Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16].C([OH:20])C.O.[OH-].[Na+]>O>[C:1]([OH:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC/C=C\CCCCCCCCCC=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC/C=C\CCCCCCCCCC(=O)O

Procedure:
(Z)-11-hexadecenoic acid was prepared as described in Example VII but starting with Z-11-hexadecenal (1.115 g, 4.68 mmol) and (0.875 g, 5.15 mmol) in 15 ml. of ethanol/water, 2/1, and NaOH (0.880 g, 22 mmol) in water (10 ml); purification by flash chromatography (H/EA/A), 8/2/1, gave 0.478 g (40%) of the acid; Rf (H/EA,7/3), 0.64; IR (film) 2800-3300 (CODH), 2850-2950 (alkane, alkane C--H), 1700 cm-1 (C=O), 1H NMR 0.95 (t, J=6 HZ, 3H), 1.20-1.50 (br S, 18 H), 2.05 (br d, J=6 HZ, 4H), 2.38 (t, J=6HZ, 2H), 5.32 (t, J=6HZ, 2H), 10.6-10.8 (br S, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH2:8][N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[S:10]([C:13]1SC=CC=1)(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].S1C=CC=C1S(Cl)(=O)=O.CS(Cl)(=O)=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH2:8][N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CN(c2cccnc2)S(=O)(=O)c2cccs2)cc(C(C)(C)C)c1O
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)(Cl)c1cccs1
Product: CC(C)(C)c1cc(CN(c2cccnc2)S(C)(=O)=O)cc(C(C)(C)C)c1O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 7, except the 2-thiophene sulfonyl chloride was replaced with methane sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](C=O)[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:31])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2F)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of 4-(2-fluoro-4-formyl-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (97 mmol) in CH2Cl2 (600 ml), m-chloroperbenzoic acid (194 mmol) is added at 0° C. for 5 min and NaHCO3 (243 mmol) is added at 0° C. The mixture is stirred at 0° C. for 20 min and at room temperature for 1 h. To the mixture, m-chloroperbenzoic acid (48.5 mmol) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h, slowly quenched with saturated NaHCO3 at 0° C. and extracted with AcOEt. The combined extracts are washed with saturated NaHCO3, brine and dried over magnesium sulfate. The solvent is evaporated. To the residue, 10% KOH/EtOH is added at 0° C. and the reaction mixture is stirred at room temperature for 1 h. After the mixture is extracted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtered. The solvent is evaporated and the residue is chromatographed on silica gel (eluent; n-hexane, n-hexane:AcOEt=5:1, n-hexane:AcOEt=4:1, n-hexane:AcOEt=3:1) to give 8.5 g of desired 4-(2-fluoro-4-hydroxy-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester.
Reaction SMILES: [C:1](OCC)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.C(O[CH:25]=[CH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])C.Cl>C(#N)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:8])[O:32][C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(F)(F)F)oc1=O
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Diethyl malonate (33.7 g, 0.2 mol) was dissolved in acetonitrile (200 mL), and magnesium chloride (21.4 g, 0.22 mol) was slowly added thereto at 0 to 5° C. After 10 minutes, triethylamine (44.5 g, 0.44 mol) was added dropwise thereto at 0 to 5° C., and the mixture was allowed to react for 1 hour at room temperature. To the reaction mixture, 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (37.0 g, 0.22 mol) was added dropwise at 0 to 5° C., and the mixture was allowed to react for 1 hour at room temperature. The reaction mixture was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. Thus obtained oily product was dissolved in toluene (100 mL), p-toluenesulfonic acid (5 g) was added thereto, and the mixture was allowed to react for 3 hours under heating. After cooling, the solvent was distilled off, and thus obtained crystal was recrystallized from ethyl acetate, to obtain 31.8 g of a desired product (yield: 67%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Nc1ccccc1
Temperature: 35 °C

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 3.6 ml (0.039 mol) of aniline, 1.3 g (0.013 mol) of triethylamine in 30 ml of DMF were reacted at room temperature for 16 hours and heated to 35° C. for 20 minutes. The residue was recrystallized in hot hexane affording 4.0 g (68.0%) of product as a beige solid; mp 91°-92° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2].[Sn](Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>CCO.O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSc2ccccc2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2ccccc2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
[4-Methoxy-3-(4-nitro-2-phenylsulfanylmethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.4 g, 0.9 mmol) and tin(II) chloride (0.6 g, 2.7 mmol) were combined in EtOH (20 mL) and stirred overnight at 70° C. CH2Cl2, H2O, and sodium bicarbonate were added, and the mixture was filtered through Celite. The organic layer was separated and concentrated to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:12][C:11]3=[CH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:10]3=[CH:9][N:8]=2)[CH2:3][CH2:2]1.CC[O:24]C(C)=O.[ClH:28]>CO>[OH2:24].[ClH:28].[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[NH:12][C:11]3=[CH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:10]3=[CH:9][N:8]=2)[CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Agent: Cl
Agent: c1cnc(-c2cc3[nH]c(C4CCNCC4)ncc-3n2)cn1
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 2-(1-pyrrolidinylvinyl)pyrazine (freshly prepared before use) (2.39 g, 13.7 mmol), 4,6-dichloro-5-nitropyrimidine (Aldrich Chemical Company) (2.60 g, 13.7 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.4 mL, 13.7 mmol), piperidine (Aldrich Chemical Company) (2.2 mL, 21.9 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (41 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 143 mg (4%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.67 (br s, 6), 3.77 (s, 4), 7.28 (s, 1), 8.28 (s, 1), 8.63 (s, 1), 8.74 (s, 1), 9.36 (s, 1), 11.48 (s, 1). MS m/z: 281 (M+1). To a hot solution of 4-piperidyl-6-pyrazin-2-ylpyrrolo[3,2-d]pyrimidine (0.14 g, 0.51 mmol) in 10:1 EtOAc: MeOH (40 mL) was added 1M etheral HCl (Aldrich Chemical Company) (0.51 mL, 0.51 mmol). Cyrstallization occurred as the mixture cooled and the precipitate was collected by filtration. The crystals were washed with Et2O (3×10 mL) and dried under vacuum to give 128 mg (80%) of the title compound as a beige colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.73 (s, 6), 4.10 (s, 4), 7.37 (s, 1), 8.66 (s, 1), 8.75 (d, 1, J=2.5), 8.83 (t, 1, J=1.5), 9.49 (d, 1, J=1.2), 12.53 (s, 1), 14.56 (s, 1). MS m/z: 281 (M+1). Anal. Calcd for C15H16N6.HCl.0.25H2O: C, 56.00; H, 5.49; N, 26.13; Cl, 11.10. Found C, 56.00; H, 5.49; N, 26.11; Cl, 11.09.
Reaction SMILES: O1C2C=CC=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.[ClH:12].N[N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]([CH3:25])[O:17][CH2:16][CH2:15]1.Cl.N1CCC(=O)CC1>>[ClH:12].[CH3:25][CH:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:4]4[CH2:3][NH:2][CH2:11][CH2:6][C:5]=4[N:14]([C:20]=23)[CH2:15][CH2:16][O:17]1
Reactant: CC1OCCN(N)c2ccccc21
Reactant: C1=Cc2ccccc2ON=C1
Agent: Cl
Agent: O=C1CCNCC1
Product: CC1OCCn2c3c(c4cccc1c42)CNCC3

Procedure:
According to the procedure described in Example 1, the appropriate benzoxazepine is converted to 1-amino-1,2,3,5-tetrahydro-5-methyl-4,1-benzoxazepine hydrochloride, m.p. 198°-200°, which is reacted with 4-piperidone hydrochloride to yield the title compound, m.p. 285°-286° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][NH2:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1ccc(Cl)cc1
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
9.25 g of ethyl 4-chlorobenzoate and 16.0 g of N-(t-butoxycarbonyl)ethylenediamine are stirred at 130° for 15 hours. The mixture is cooled to room temperature, taken up in 100 ml of water and extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extract is washed twice with 50 ml of water each time, dried over sodium sulfate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and filtered off under suction. There are obtained 3.9 g of t-butyl [2-(4-chlorobenzamido)ethyl]carbamate, m.p. 141°-143°.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][C:20]([C:1]#[N:2])([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2.9 g of potassium cyanide in 8 ml of water is added dropwise to a mixture of 16.3 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-piperidone (oil; its hydrochloride: m.p. 214°-217° C), 4.1 g of aniline and 40 ml of acetic acid at room temperature with stirring. The resulting mixture is stirred at room temperature for 6 hours and allowed to stand at room temperature overnight. The reaction mixture is poured into ice water, the aqueous mixture is made alkaline with potassium carbonate, and the alkaline mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual oil is dissolved in acetone, and 20% ethanolic hydrochloric acid is added thereto. After cooling the precipitated hydrochloride is collected by filtration and converted in a conventional manner into the base. The obtained crystals are recrystallized from a mixture of acetone and petroleum ether to give 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-cyano-4-anilinopiperidine as white crystals, melting at 139° -140° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([CH:8]=[CH:7][CH:6]=1)[O:1][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: Nc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ccnc(N)c2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
3-Hydroxyaniline (2.07 g, 19.0 mmol) was dissolved in dry DMF (65 mL) and the solution was degassed by argon bubbling for 10 minutes. Potassium tert-butoxide (2.13 g, 19.0 mmol) was added and the stirring was continued for 1 hour at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 80° C. for 20 hours. The solvent was evaporated in vacuo and the brown oily residue was taken up in 1M HCl (aq) (50 mL). This layer was washed with EtOAc (3×50 mL) and subsequently basified to pH ˜10 with 1M NaOH (aq). The brown precipitate was collected, washed with H2O (3×25 mL) and dried in vacuo, to afford 4-(3-aminophenoxy)-3-nitropyridin-2-amine (3.50 g, 80%). 1H-NMR (δ, ppm, DMSO-d6): 5.39 (s, 2H, NH2), 6.02 (d, 1H, HPy,5, J=5.7 Hz), 6.23-6.30 (m, 2H, Harom,Ph′), 6.47 (d, 1H, Harom,Ph′, J=8.0 Hz), 7.04-7.24 (m, 3H, NH2+Harom,Ph′), 7.48 (m, 2H, Harom), 7.98 (d, 1H, HPy,5); LC-MS (m/z): 247 (M+H, 100).
Reaction SMILES: CN(C)[CH:3]=[O:4].[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[CH3:7].O.O.O.C([O-])(=O)C.[Na+]>O>[C:22]([O:21][CH2:20][CH2:19][N:12]([CH2:11][CH2:10][O:9][C:6](=[O:8])[CH3:7])[C:13]1[CH:18]=[CH:17][C:16]([CH:3]=[O:4])=[CH:15][CH:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 60 °C

Procedure:
To 450 ml of dry dimethyl formamide were slowly added dropwise with stirring and at a temperature of 0°-10° C. 100 ml of freshly distilled phosphoroxytrichloride. This mixture was stirred for 2 hours at 20° C. To this mixture there was subsequently added dropwise with proper stirring and over a period of 60 minutes the crude reaction product of the previous step, viz. N,N-di(2-acetyloxyethyl)aniline, the reaction mixture being kept at a temperature of 20° C. Next, the reaction mixture was heated to 60° C. for 60 minutes and then poured, with vigorous stirring, into a mixture of 1 kg of ice and a solution of 525 g of sodium acetate trihydrate in 1 l of water. The organic layer was separated and the water layer was extracted four times, each time with 300 ml of dichloromethane. The combined organic layers were washed three times, each time with 200 ml of water, dried on magnesium sulphate, and concentrated by evaporation. The residue (about 280 g of dark brown oil), which consisted almost entirely of 4-di(2-acetyloxyethyl)aminobenzaldehyde, was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 51 (0.224 g, 0.000456 mol) was taken in THF (4 mL) and MeOH (1 mL). To this reaction mixture, 1 N LiOH (0.095 g, 0.0022 mol) was added and the reaction mixture was stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:37][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(O)C.O.OS(O)(=O)=O>CCCCCC>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 5 °C

Procedure:
A mixture of 120 g (0.238 mol) of 5, 3.0 liters of 95% ethanol, and 350 mL of water in a 5 liter round bottom flask is cooled to 5° C. in an ice bath for 30 minutes. Concentrated H2SO4 (650 mL) is added to this mixture over a period of 10 minutes in 50 mL portions. Any large chunks of suspended material are broken up mechanically. The mixture is heated under reflux for 20-24 hours. The brownish reaction mixture is cooled to 20° C. using an ice bath and then poured into 7 Kg of ice in a 12 liter carboy. The paste-like precipitate is collected on a Buchner funnel using either polypropylene filter cloth (Aldrich) or three layers of Whatman #1 filter paper, which is occasionally scratched to facilitate filtration. The pale-yellow cake is washed three times with 1 liter of cold water and dissolved in 1 liter of hot methanol, to which 1 liter of hexane and 50 mL of hot water are added. The resulting two-phase system is heated on a steam bath until all solid material is dissolved. This mixture is allowed to cool for 2-3 hours to 20° C.; at this point crystals begin to form at the solvent interface. The mixture is then cooled overnight at -15° C. to give a brown upper hexane phase, a lower light yellow aqueous phase, and white crystalline material. The crystals (roughly 90% pure by TLC) are collected by suction filtration and recrystallized again from methanol/hexane/water (2:2:1) as described above.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:24]=[O:25])=[N:20][C:21]=1[O:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:24]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[OH:25])=[N:20][C:21]=1[O:22][CH3:23]
Reactant: CSc1ccc(Br)cc1
Reactant: COc1nc(C=O)ccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(C(O)c2ccc(SC)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
n-Butyllithium (2.64 M, 2.9 mL) was added to a solution of 4-bromothioanisole (1.61 g) in tetrahydrofuran (20 mL) at −78° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.14 g) in tetrahydrofuran (10 mL) was added to the reaction solution, followed by stirring for one hour. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→4:1) to give (5-chloro-6-methoxypyridin-2-yl)[4-(methylsulfanyl)phenyl]methanol as a pale yellow oil (1.42 g).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][O:5][CH2:4][O:3][CH2:2]1>[Pd].C(O)C.C(OCC)(=O)C>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:2][O:3][CH2:4][O:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2COCOC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)N2COCOC2)cc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of 1-(3,5-dioxapiperidin-1-yl)sulphonyl-4-nitrobenzene (Method 8) (500 mg, 1.82 mmol) and 10% palladium on charcoal catalyst (150 mg) in ethanol (25 ml) and ethyl acetate (25 ml) was stirred under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtration through diatomaceous earth and the filter pad was washed with ethanol and ethyl acetate. The volatiles were removed from the filtrate by evaporation and the residue triturated with ether and hexane to give the tide compound (395 mg, 88%). NMR: 4.90 (s, 2H) 5.10 (s, 4H), 6.02 (s, 2H), 6.58 (d, 2H), 7.50 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1.FC(F)(F)C(O[C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])=O.N1C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([O:17][C:26]3[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=3[F:32])=[O:16])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 97 %

Procedure:
4-(4-Bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (97%). 1H NMR [400 MHz, (CD3)2SO] δ 9.03 (s, 1H), 8.70 (s, 1H), 7.71 (dd, J=10.6, 2.0 Hz, 1H), 7.49 (dd, J=8.5, 2.0 Hz, 1H), 7.46 (t, J=8.7 Hz, 1H), 5.34 (d, J=1.6 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:19])=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]=2[C:17]=1[CH3:18])=[O:5].C1C[O:25][CH2:24]C1.CCCCCC>>[CH:24]([C:9]1[C:10]2[O:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]=2[C:17]([CH3:18])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:8]=1[CH3:19])=[O:25]
Reactant: C1CCOC1
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Yield: 85 %

Procedure:
Using 3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide obtained in Example 339, the title compound was synthesized in the same manner as in Example 20. Yield: 85%. Melting point: 180-181° C. (THF-hexane).