et al., J. Org. Chem., 27, 4571 (1962))), (3-hydroxypropyl)carbamic acid tert-butyl ester (1.58 g, Tokyo Kasei Kogyo) and 1,1′-azobis(N,N-dimethylformamide) (1.55 g) in tetrahydrofuran (8 ml) was added with tri(n-butyl)phosphine (2.24 ml) with ice cooling and stirred at room temperature for 24 hours. The deposited solid was removed by filtration, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (860 mg) as white powdery solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][CH:35]([C:37]([O:39]CC)=[O:38])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][CH:35]([C:37]([OH:39])=[O:38])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)COc1ccc(Br)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 52.7 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.3 mmol), NaOH (40 mg, 1 mmol), H2O (5 mL) and THF (5 mL) was heated at 80° C. for 2 h. Then THF was removed in vacuum. The water solution was acidified by concentrated hydrochloric acid (1.5 mL) to “pH” 2. The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 100 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:22]3[CH:23]=[CH:24][NH:20][N:21]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cc[nH]n1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cc[nH]n1
Yield: 57 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 57% yield.
Reaction SMILES: C([C:3]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH:5]=[CH:6][N:7](C)[CH3:8])#N.[BrH:21]>C(O)(=O)C>[CH3:20][O:19][C:17](=[O:18])[C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][CH:6]=[N:7][C:8]=1[Br:21]
Reactant: COC(=O)C(C#N)=C(C=CN(C)C)c1ccc(Cl)cc1
Reactant: Br
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Temperature: 25 °C
Yield: 83.5 %

Procedure:
80.0 g (0.28 mol) of 1-cyano-1-methoxycarbonyl-4-(N,N-dimethylamino)-2-(4-chlorophenyl)-1,3-butadiene was weighed, and 100 ml of acetic acid was added thereto and an acetic acid solution of 25% HBr was then gradually added dropwise thereto at room temperature under stirring. After the dropwise addition, the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into ice water to precipitate a crystal. The crystal thus precipitated was filtrated out and washed with water and was dried to obtain 75.0 g of a white crystal of the aimed product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[C:3]=1[N+:9]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:9][C:3]1[C:4]([OH:8])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)ccnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
4-chloro-3-nitro-pyridin-2-ol (1.69 g, 9.72 mmol) and tin tetrachloride dihydrate (SnCl2.2H2O) (10.97 g, 48.62 mmol) was dissolved in ethanol (32 ml), heated to 70□ and stirred for 2 hours. The reaction mixture was cooled to room temperature and the ethanol was evaporated under reduced pressure. The residue was neutralized with saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain pale-yellow solid (650 mg, 46%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][C:10]([CH:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)=[O:12]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)NCC(=O)c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
A suspension of 1-acetyl-4-piperidine carboxylic acid (93 g, 542 mmol) in CH2Cl2 (700 mL) is treated portionwise at 23° C. with carbonyldiimidazole (80 g, 542 mmol). The solution is allowed to stir at 23° C. under N2 for 1.5 h, then treated with 2-aminoacetophenone hydrochloride (93 g, 542 mmol) and diisopropylethylamine (113 mL, 650 mmol). The orange solution is stirred for 15 h, then washed with 2 N NaOH (2×200 mL), 2 N HCl (2×200 mL), and brine (1×300 mL), dried (MgSO) and concentrated to a red solid. The solid is dissolved in hot MeOH, and addition of hexane gave a pale orange solid which is obtained by filtration. The mother liquid is concentrated, the residue taken up in hot MeOH, and another crop of product is obtained by addition of hexane, to give a combined yield of 122 g of 1-Acetyl-piperidine-4-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide as a pale orange solid.