Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[S:26][C:27]([C:31]([NH:33][CH:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]4)=[O:32])=[C:28]([CH3:30])[N:29]=3)[CH2:21][C@H:20]2[O:47][CH3:48])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]>CO>[ClH:8].[ClH:1].[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[S:26][C:27]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]4)=[O:32])=[C:28]([CH3:30])[N:29]=3)[CH2:21][C@H:20]2[O:47][CH3:48])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)s3)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC4CCNCC4)s3)C[C@H]2OC)nc1Cl
Reaction time: 0.5 h
Yield: 144.1 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (2 ml, 8 mmol) was added to a solution of tert-butyl cis(±)-4-({[2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}amino)piperidine-1-carboxylate obtained in Example (266a) (30 mg, 0.05 mmol) in methanol (0.4 mL), followed by stirring for 30 minutes. The solvent was evaporated under reduced pressure. The residue was solidified by adding ethyl acetate, diethyl ether and hexane, to obtain 21 mg of the title compound as a cream-colored solid (72%).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][CH:24]([CH3:33])[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[Na].C(O)C>C(Cl)Cl>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:2]([CH:26]([C:25](=[O:32])[CH:24]([CH3:33])[CH3:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:10]4[C:5](=[N:6][CH:7]=[CH:8][N:9]=4)[C:4]3=[O:11])=[N:13]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=C1c2nccnc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)C(C)C)C1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 43.9 %

Procedure:
Ethyl 2-{6-(7-chloro-1,8-naphthyridin-2-yl)-6, 7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl}-4-methyl-3oxopentanoate may be obtained as in Example 29, but starting with 5-chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-6, 7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazine (13 g), ethyl 4-methyl-3-oxopentanoate (8.7 g), sodium (1.1 g), ethanol (400 cc) and methylene chloride (200 cc). After recrystallization in methanol, ethyl 2-{6-(7-chloro-1, 8-naphthyridin-2-yl)-6,7-dihydro-7-oxo-5H-pyrrolo[3, 4-b]pyrazin-5yl}-4-methyl-3-oxopentanoate (7.8 g), m.p. 214° C., is thereby obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:9]([OH:20])(=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCCCCCCCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Product: CCCCCCCCCCC(=O)O

Procedure:
According to the same procedure as described in Preparation 1, hydroquinone and n-undecanoyl chloride (prepared by chlorination of n-undecanoic acid with thionyl chloride) were reacted and the reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was dissolved in n-hexane and crystallized with cooling to give crude hydroquinone monoundecanoate. The crude product was recrystallized from n-hexane. m.p. 72°-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15](=O)[O:16]C(C)(C)C)([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:16])[NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-4-methyl-phenol (6.15 gm; 50 mmol) in dioxane (100 mL) was added carbonic acid di-tert-butyl ester (9.8 gm; 45 mmol) followed by sodium bicarbonate (12.6 gm; 150 mmol in 75 mL of H2O) After stirring for 8 hours, the reaction was diluted with 100 mL of ethyl acetate and washed with 1N aqueous hydrochloric acid (2×100 mL), saturated aqueous sodium bicarbonate (1×100 mL), and brine (100 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to provide the desired (2-Hydroxy-5-methyl-phenyl)-carbamic acid tert-butyl ester as a brown solid (95% yield).
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]2[C:13]/1=[CH:12][C:11]([N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[CH:10][CH:9]=2.CN(C)C=O.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1>CCOCC>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33]/[CH:3]=[C:4]2\[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]3[C:13]\2=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][CH:9]=3)=[N:31][CH:32]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-n3cccc3)cc2/C1=C/Nc1ccc(Br)cn1
Temperature: 125 °C

Procedure:
A mixture of (E)-4-(methoxymethylene)-6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (268 mg, 1.0 mmole), dimethylformamide (8 mL), and 5-bromopyridin-2-amine (173 mg, 1.0 mmole) is heated at 125° C. for four hours. The reaction mixture is cooled, diluted with ether, filtered, washed with fresh ether and dried to give a salmon solid, 176 mg, (43%), mp 317-8° C. dec; MS (ES−): m/z 407.0 (M−H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl>[Fe].CO>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1ccc(C2CC2)cc1
Yield: 553.4 %

Procedure:
The title compound was prepared following the procedure described for Step-9 of Intermediate-1 using 1-cyclopropyl-4-nitrobenzene (0.400 g, 0.407 mmol), methanol (10 mL), iron powder (catalytic amount) and conc. HCl (0.5 mL) to afford 0.300 g of the desired product. 1HNMR (DMSO-d6): δ 0.43-0.48 (m, 2H), 0.74-0.80 (m, 2H), 1.23-1.74 (m, 1H), 4.79 (s, 2H), 6.44 (d, J=8.1 Hz, 2H), 6.73 (d, J=8.1 Hz, 2H); [M+H]+: 134.20.
Reaction SMILES: N1C=CC=CC=1C[C:8]1(CC2C=CC=CN=2)[N:12]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[C:11](=S)[NH:10][C:9]1=[O:24].C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:13]12([N:12]3[CH2:8][C:9](=[O:24])[N:10]=[CH:11]3)[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2
Reactant: O=C1NC(=S)N(C23CC4CC(CC(C4)C2)C3)C1(Cc1ccccn1)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: O=C1CN(C23CC4CC(CC(C4)C2)C3)C=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere in 50 ml of acetone were combined 0.432 g (1 mmol) of bispyridylmethyl N-1-adamantyl thiohydantoin, 0.138 g (1 mmol) of potassium carbonate and 0.142 g (1 mmol) of methyl iodide and the reaction mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and partitioned in 100 ml EtOAc/10 ml H2O. The organic layer was separated, washed with H2 O(4×10 ml), brine (1x), dried over NaSO4 and concentrated in vacuo. The crude product was purified via column chromatography (silica gel: 92.5/7.25 EtOAc/MeOH) and crystallized from isopropyl ether/hexane (IPE/Hex) to yield N-1-adamantylimidazolinone
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3ccccc32)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
To a solution of 2-phenyl-1H-indole (4.64 g, 24.0 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.96 g, 24.0 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was added to the obtained mixture, and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 3-[(2-phenyl-1H-indol-1-yl)methyl]benzoate (3.67 g). Then, to a solution of the product in tetrahydrofuran (37 mL) was added lithium aluminum hydride (0.41 g, 10.7 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, sodium hydrogensulfate decahydrate (6.9 g, 21.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (2.63 g, yield 79%) as a yellow oil. 1H NMR (CDCl3) δ: 1.57 (1H, m), 4.62 (2H, d, J=2.1 Hz), 5.37 (2H, s), 6.66 (1H, s), 6.93 (1H, m), 7.07 (1H, s), 7.11-7.20 (3H, m), 7.22-7.31 (2H, m), 7.33-7.48 (5H, m), 7.67 (1H, m).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=[CH:8][N:7]=1)=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1[C:6]([C:4]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:5])=[N:7][CH:8]=[N:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cncnc1C(=O)OCC
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cncnc1C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a THF solution(30 ml) of pyrimidine-4,5-dicarboxylic acid diethyl ester(1.46 g,6.52 mmol) which was prepared by the method described in the literature(Chem. Pharm. Bull.,1972,20,1513-1521) was added a THF solution of 4-methoxyphenyl magnesium bromide (1.25M,5.47 ml) dropwise at -78° C. The reaction solution was stirred at -78° C. for 30 min, treated with 1N HCl and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under reduced pressure the residue was purified by silica gel column chromatography(E. Merck Kieselgel 60/chloroform) to give 4-(4-methoxyphenylcarbonyl)pyrimidine-5-carboxylic acid ethyl ester(1.57 g) as a pale yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#N.S(=O)(=O)(O)[OH:14].[OH2:18]>>[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]([OH:14])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: N#CCCCCCCCC(=O)O
Reactant: O
Product: O=C(O)CCCCCCCC(=O)O

Procedure:
84.5 g of 8-cyanooctanoic acid are heated to 130° C. for 10 hours in the presence of 250 ml of concentrated sulfuric acid. After cooling, the reaction mixture is diluted with water and ice and the solid crystalline precipitate is filtered. After drying, one obtains 90 g of azelaic acid with a m.p. of 107° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1.Cl.Cl.[NH:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH2:20].C([O-])(=O)C.[Na+]>C(O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([NH:19][N:20]=[CH:7][C:5]2[C:4]([C:9]3[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=1
Reactant: Cn1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Reactant: NNc1cnc2ccccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(C=NNc2cnc3ccccc3c2)c(-c2ccc([N+](=O)[O-])o2)n1
Reaction time: 8 h
Yield: 86 %

Procedure:
Heat 2.0 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde together with 2.5 g of 3-hydrazinoquinoline dihydrochloride and 1.8 g of anhydrous sodium acetate in 40 ml of ethanol for 3 hours at boiling point and then allow the resulting admixture to stand overnight. Separate the formed precipitate by filtration and stir it up with a little water to obtain an 86% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-3-quinolylhydrazone [m.p. 236° to 238° C (with decomposition)].
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NN1CCCC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NN2CCCC2)cn1
Yield: 17 %

Procedure:
As described for example 8d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.66 mmol) was converted, using N-aminopyrrolidine instead of N-aminomorpholine, to the title compound (40 mg, 17%) which was obtained as an off white solid. MS: m/e=359.2 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]=12>>[Cl:18][C:16]1[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]2=[C:12]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]=1
Reactant: NCCOc1ccccc1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: Cn1ncc2c(NCCOc3ccccc3)nc(Cl)nc21

Procedure:
Reaction of 2-phenoxyethylamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-phenoxy-ethyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[CH:19]=[CH:20][CH2:21][OH:22])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[C:26]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOCC.O>[C:26]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:22][CH2:21][CH:20]=[CH:19][CH:18]([O:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:7]3[CH:6]=[N:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=3)=[CH:25][CH:24]=2)[CH3:23])=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)OCC=CC(C)Oc2ccc(Oc3cnc4cc(Cl)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 1.5 g (4.2 mmol) of the pentenol obtained in Example 3 above, 0.82 g (4.6 mmol) of 4-(acetylamino)benzoic acid, 0.95 g (4.6 mmol) of dicyclohexylcarbodiimide and 0.05 g of 4-(dimethylamino)pyridine in 20 ml of dimethylformamide was stirred at room temperature for 72 hours. The mixture was diluted with ether and water and filtered. The filtrates were separated, and the organic layer washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with a 65:35 hexane:acetone mixture to give 0.6 g of the desired product as a pale yellow, glassy solid, m.p. 62°-68° C. (Compound 23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: O=C(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)COc1ccc(NC(=O)c2cnn(-c3ccc(F)cc3)c2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
1-(4-Fluorophenyl)pyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (2 g) and diethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (1.2 g), melting point: 196–197° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12](=[O:19])[C:13](=[CH:17][CH:18]=2)[C:14](O)=O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].S(Cl)([Cl:24])=O.[ClH:26]>ClCCl>[ClH:24].[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12](=[O:19])[C:13](=[CH:17][CH:18]=2)[CH2:14][Cl:26])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)c1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)c1cccc(-c2ccc(CCl)c(=O)[nH]2)c1
Reaction time: 8 h

Procedure:
A suspension of 3.0 g. (10.48 mmoles) of 6-[m-(diethylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid in 50 ml. dichloromethane under nitrogen is treated with 0.85 ml. (11.54 mmoles) of thionyl chloride. Solution occurred at once and in about 15 minutes a solid started to appear. The suspension is allowed to stire at room temperature overnight. The solid 6-[m-(diethylamino)-phenyl]-1,2-dihydro-2-oxonicotinyl chloride, hydrochloride is collected and washed with dichloromethane. There is obtained 3.28 g. of the acid chloride, hydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=O.Cl.Cl.[N:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>CN1CCCC1=O>[I:16][C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[N:25]([C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[N:26]=[CH:10]2
Reactant: NNc1ccncc1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5-iodobenzaldehyde (6.87 g, 27.46 mmol) and 4-pyridylhydrazine dihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. The reaction mixture is stirred overnight at r.t. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for 4 h at 160° C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured on 1000 mL ice water. After vigorously stirring at r.t. for 45 min, the precipitated product is sucked off via a glass microfibre filter, washed with water and dried at the evaporator at 45° C. The title compound is obtained with a yield of 92.3% (8.14 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:51])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[O:30][C:29]2[CH:31]=[C:32]([CH:35]([O:43][Si](C(C)(C)C)(C)C)[CH2:36][CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=[CH:34][C:28]=2[O:27]1>C1COCC1.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:51])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[O:30][C:29]2[CH:31]=[C:32]([CH:35]([OH:43])[CH2:36][CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=[CH:34][C:28]=2[O:27]1
Reactant: COC(=O)CCCCC1Oc2ccc(C(CCc3cccs3)O[Si](C)(C)C(C)(C)C)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Yield: 99.6 %

Procedure:
Tetrabutylammonium fluoride (0.58 mL of a 1.0M solution in THF, 0.58 mmol) was added to (±)-methyl-5-[[6-(1-t-butyldimethylsilyloxy-3-(2-thienyl)propyl)]-1,3-benzodioxolyl]pentanoate (Compound E, 178 mg, 0.36 mmol) in THF (4.5 mL). After 16 hours the reaction was diluted with EtOAc and washed with H2O. The organic portion was dried (MgSO4) filtered and concentrated in vacuo. Flash column chromatography (silica gel, 2:1 hex/EtOAc) gave 135 mg (99%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.14 (d, J=5.1 Hz, 1H), 7.01 (s, 1H), 6.93 (dd, J=3.3, 5.1 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.60 (s, 1H), 5.92 (s, 2H), 4.88-4.91 (m, 1H), 3.67 (s, 3H), 2.96-3.03 (m, 2H), 2.43-2.49 (m, 2H), 2.29 (t, J=6.9 Hz, 2H), 1.88-2.20 (m, 2H), 1.80 (d, J=3.0 Hz, 1H), 1.44-1.66 (m, 4H).
Reaction SMILES: [OH-].[K+].C([NH:6][CH2:7][CH2:8][C:9]1[N:10]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[CH:15][C:14]([Cl:30])=[CH:13][CH:12]=2)(=O)C.Cl>O.CO>[NH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=1)=[CH:15][C:14]([Cl:30])=[CH:13][CH:12]=2
Reactant: CC(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 86 °C
Yield: 96.9 %

Procedure:
Methanol (660 mL), water (165 mL) and potassium hydroxide (365 g, 5.53 mol) was combined with 4-{2-[2-(2-Acetylamino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid (165 g, 0.291 mol). The reaction mixture was stirred at 86° C. (gentle reflux) for 16-24 hours. The reaction mixture was cooled to 75° C. and methanol (1.5 L) was added keeping the internal temperature 50° C.-55° C. The reaction mixture was neutralized (pH 5-7) by adding concentrated HCl (450 mL) over 30 minutes maintaining 60° C.-65° C. The reaction mixture became thicker and lighter in color. Water (3 L) was added to the mixture over 30 minute maintaining 60° C.-65° C. The reaction mixture was cooled to 22° C.-28° C. The product was collected by vacuum filtration followed by waster wash (3×500 mL) and cold (0°-5° C.) methanol (2×300 mL). The product was dried to give the desired product (148 g, 96.5% purity, HPLC). 1HNMR (DMSO−d6): δ7.75 (d, 2H, J=8 Hz), 7.64 (d,1H, J=2 Hz), 7.30 (m, 5H), 7.17 (brs, 1H), 7.09 (d, 1H, J=2 Hz), 7.07 (s, 1H), 6.81 (dd, 1H, J=9 Hz, 2 Hz), 6.72 (d, 2H, J=9 Hz), 6.55 (d, 1H, J=9 Hz), 4.09 (br m, 2H), 3.16 (br m, 4H), 2.50 (br m, 2H).