Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:16][N:17]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=1>>[CH3:16][N:17]([CH2:25][C:26]([F:29])([F:27])[F:28])[C:18]1[N:19]=[CH:20][C:21]([NH:24][C:13]([C:3]2[C:2]([CH3:1])=[N:6][N:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:4]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: CN(CC(F)(F)F)c1ccc(N)cn1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)CC(F)(F)F)nc1

Procedure:
With a procedure similar to example 16 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N2-methyl-N2-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine. LCMS calcd for C18H17F3N6O (m/e) 390, obsd 391 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>CC(=O)CC.C(Cl)Cl>[CH3:37][O:38][CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(O)cc4)n3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)c4cccc(OC)c4)nn23)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(S)-1-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]urea (the compound obtained in Example 223; 20.3 mg) was suspended in 2-butanone (2 ml). Thereafter, potassium carbonate (69.4 mg) and 2-methoxyethyl bromide (47.2 μl) were added to the suspension, and the obtained mixture was stirred at 80° C. for 5 hours. Thereafter, the reaction solution was diluted with methylene chloride (5 ml), and the resultant product was then washed with 1 M hydrochloric acid (5 ml×3), saturated sodium bicarbonate (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (10.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]1[SH:14].[CH3:19]I.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]1[S:14][CH3:19]
Reactant: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1ncc(C(=O)O)n1Cc1cc(F)cc(F)c1

Procedure:
Reaction of 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid prepared as in Example 1 with methyl iodide and sodium methoxide in methanol by standard techniques yields 1-(3,5-difluorobenzyl)-2-methylmercaptoimidazole-5-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].Br[CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH2:17]([N:4]([CH3:3])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: CNC(=O)C(F)(F)F
Reactant: CCCCC=CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (1.05 eq) was slowly added at 0° C. to a solution of N-methyltrifluoro-acetamide (25 g) in DMF (140 mL). The mixture was stirred for 1 h at room temperature under nitrogen. Then, a solution of bromohexene (32.1 g) in DMF (25 mL) was added dropwise and the mixture was heated to 70° C. for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4×50 mL), dried (MgSO4), filtered and evaporated to give 35 g of the target product 18 as a yellowish oil which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3]1.[C:11]([OH:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1CCCCC1>[C:11]([S:18][C@@H:3]1[C:2]([CH3:10])([CH3:1])[CH2:6][CH2:5][C@H:4]1[C:7]([OH:9])=[O:8])(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)C=C(C(=O)O)CC1
Reactant: OC(=S)c1ccccc1
Solvent: C1CCCCC1
Product: CC1(C)CC[C@@H](C(=O)O)[C@@H]1SC(=O)c1ccccc1
Temperature: 120 °C
Yield: 51.6 %

Procedure:
A mixture of 3,3-dimethyl-1-cyclopentene-1-carboxylic acid (2 g) and thio-benzoic acid (2.37 g) is heated to 120° C. for 14 hours under Argon stream. The reaction mixture is cooled, taken up with a small amount of cyclohexane and filtered yielding 2.05 g of trans 2-benzoylthio-3,3-dimethylcyclopentyl carboxylic acid. M.p. 131° C. (from hexane)
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][S:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[O-:14]I(=O)(=O)=O.[Na+]>O.CO>[C:1]([Si:5]([CH3:12])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][S:10]([CH3:11])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyldimethyl(3-(methylthio)propoxy)silane (0.1 mol) in water/MeOH (3:2, 500 mL) at 0° C. was added sodium (meta)periodate (˜30 g). The reaction mixture was stirred first at 0° C. for 20 hours, then at room temperature for 3 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to remove the most of the organic solvent. The aqueous residue was then extracted with CHCl3 (2×) and the combined organic extracts were dried with anhydrous sodium sulfate. The organic phase was decanted and concentrated to yield the title compound as an oil which solidified to provide a white solid upon standing (17.65 g).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:9]2=[C:10]3[C:15](=[CH:16][CH:17]=[C:8]2[NH:7][C:6]1=[O:18])[N:14]=[CH:13][CH:12]=[CH:11]3)[CH3:3].[CH3:19][N:20]([CH2:22][C:23]1[CH:29]=[CH:28]C(N)=[CH:25][CH:24]=1)[CH3:21].Cl>C(O)C>[CH3:19][N:20]([CH2:22][C:23]1[CH:29]=[CH:28][C:3]([NH:2]/[CH:4]=[C:5]2\[C:6](=[O:18])[NH:7][C:8]3[C:9]\2=[C:10]2[C:15](=[CH:16][CH:17]=3)[N:14]=[CH:13][CH:12]=[CH:11]2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CN(C)C=C1C(=O)Nc2ccc3ncccc3c21
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccc(N/C=C2\C(=O)Nc3ccc4ncccc4c32)cc1
Temperature: 25 °C

Procedure:
A mixture of dimethylaminomethylidene-1,3-dihydro-2H-pyrrolo[3,2-f]quinoline-2-one (0.1 mmol), 4-dimethylaminomethylaniline (0.1 mmol) and conc. hydrochloric acid (0.02 mL) in ethanol (1 mL) was heated at reflux until the reaction was complete as determined by tic analysis. The reaction mixture was allowed to cool to room temperature. The solvent was evaporated and the residue purified using silica gel chromatography to give the title compound as an orange-brown solid, 15 mg. (42%). 1H NMR (DMSO-d6): δ 2.17 (s, 6H), 3.17 (s, 2H), 7.31-7.51 (m, 6H), 7.74 (d, J=8.7 Hz, 1H), 8.74 (d, J=3.3 Hz, 1H), 8.83 (d, J=6.0 Hz, 1H), 8.86 (d, J=12 Hz, 1H), 10.95 (s, 1H), 11.80 (d, J=12 Hz, 1H); APESI+MS m/z 345 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].[O:10]1[C:14]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:13][N:12]=[CH:11]1.O>CS(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]3[CH:17]=[CH:16][C:15]([C:14]4[O:10][CH:11]=[N:12][CH:13]=4)=[CH:22][CH:21]=3)[S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S
Reactant: O=Cc1ccc(-c2cnco2)cc1
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc2nc(-c3ccc(-c4cnco4)cc3)sc2c1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
2 Amino-5-bromobenzenethiol (102 mg) and 4-(1,3-oxazol-5-yl)benzaldehyde (87 mg) were dissolved in dimethylsulfoxide (1 mL), followed by stirring at 160° C. for 10 minutes. Water (10 mL) was added to the reaction mixture. The precipitated matter was recovered through filtration, and washed with methanol, to thereby yield the title compound (105 mg).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1>CN(C=O)C>[F:1][CH2:2][CH2:3][O:4][C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1
Reactant: OCCF
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCF)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
530 μl (8.68 mmol) of 2-fluoroethanol are added to a suspension of 347.05 mg (8.68 mmol) of sodium hydride in 10 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone in 3 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room temperature overnight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 10% B, t 30 min 30% B), 362 mg of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone were obtained, corresponding to the following characteristics:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:32]3[C:27](=[N:28][C:29]([NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:30][CH:31]=3)[N:26](COCC[Si](C)(C)C)[N:25]=2)[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([CH2:35][CH2:34][NH:33][C:29]2[N:28]=[C:27]3[NH:26][N:25]=[C:24]([C:20]4[CH:19]=[C:18]([NH:17][CH:10]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:9][CH2:8][NH2:7])[CH:23]=[CH:22][CH:21]=4)[C:32]3=[CH:31][N:30]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NCCN4CCOCC4)ncc23)c1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(Nc1cccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of crude (3-{3-[6-(2-morpholin-4-yl-ethylamino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester (329 mg, crude) in dichloromethane (1.5 mL) was added TFA (1.5 mL) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure and partitioned between saturated NaHCO3 solution and ethyl acetate. The water phase was extracted with ethyl acetate again. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, MeOH:dichloromethane, 1:100 to 1:10). The obtained solid was dissolved in a solution of HCl in MeOH and concentrated to give N1-{3-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl}-1-phenyl-propane-1,3-diamine; hydrochloride. (Yield 20 mg).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([Br:19])=[CH:4][N:3]=1.C[N:21]1C(=O)CCC1>N>[Br:19][C:5]1[C:6]2[C:7](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[C:2]([NH2:21])=[N:3][CH:4]=1
Reactant: CN1CCCC1=O
Reactant: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Br)c2n1
Agent: N
Product: Nc1ncc(Br)c2nn(-c3c(Cl)cccc3Cl)cc12
Yield: 84 %

Procedure:
A solution of 4,7-dibromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (730 mg, 1.73 mmol) in NMP (6.5 mL) and 33% aqueous ammonia (3.5 mL) was sealed in a microwave vial and irradiated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to afford the title compound as a beige solid (515 mg, 84% yield). LCMS (Method C): RT=2.00 min, m/z: 357 [M+H+].
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C@H:16]([CH2:21][N:22]([CH2:30][C@H:31]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:46][O:47][CH2:48][C:49](O)=[O:50].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:39]([O:38][C@H:31]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][N:22]([CH2:21][C@@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])(=[O:4])=[O:3])[CH:6]=3)[CH:12]=2)[O:17]1)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3cccc(S(N)(=O)=O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)c1

Procedure:
A solution of the compound of Example 281 (60 mg, 0.091 mmol), methoxyacetic acid (13 mg, 0.13 mmol), EDCI (26 mg, 0.14 mmol), and DMAP (11 mg, 0.091 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated down and the crude product was purified by preparative TLC plate with CH2Cl2:MeOH:NH4OH (90:15:2) to obtain (60 mg). ESLC-MS: m/z=725 (MH+); 1H NMR (MeOH-d4): 8.566˜8.439 (m, 2H), 8.077 (s, 1H), 7.889˜7.780 (m, 1H), 7.675 (m, 1H), 7.453 (m, 2H), 7.313 (m, 2H), 6.767 (d, 1H), 5.180˜5.035 (m, 1H), 4.220 (s, b, 1H), 3.907 (s, 2H), 3.760˜3.333 (m, 4H), 2.835 (m, 2H), 2.041 (m, 1H), 1.711 (m, 1H), 1.445 (d, 9H), 0.892 (s, 9H), 0.076 (s, 3H), −0.109 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[CH:14]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])Cl)([CH3:16])[CH3:15]>O1CCCC1>[CH3:1][C:2]1[N:3]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (purchased from Beta Pharma Scientific, 9.91 g, 64.7 mmol) in tetrahydrofuran (200 mL) at 0° C. under N2 was treated portionwise with sodium hydride (dry, 95%) (2.06 g, 82 mmol). The resulting mixture was stirred for 20 minutes and treated with triisopropylchlorosilane (16.5 mL, 78 mmol). The mixture was stirred for 30 minutes, then the ice bath was removed. After warming to ambient temperature over 90 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate) filtered and concentrated. Purification by chromatography on a 330 g silica cartridge eluting with 0-20% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1.C([N:36]1[CH:40]=[C:39]([C:41](=[O:44])[CH2:42][CH3:43])[N:38]=[CH:37]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:44][C:41]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1)([C:39]1[N:38]=[CH:37][NH:36][CH:40]=1)[CH2:42][CH3:43]
Reactant: CCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CN1Cc2c(ccc3cc(Br)ccc23)C1=O
Product: CCC(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1c[nH]cn1
Yield: 67.1 %

Procedure:
By the reaction in the same manner as in Example 18 using 7-bromo-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.14 g) and 1-(1-trityl-1H-imidazol-4-yl)-1-propanone (0.17 g), the title compound (0.10 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:12]([O:14][CH3:15])=[O:13])[C:4]2([CH2:9][CH2:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][C:2]12[O:24][CH:11]1[CH2:10][CH2:9][C:4]1([CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:3]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1C(C)=CCCC12CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C1C2(CCCC2)CCC2OC21C
Temperature: 20 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
At 5° C., a solution of methyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (13.5 g, 60 mmol, prepared as described in Example 25) in dichloromethane (150 ml) was treated with MCPBA (17.8 g, 72 mmol). The resulting mixture was stirred for 4 h at 20° C., filtered, and the organic phase was washed with water (100 ml), dried (MgSO4), concentrated, and gave crude methyl 1-methyl-7-oxaspiro[bicyclo[4.1.0]heptane-3,1′-cyclopentane]-2-carboxylate (13 g). Boiling point: 130° C. (0.08 mbar).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].C(=O)([O-])[O-].[K+].[K+].[SH:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1>C(#N)C>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1ncco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)=C(F)CCSc1ncco1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
7.5 g of 4-bromo-1,1,2-trifluoro-1-butene and 7.0 g of potassium carbonate were added to 50 ml of acetonitrile, 3.8 g of 2-mercaptooxazole, and refluxed for 5 hours by heating. After cooling the reaction mixture to room temperature, solid substance was filtered by suction and the filtrate was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=1:1) to obtain 6.5 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 82.7%, n20D=1.4631).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N2CCCC2=O)cc1
Yield: 94 %

Procedure:
A mixture of 1-(4-carboxyphenyl)pyrrolidin-2-one (3.0 g, 14.6 mmol) from example 1 and sulfuric acid (0.2 mL) in 100 mL of methanol was stirred at reflux for 18 h. The solvent was removed under vacuum. The crude material was dissolved in 100 mL of ethyl acetate and the solution was washed with a saturated sodium bicarbonate solution (3×15 mL), dried and evaporated to give 3.0 g (94%) of 1-(4-methoxycarbonylphenyl)pyrrolidin-2-one as a white solid, mp 118-120° C. (chloroform/ether).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.Cl.[NH2:42][CH:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45]>O1CCOCC1.C(N(CC)CC)C>[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:42][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(C)C[C@H](NOCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
22.90 g of dicyclohexylcarbodiimide was added to 300 ml of a solution of 26.39 g of N-benzyloxyleucine and 13.35 g of N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, whereby a colorless solution was obtained. Separately, 20 ml of triethylamine was added to 300 ml of a suspension of 28.57 g of diethyl aminomalonate hydrochloride in anhydrous dioxane. To the mixture was applied an ultrasonic wave for 1 hour. Thereto was added the above colorless solution. The mixture was stirred at room temperature for 16 hours and then at a bath temperature of 100° C. for 3.5 hours. The reaction mixture was subjected to distillation to remove the solvent. The residue was dissolved in 1,000 ml of ethyl acetate. The solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent to obtain 39.22 g of diethyl N-(N-benzyloxyleucyl)aminomalonate as a yellow oily substance.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([C:17](=[O:19])[CH3:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].COC(OC)OC>C([O-])(O)=O.[Na+]>[CH3:18][C:17]1([C:14]2[CH:13]=[C:12]([CH2:11][N:9]3[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]3)[O:16][N:15]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: CC(=O)c1cc(Cn2cc([N+](=O)[O-])cn2)on1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cc(Cn3cc([N+](=O)[O-])cn3)on2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[5-(4-nitro-pyrazol-1-ylmethyl)-isoxazol-3-yl]-ethanone (336 mg, 1.42 mmol) in ethylene glycol (1.59 mL, 28.45 mmol) was treated with trimethylorthoformate (0.31 mL, 2.84 mmol) followed by LiBF4 (27 mg, 0.29 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with EA (10 mL). The org. extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:10 hept-EA) gave the title compound as a yellow oil. TLC: rf (20:10 hept-EA)=0.19. LC-MS-conditions 02: tR=0.86 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>>[C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:14][C:15](=[O:23])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Temperature: 185 °C
Reaction time: 0.08 h

Procedure:
A stirred slurry of 66 g. (0.5 mole) of aluminum chloride and 42.5 g. (0.3 mole) of benzoyl chloride was heated to 150°C. and then 133 g. (0.1 mole) of indolin-2-one was slowly added at a rate so that the temperature of the stirred reaction mixture was maintained at 180°-185°C. After addition the reaction mixture was stirred for five minutes at 185°C., cooled and poured into ice water. The 5-benzoylindolin-2-one which precipitated was collected and recrystallized from methanol; it melted at 204°-205°C. The yield was 17.5 g. (73%).