Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]([CH3:19])=[CH2:18].[Cl-].[NH4+].OS(O)(=O)=O>O.[Zn].CCCCCCC.CCOC(C)=O.C1COCC1>[OH:14][C:11]1([CH2:18][C:17]([CH3:19])=[CH2:16])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1
Reactant: C=C(C)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=C(C)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
t-butyl-4-oxopiperidine-1-carboxylate (10 g, 0.05 mol) was dissolved in 3-bromo-2-methylprop-1-ene (16.9 g, 0.126 mol), THF (100 mL) and saturated ammonium chloride solution (500 mL). The reaction was cooled to 10° C. and zinc dust (6.6 g, 0.01 mol) was added portionwise. After addition, the reaction mixture was stirred overnight, when TLC (heptane/EtOAc 7:1) indicated that the reaction was complete. The reaction mixture was then diluted with water and acidified with 10% H2SO4 to pH 6. The reaction mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed with saturated solution of NaHCO3, brine and evaporated to give tert-butyl 4-hydroxy-4-(2-methylallyl)piperidine-1-carboxylate (12.28 g). 1H NMR (CHLOROFORM-d) δ: 4.94-5.04 (m, 1H), 4.80 (s, 1H), 3.85 (dt, J=13.0, 3.4 Hz, 2H), 3.08-3.26 (m, 2H), 2.21 (s, 2H), 1.86 (s, 3H), 1.52-1.60 (m, 4H), 1.43-1.50 (m, 9H).
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[F:9][C:10]1[CH:11]=[C:12]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:13]=[C:14]([F:19])[C:15]=1[S:16]([CH3:18])=[O:17].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>O.CO.ClCCl>[F:19][C:14]1[CH:13]=[C:12]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:11]=[C:10]([F:9])[C:15]=1[S:16]([CH3:18])(=[O:2])=[O:17]
Reactant: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)=O)c(F)c1
Reactant: O=S(=O)([O-])O[O-]
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.5 %

Procedure:
Potassium peroxymonosulfate (0.25 g, 0.40 mmol) and water (7 mL) were added to a mixture of 4-[3,5-difluoro-4-(methyl-sulfinyl)phenyl]-5-methyl-3-phenylisoxazole (0.10 g, 0.30 mmol), dichloromethane (4 mL), and methanol (4 mL). The mixture was stirred for four days at room temperature. To the mixture was added magnesium monoperoxyphathalate hexahydrate (0.50 g, 0.80 mmol), dichloromethane (20 mL), methanol (10 mL). The mixture was stirred vigorously for 18 hours. To the mixture was added potassium peroxymonosulfate (0.35 g, 0.57 mmol), and the reaction continued for 18 hours. The mixture was poured into water and extracted with dichloromethane (4×75 mL). The combined extracts were dried with magnesium sulfate, concentrated, and the residue purified by silica gel chromatography using 30% ethyl acetate in hexanes. A white solid (98 mg, 93%) was obtained. MP 140.4-143.4° C. 1H NMR (CDCl3/400 MHz) 7.35-7.45 (m, 5H), 6.84 (d, 2H, J=9.4), 3.32 (s, 3H) 2.52 (s, 3H). ESHRMS m/z 350.0642 (M+H+, Calcd 350.0662).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:45])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[N:20][NH2:21])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([O:42][CH3:43])=[CH:37][CH:38]=3)[CH:33]=2)(=[O:31])=[O:30])[C:24]1=[O:44].[OH-].[Na+]>CCO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:21][N:20]=[CH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]([OH:45])=[O:9])=[C:14]([CH2:22][N:23]2[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[CH:37][CH:38]=4)[CH:33]=3)(=[O:31])=[O:30])[C:24]2=[O:44])[CH:15]=1
Reactant: COC(=O)COc1ccc(C=NN)cc1CN1CCC(NS(=O)(=O)c2ccc3ccc(OC)cc3c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4cc(C=NN)ccc4OCC(=O)O)C3=O)cc2c1
Reaction time: 5 h
Yield: 388.9 %

Procedure:
To a solution of {4-(aminoiminomethyl)-2-[3-(7-methoxynaphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-phenoxy}-acetic acid methyl ester trifluoroacetate (0.1 g, 0.18 mmol), prepared as in EXAMPLE 120, Part F, in 2 mL of EtOH is added 10 N NaOH (0.05 mL). The solution is stirred for 5 hours. After this time, the solution is concentrated. The residue is dissolved in 2 mL of H2O and the pH is adjusted to 3 using 1 N HCl. The solid which forms is collected by filtration. The solid is purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate fraction are lyophilized to afford the title compound (0.05 g, 0.7 mmol) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:17])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:25]1(Br)[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([O:17][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:47])[CH3:48])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C
Reactant: CC(C)(C)C(=O)OC[C@H]1OC(Br)(Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a suspension of 1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.75 g) in acetonitrile (5 mL) and tetrahydrofuran (3 mL) was added potassium carbonate (0.675 g) under stirring at room temperature. After the mixture was stirred at 50° C. for 1 hour, 1-bromo-2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.27 g) was added to the mixture. The mixture was stirred at 50° C. for 6 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10 to 1/5) to give 1-acetyl-4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.88 g).
Reaction SMILES: C1CO[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:4][O:5][CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[O:10][CH:9]=2)[O:2]1.O>C1COCC1.Cl>[O:2]=[C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][O:5][CH2:6][CH2:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[O:10][CH:9]=1
Reactant: Oc1cccc2c(CCOCC3(c4ccccc4)OCCO3)coc12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(COCCc1coc2c(O)cccc12)c1ccccc1
Temperature: 50 °C
Reaction time: 29 h
Yield: 68.9 %

Procedure:
3-(2-(2,2-ethylenedioxy-2-phenylethoxy)ethyl)-7-hydroxybenzofuran (185 mg) was dissolved in THF (3 ml). To this solution, one drop of concentrated hydrochloric acid was added and the solution was stirred at 50° C. for 29 hours, followed by refluxing the solution for 3 hours. The reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (111 mg, yield: 69%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH3:19].C(O)C>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([NH2:19])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: N
Solvent: CC(=O)O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N)nc21

Procedure:
1 Gram of 1-ethyl-1,4-dihydro-4-oxo-6-fluoro-7-chloro-1,8-naphthyridine-3-carboxylic acid (for example, described in European Patent Application No. 0,027,752) is mixed with 25 ml of concentrated ammonia solution containing 20% of ethanol. The mixture is maintained in a sealed tube for 4 hours at 120°-125° C. The mixture is cooled, and acetic acid added until the pH is slightly acid, when the precipitate formed is filtered off and washed with water. The product is dried, 0.8 gram of 1-ethyl-1,4-dihydro-4-oxo-6-fluoro-7-amino-1,8-naphthyridine-3-carboxylic acid being obtained, of melting point 299°-303° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C2C=CC(C([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=O)=CC=2)C=CC=CC=1.CC#N>C1(C)C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+]>[OH:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][CH:29]([OH:31])[CH2:30][C@@H:26]2[C@H:25]1[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](O)C[C@@H]2O1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A 1.5 M solution of Diisobutylaluminum hydride in toluene (46.0 g, 69 mmol) was added dropwise to a stirred solution of compound [9a] (17.0 g, 30 mmol) in toluene (500 mL) at −20-−10° C. The mixture was stirred for 1 hour at the same temperature. Methanol (200 mL) was added dropwise to the stirred mixture at −20-−10° C. The obtained mixture was stirred for 1 hour at room temperature, filtered and evaporated under reduced pressure. Dichloromethane (250 mL) was added to the residue. The resulting solution was washed with brine (2×220 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. To complete hydrolysis of p-phenylbenzoate-groups a mixture of the residue and potassium carbonate (10:0 g) in methanol (100 mL) was stirred at room temperature for 7 hours (TLC monitoring). The mixture was evaporated under reduced pressure. A mixture of the residue, dichloromethane (300 mL) and water (300 mL) was stirred for 10 min at room temperature. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel exane/ethyl acetate 1:2 v/v) to obtain 10.3 g of the compound [11a] (88% yield), [α]D20 −53.5° (c 1.0, MeCN). 1H NMR (CDCl3) δ: 7.10-7.29 (m, 5H); 5.47-5.63 (m, 1H); 4.57-4.69 (m, 2H); 3.69-3.94 (m, 2H); 3.60-3.75 (m, 1H); 3.40-3.55 (m, 1H). 13C NMR (CDCl3) δ: 19.9; 25.4; 29.0; 31.2; 31.9; 36.6; 40.2; 41.5; 42.5; 46.4; 48.0; 55.3; 55.6; 62.8; 79.4; 79.9; 82.4; 86.4; 97.6; 100.0; 101.1; 125.6; 128.2; 128.3; 142.5. IR (neat): 3398, 2944, 2867, 1451 cm−1.
Reaction SMILES: C([N:5]1[C:21](=[O:22])[N:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:11]=[C:12](Cl)[C:7]2=[N:6]1)(C)(C)C.B(Br)(Br)[Br:24]>ClCCCl>[Br:24][C:12]1[C:7]2[N:8]([C:21](=[O:22])[NH:5][N:6]=2)[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:11]=1
Reactant: BrB(Br)Br
Reactant: CC(C)(C)n1nc2c(Cl)nc(-c3ccc(Cl)cc3)cn2c1=O
Solvent: ClCCCl
Product: O=c1[nH]nc2c(Br)nc(-c3ccc(Cl)cc3)cn12
Temperature: 125 °C

Procedure:
A solution of 335 mg of 2-tert-butyl-8-chloro-6-(4-chloro-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one in 1,2-dichloroethane (10.0 mL) was treated with 2.35 g of boron tribromide and the solution was heated to 125° C. in a sealed tube. After two h, the reaction was cooled to ambient temperature and the excess boron reagent was carefully destroyed by the careful addition of water. The reaction mixture was basified with 2N NaOH to pH 9 and then acidified with sat. ammonium chloride solution. The aqueous layer was extracted with EtOAc and the organic layers were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to provide 8-bromo-6-(4-chloro-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a tan solid. MS (M+H+)=438.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.188 g (1.86 mmol) of triethylamine and 15 ml of tetrahydrofuran at 0° C. is added 0.275 g (1.55 mmol) of 4-cyanobenzoyl chloride dropwise and the reaction mixture is allowed to stir overnight while slowly reaching room temperature. A precipitate is formed overnight which is collected by filtration, washed with water and ether and dried to yield a crude product which is triturated with methanol/chloroform to yield 0.14 g (23%) of the title compound as a white solid: m.p.>300° C.; m/e 386.
Reaction SMILES: C1(CO[C:9](=[O:16])[NH:10][C@H:11]2[CH2:14][NH:13][C:12]2=[O:15])C=CC=CC=1.[CH3:17][C:18]([CH3:57])([O:20][C:21](=[O:56])[C:22]([CH3:55])([CH3:54])[O:23]/[N:24]=[C:25](/[C:29]1[N:30]=[C:31]([NH:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:32][CH:33]=1)\C(O)=O)[CH3:19].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>[Pd].O.CN(C=O)C.CO>[CH3:19][C:18]([CH3:57])([O:20][C:21](=[O:56])[C:22]([CH3:55])([CH3:54])[O:23]/[N:24]=[C:25](/[C:29]1[N:30]=[C:31]([NH:34][C:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:32][CH:33]=1)\[C:9]([NH:10][C@H:11]1[CH2:14][NH:13][C:12]1=[O:15])=[O:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@H]1CNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 59396.9 %

Procedure:
A mixture of 2.20 g (0.01 mmol) of (S)-(2-oxo-3-azetidinyl) carbamic acid phenylmethyl ester, 125 mL of methanol, and 0.68 g of 10% palladium on carbon catalyst was hydrogenated (5 minutes) on a parr apparatus at an initial gauge pressure of 50 psi. After filtration of the catalyst, the solution was concentrated to dryness under reduced pressure. The residual (S)-3-amino-2-azetidinone was dissolved in 10 mL of DMF and added to a mixture of 5.71 g (0.01 mol) of (Z)-α-[[2-(1,1-dimethylethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[(triphenylmethyl)amino]-4-thiazole acetic acid, 40 mL of DMF, 2.06 g (0.01 mol) of N,N'-dicyclo-hexylcarbodiimide and 1.35 g (0.01 mol) of 1-hydroxybenzo-triazole. The mixture was stirred for 4 hours, diluted with 500 mL of water and adjusted to pH 7.5 with aqueous NaHCO3. The mixture was extracted with four 300 mL portions of ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), decolorized with charcoal and concentrated to dryness. After purification by HPLC on a Waters Prep 500, using 4:1 ethyl acetate-hexane, 3.8 g of (S,Z)-α-[[2-(1,1-dimethylethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-N-(2-oxo-3-azetidinyl)-2-[(triphenylmethyl)amino]-4-thiazoleacetamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.Cl.[NH2:20][OH:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:20][OH:21]
Reactant: O=Cc1c(Cl)cc(-c2ccc(O)c(F)c2)cc1Cl
Reactant: NO
Agent: Cl
Product: ON=Cc1c(Cl)cc(-c2ccc(O)c(F)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 3,5-dichloro-3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (290 mg, mmol) with hydroxylamine hydrochloride (140 mg, 1.27 mmol) according to Method F to yield 260 mg (85%) of a white solid: mp 185-190° C.; 1H NMR (DMSO-d6): δ 7.03 (1H, t, J=8.86 Hz), 7.46-7.49 (1H, m), 7.68 (1H, dd, J=12.74 Hz, J=2.26 Hz), 7.82 (2H, s), 8.25 (1H, s), 10.24 (1H, s), 11.80 (1H, s); MS (ESI) m/z 298/300/302 (M−H)−, 300/302/304 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33]>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: Fc1ccc(F)c(CBr)c1
Product: Cc1nc(N2CCCC(Cc3cc(F)ccc3F)C2=O)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 2-(bromomethyl)-1,4-difluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 32% yield: mp 144-145° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (m, 5H), 7.02-6.81 (m, 3H), 6.01 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.32-4.20 (m, 1H), 4.03-3.94 (m, 1H), 3.47-3.37 (m, 1H), 2.90-2.73 (m, 2H), 2.63 (s, 3H), 2.12-1.98 (m, 1H), 1.96-1.75 (m, 2H), 1.64-1.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.5, 162.6, 160.2, 158.6, 157.3, 156.9, 152.2, 137.9, 128.8, 127.9, 127.5, 119.6, 117.7, 116.3, 114.7, 47.9, 44.1, 43.0, 30.6, 24.9, 21.3, 17.3; MS (ES+) m/z 456.2 (M+1).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:33]=[CH:32][C:20]([CH2:21][CH:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([OH:25])=O)=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>O>[CH2:26]([CH:22]1[CH2:21][C:20]2[C:32](=[CH:33][C:17]([C:14]3[N:15]=[CH:16][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][N:13]=3)=[CH:18][CH:19]=2)[C:23]1=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(CC(CCCCCC)C(=O)O)cc2)nc1
Solvent: O
Product: CCCCCCCCCCc1cnc(-c2ccc3c(c2)C(=O)C(CCCCCC)C3)nc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 65.1 %

Procedure:
0.4 g (0.88 mM) of 2-[4-(5-decylpyrimidine-2-yl)benzyl]octanoic acid and 1.3 g of polyphosphoric acid were placed in a flask, followed by stirring for 6 hours at 130° C. After the reaction, 10 ml of water was added to the reaction mixture, followed by extraction with toluene. The extract was dried, followed by distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.25 g (0.57 mM) of 2-hexyl-6-(5-decylpyrimidine-2-yl)-1-indanone (Yield: 65%, m.p.=87° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1.COC(=O)C(C(=O)C1C=CC(C)=C(C)C=1)=COC.[F:43]C1C=C(C=CC=1)N>>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:43])[CH:8]=1
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1ccc(C)c(C)c1
Reactant: Nc1cccc(F)c1
Agent: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1cccc(F)c1)C(=O)c1ccc(C)c(C)c1
Yield: 50.1 %

Procedure:
Compound 2h was prepared following the procedure described in Step 1 of Example 1 using from 2g (8.06 mmol) of crude 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a and 0.806 g (7.26 mmol) 3-fluoroaniline. The crude product 2h was purified by recrystalization with dichloromethane/hexane to yield 1.19 g of 2-(3,4-Dimethyl-benzoyl)-3-(3-fluoro-phenylamino)-acrylic acid methyl ester as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1

Procedure:
By alkylating ethyl 4-hydroxy-naphthalene-2-carboxylate [J. Agric. Chem Soc. Japan 24, 313 (1950)] with benzyl bromide in an analogous manner to that described in Example 14(a) there was obtained ethyl 4-benzyloxy-naphthalene-2-carboxylate as an almost colourless solid; MS: 216 (M)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[CH:30]1([C:33]([CH:42]2[CH2:44][CH2:43]2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([SH:41])[CH:36]=2)[OH:34])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:42]1([C:33]([CH:30]2[CH2:31][CH2:32]2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([S:41][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]3[C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[N:13][N:14]=[C:7]3[CH:6]=[CH:5]4)[CH:36]=2)[OH:34])[CH2:44][CH2:43]1
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: OC(c1cccc(S)c1)(C1CC1)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OC(c1cccc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)c1)(C1CC1)C1CC1
Temperature: 100 °C

Procedure:
To 7-iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (10j, 176 mg, 0.47 μmmol) in 1,4-dioxane (4.5 mL) was added iPr2NEt (0.16 mL, 0.94 mmol), and the reaction was degassed with N2 for 5 minutes. 10i (174 mg, 0.47 mmol) was added, followed by Pd2dba3 (22 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.05 mmol). The reaction was sealed and heated at 100° C. for 6 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (60-80% EtOAc in hexanes) to give the desired product, 10k.