Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[C:8](=[O:23])[C:9]1[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C>FC(F)(F)C(O)=O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:7][C:8]([C:9]1[C:10]([O:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1Cl)C(=O)c1cccnc1Oc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccccc1Cl)c1cccnc1Oc1ccc(F)cc1
Yield: 68 %

Procedure:
A solution of 226 mg (0.496 mmol) a-[(2-Chlorophenyl)methyl]-2-(4-fluorophenoxy)-β-oxo-3-pyridinepropanoic Acid t-Butyl Ester in 5 mL of trifluoroacetic acid was stirred at rt for 4 h. The mixture was evaporated, and the residue was diluted with 5 mL of toluene, heated to reflux for 2 h, and evaporated. The residue was dissolved in 100 mL of EtOAc, washed successively with saturated aqueous sodium hydrogencarbonate solution (1×50 mL) and brine (1×50 mL), dried (Na2SO4), and and evaporated to 125 mg of an oil. Purification by flash chromatography using 40% ether-hexane as eluant yield 120 mg (68% yield) of the title compound as a colorless oil. 1H NMR (CDCl3) d 3.20 (2H, t, J=8 Hz), 3.49 (2H, t, J =8 Hz), 7.06-7.32 (9H, m), 8.19 (1H, dd, J=2.7 Hz), 8.25 (1H, dd, J=2.5 Hz); Thermospray MS (m/e) 356,358 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=[O:21])C(F)(F)F)=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[OH-:22].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([OH:21])=[O:22])=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 1-[6-chloro-1-(3-methyl-butyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (284.9 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C. and was diluted with water (75 mL). This mixture was extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-(3-methyl-butyl)-1H-indole-3-carboxylic acid (149.3 mg, 69.5%) as a light orange solid: mp 53-55° C.; EI-HRMS m/e calcd for C14H16ClNO2 (M+) 265.0870, found 265.0860.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7](Cl)=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]>C1COCC1.O>[NH2:15][CH2:14][CH2:13][CH2:12][N:4]1[C:5]2[N:6]=[C:7]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:8]=[CH:9][C:10]=2[C:2]([Br:1])=[CH:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCn1cc(Br)c2cnc(Cl)nc21
Reactant: NCCCCC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: NCCCn1cc(Br)c2cnc(NCCCCC(=O)O)nc21
Temperature: 150 °C

Procedure:
A solution of the crude 2-(3-(5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl)isoindoline-1,3-dione in a mixture of THF and water (10 mL, 3:2, v/v) was added 5-aminopentanoic acid (172.3 mg, 1.47 mmol). The resulting mixture was heated at 150° C. under microwave irradiation for 1 h. After the solvent was removed, the residue was dissolved in a mixture of ethanol and water (20 mL, 3:2, v/v) followed by the addition of hydrazine (1.5 mL). Then the reaction mixture was heat at 80° C. for overnight. The solvent was removed and the residue was purified on HPLC to provide 5-((7-(3-aminopropyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pentanoic acid as an clear oil (MS m/z 371.10 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)cn1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give crude 5-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)pyridin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 127 after purification by reverse HPLC. MS (Q1) 408 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([OH:18])=O)=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:28].[OH-]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([NH2:28])=[O:18])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: [NH4+]
Reactant: CCn1cc(C(=O)O)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C(N)=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) is suspended in a solution of CH2Cl2 (27 ml) and DMF (20 μL). Oxalyl chloride (470 μL, 5.38 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (10 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](OC)=[O:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)(=[O:4])=[O:3].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH3:1][S:2]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][OH:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc2c1CN(S(C)(=O)=O)CC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCc2cccc(CO)c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Formula 8-2 (0.080 g, 0.297 mmol) was dissolved in 1.5 mL of THF and the solution was cooled to 0° C., then treated with 1.5 mL di-isobutyl aluminum hydride (DIBAl—H 1.5 mmol). The reaction mixture was stirred for 1 hour maintaining the temperature at 0° C., then quenched with 2N HCl and stirred at RT for 30 minutes additional. The reaction mixture was extracted into EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 8-3 ([2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]methanol).
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([I:10])[C:5]([CH2:11][OH:12])=[C:4]([I:13])[C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.N1C=CC=CC=1>CS(C)=O>[I:1][C:2]1[C:3]([CH:14]=[O:15])=[C:4]([I:13])[C:5]([CH:11]=[O:12])=[C:6]([I:10])[C:7]=1[CH:8]=[O:9]
Reactant: OCc1c(I)c(CO)c(I)c(CO)c1I
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=Cc1c(I)c(C=O)c(I)c(C=O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,3,5-Triiodo-2,4,6-trihydroxymethylbenzene (4.5 g, 8.2 mmol) was dissolved in DMSO (80 ml). Triethylamine (51.7 ml, 371 mmol) and pyridine. SO3 (11.8 g, 74.2 mmol) were added and the mixture was stirred for two hours. The two phases were separated and the lower phase was cooled to 0° C., poured into water (150 ml) and stirred for 30 min at 0° C. The white solid was collected by filtration, washed with water and dried. Yield: 3.0 g (67%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([CH2:18][CH2:19][CH3:20])[N:7]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][N:12]([C:10]2[N:9]=[C:8]([CH2:18][CH2:19][CH3:20])[N:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[N:11]=2)[CH2:17][CH2:16]1
Reactant: CCCc1nc(N)nc(N2CCOCC2)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc(NC(C)=O)nc(N2CCOCC2)n1
Reaction time: 6 h
Yield: 43.3 %

Procedure:
4 g (0.05 mole) of acetyl chloride are added dropwise into a solution of 11.2 g (0.05 mole) of 2-amino-4-morpholino-6-propyl-1,3,5-triazine in 100 ml of anhydrous pyridine at room temperature. The mixture is stirred for 6 hours and then allowed to stand for 48 hours. The pyridine hydrochloride is filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is taken up once in toluene, and the mixture is evaporated again. The residue is then taken up in dichloromethane and the solution is washed with water and dried over sodium sulfate. The residue obtained after evaporation of the solvent is purified by chromatography over silica (eluent: 90:10 v/v) dichloromethane-ethanol) and the product is finally recrystallized from ethyl acetate. 5.75 g of N-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)-acetamide are obtained. Yield: 43.4%. M.P.: 141°-142° C. (Compound 21a). Hydrochloride: M.P.: 145°-146° C. (isopropyl alcohol-ether). (Compound 21b).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[C:24]3[C:23]([Cl:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[O:15])[CH:11]=[N:12][CH:13]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[C:24]3[C:23]([Cl:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([CH3:1])[CH:17]=2)=[O:15])[CH:11]=[N:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cncc(Br)c1)c1c[nH]c2ncnc(Cl)c12
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Reaction time: 0.5 h

Procedure:
Cs2CO3 (2.32 g, 7.11 mmol) was added to a suspension of (5-Bromo-pyridin-3-yl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (1.0 g, 5.93 mmol) in DMF (60 mL) at room temperature. The resulting mixture was stirred for 30 min. Mel (1.01 g, 7.11 mmol) was added and the reaction and stirred for 2 h at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with hot EtOAc (3×50 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/hexanes 2:8-7:3) provided a solid. The solid was triturated with EtOAc to provide the title compound as an off white solid (1.52 g, 73%). MS: 351.9/353.9 (MH+); HPLC Rf: 4.45 min. (HPLC method 4).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=2)[N:8]([CH2:23][CH3:24])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:23]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:11]([CH3:22])[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)[CH3:24]
Reactant: CCCC(=O)c1cc2c(=O)c(C(=O)OCC)cn(CC)c2cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)c1cc2c(=O)c(C(=O)O)cn(CC)c2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of 1-ethyl-6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester are dissolved in 250 ml of ethanol, 30.4 ml of N sodium hydroxide solution are added and the mixture is stirred for 1 hour at room temperature. The ethanol is removed under reduced pressure, and the aqueous phase is extracted with chloroform and acidified with hydrochloric acid. The precipitated crystallisate is filtered with suction. 1-Ethyl-6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid having a melting point of 208°-209° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:22]Br.C(OCC)C>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH2:11][Br:22])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 2.5 h
Yield: 55 %

Procedure:
The product of step (a) (10.0 g, 35.2 mmol) was dissolved in chloroform (250 mL) in a 500 mL flask under a nitrogen atmosphere. Bromine (1.63 mL, 31.7 mmol) dissolved in chloroform (50 mL) was added using a dropping funnel over 30 min. The reaction mixture was stirred for 2.5 h and then concentrated to give a solid. The solid was dissolved in toluene (150 mL) with some gentle heat, followed by the addition of ethyl ether (150 mL) to yield the title compound as a crystalline solid (55% yield).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1(OB(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[Br:23]>C(O)C.C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:23][C:22]1[CH:21]=[CH:20][S:19][C:18]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccsc1Br
Reactant: OB(O)Oc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Brc1ccsc1-c1ccccc1
Yield: 45.7 %

Procedure:
Tetrakis (triphenylphosphine) palladium (400 mg), Na2CO3 (4M, 80 ml, 320 mmol) and phenylboric acid (3.81 g, 30.3 mmol) as a solution in ethanol (80 ml) were sequentially added to a solution of 2,3-dibromothiophene (7.33 g, 30.3 mmol) in benzene (100 ml). The mixture was heated at reflux for 12 hours. The aqueous layer of the crude mixture was removed and the organic layer was diluted with Et2O (200 ml), washed with 1N NaOH (2×150 ml) and was dried (MgSO2), filtered and the soluent was evaporated. The residue was chromatographed using hexane as the eluent to give 3-bromo-2-phenylthiophene as a clear oil (3.31 g, 47% yield).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to Example 61e. Product isolated as a white solid (0.011 g, 11%). MP: 165-167° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.94 (s, 1H), 8.65 (d, 1H, J=8.6 Hz), 8.10 (d, 1H, J=1.5 Hz), 8.09-8.07 (m, 1H), 7.53-7.39 (m, 3H), 7.12-7.06 (m, 1H), 6.64 (s, 1H), 6.13 (br s, 1H), 3.86 (s, 3H), 3.57-3.48 (m, 2H), 2.90-2.73 (m, 10H), 1.69 (t, 3H, J=18.6 Hz), 1.30-1.24 (m, 3H). MS: 545.21 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[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[CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[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]([NH:21][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3-{4-Amino-2-[(benzyloxycarbonyl-ethyl-amino)-methyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester (0.1 g, 0.19 mmol), 4-chlorobenzoyl chloride (0.1 g, 0.57 mmol), and triethylamine (0.5 mL, 3.6 mmol) were combined in CH2Cl2 (10 mL) and stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[O:10][C:11]([CH3:32])=[C:12]([CH:14]([OH:31])[CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)[N:13]=1.O>CS(C)=O>[CH3:8][C:9]1[O:10][C:11]([CH3:32])=[C:12]([C:14](=[O:31])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[N:13]=1
Reactant: Cc1nc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(C)o1
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(C)o1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
Acetic anhydride (1.0 ml) was added to a solution of 5-{4-[2-(2,5-dimethyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione (0.5 g) in dimethylsulfoxide (10 ml), and the mixture was allowed to stand overnight and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concetrated. The oily residue was chromatographed on a column of silica gel (40 g), and from the fractions eluted with benzene-acetone (9:1 V/v), there was obtained 5-{4-[2-(2,5-dimethyl-4-oxazolyl)-2-oxoethoxy]benzyl}-2,4-thiazolidinedione (0.24 g, 48.3%). Recrystallization from ethyl acetate-hexane afforded colorless plates, m.p. 161°-162° C. Elemental analysis for C17H16N2O5S, Calcd.: C, 56.66; H, 4.47; N, 7.77. Found: C, 56.62; H, 4.38; N, 7.60.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:11][OH:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([C:11]([OH:20])=[O:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCn1c(CO)nc2cc(C(C)=O)ccc21
Agent: [K+]
Product: CCCCn1c(C(=O)O)nc2cc(C(C)=O)ccc21

Procedure:
In a manner analogous to that described in Example 12, 4.9 g of 5-acetyl-1-n-butyl-benzimidazole-2-methanol can be oxidised with 4.5 g of potassium permanganate to give 5-acetyl-1-n-butyl-benzimidazole-2-carboxylic acid with a melting point >75° (decomposition).
Reaction SMILES: CO.[OH-].[Na+:4].C[O:6][C:7](=[O:43])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]4([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33]4)=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][C:16]=2[CH3:41])=[CH:11][C:10]=1[F:42].[Cl-].[NH4+]>O1CCCC1>[CH2:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][C:7]([O-:43])=[O:6])=[C:10]([F:42])[CH:11]=2)=[C:16]([CH3:41])[CH:17]=1)([C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23].[Na+:4]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)[O-])c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 54.6 %

Procedure:
Methanol (1.3 mL), tetrahydrofuran (1.3 mL) and a 1 M sodium hydroxide aqueous solution (0.129 mL, 0.129 mmol) were added to [4′-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-3-fluoro-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 84-(1); 22.8 mg, 0.043 mmol), and the mixture was stirred at room temperature for 25 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crudely purified by preparative TLC (chloroform/methanol=10/1). The crude purified product was diluted with methanol. After addition of sodium methoxide, the mixture was dried under reduced pressure. The residue was purified by preparative TLC (developer obtained by saturating chloroform/methanol=10/1 with water). The purified product was diluted with methanol. After addition of sodium methoxide, the mixture was dried under reduced pressure to give the title compound (12.6 mg, 57%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[N:19]=[C:18]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH2:17]3)[CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:36][OH:37].O>C(O)C>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:16]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[N:36][OH:37])[CH3:2])=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][C:18]([C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])=[N:19]1
Reactant: CC(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
5-(4′-acetyl-biphenyl-3-yl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (18.0 mg, 0.04 mmol) prepared in Example 107 and hydroxylamine hydrochloride (5.0 mg, 0.07 mmol) were added to a mixed solvent of distilled water (30.0 uL) and ethanol (1.5 mL). The reaction mixture was stirred at 50° C. for 3 hours, concentrated under reduced pressure and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 17.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12].N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:11]([NH2:12])[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(N)S(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.1 %

Procedure:
A solution of 40 g of 4-chloro-1-butanesulphonyl chloride in 400 ml of diethyl ether was added dropwise to a solution of 30.4 g of tert-butyl carbazate and 17 ml of pyridine in 400 ml of diethyl ether at room temperature. The mixture was stirred at room temperature for 72 hours and then washed with water. The separated organic phase was dried over anhydrous magnesium sulphate. The oily residue obtained after evaporation of the solvent was purified by flash column chromatography on silica gel using hexane/ethyl acetate (8:2, increasing to 6:4) for the elution. 10.25 g of tert-butyl 2-[(4-chlorobutyl)sulphonyl]carbazate were obtained in the form of a white solid.