Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([P:20]([O:24][CH3:25])([O:22][CH3:23])=[O:21])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>C(#N)C>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH:12]=[C:13]([P:20]([O:22][CH3:23])([O:24][CH3:25])=[O:21])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1
Reactant: COc1cc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)cc(OC)c1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(COc2c(OC)cc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropyl 3-(3,5-dimethoxy-4-hydroxyphenyl)-2-(dimethoxy-phosphinyl)propenoate (4 g; 0.01 mol; Table 1, No. 10) was dissolved in 60 ml of acetonitrile, and potassium carbonate (4.45 g; 0.032 mol) and 4-methoxybenzyl chloride (1.4 ml; 0.011 mol) were added and the mixture was initially stirred at room temperature for 8 hours. To complete the reaction, 0.7 ml of 4-methoxybenzyl chloride was added, followed by stirring for 4 hours, after which the result of a thin-layer chromatography showed that the reaction was complete. The filtrate after removal of potassium carbonate by filtration was evaporated to dryness under reduced pressure, and the residue is chromatographed (SiO2 ; CH2CI2 : AcOEt=8:2). This resulted in a slowly crystallizing oil which, on solidification, had a melting point of 68° to 69° C.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)(O)[O-].[Na+]>O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Oc1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 10 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), m-chlorophenol (26 g), sodium bicarbonate (34 g), and water (200 ml) was stirred at 85°C for 10 hours. After cooling, excess m-chlorophenol was removed by extraction with diethyl ether, and 4-(m-chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitated from the aqueous layer by the addition of 4N hydrochloric acid. After recrystallization from aqueous methanol, the melting point was 230°-232°C.
Reaction SMILES: C([Li])CCC.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C=CC=CC=1.[C:34]([O:38][C:39](=[O:51])[NH:40][C@@H:41]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:42]=O)([CH3:37])([CH3:36])[CH3:35]>CCCCCC.C1COCC1>[C:34]([O:38][C:39](=[O:51])[NH:40][C@H:41](/[CH:42]=[CH:14]\[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](/C=C\Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, 842 μL (2.1 mmol) 2.5 M n-butyllithium solution in hexane was added to a suspension of 986 mg (2.2 mmol) triphenyl-(2-phenylethyl)phosphonium bromide [can be synthesized, e.g., according to R. W. Hartmann, M. Reichert, Archiv der Pharmazie 333, 145 (2000); K. C. Nicolaou et al., European J. Chem. 1, 467 (1995)] in 125 mL THF at −78° C., and the mixture was then stirred for one hour at 0° C. The reaction mixture was then cooled back to −78° C. and a solution of 500 mg (2.0 mmol) tert-butyl-[(2S)-1-oxo-3-phenylpropan-2-yl]carbamate in 5 mL dry THF was added. The batch was heated to 0° C. and stirred further for three hours at this temperature. The reaction was then terminated by adding saturated aqueous ammonium chloride solution. The mixture was diluted with MTBE, the phases were separated, and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified over a silica gel column using cyclohexane/ethyl acetate 5:1 as the mobile phase. After concentrating the corresponding fractions, 173 mg (25.6% of the theoretical) of the Boc-protected intermediate, tert-butyl-[(2S,3Z)-1,5-diphenylpent-3-en-2-yl]carbamate was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([Li])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cccc(C(=O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C(O)(c2ccccc2)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of (2-(benzyloxy)-3-tert-butylphenyl)(3-(pyridin-2-yl)phenyl)methanone (0.96 g, 2.28 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred at −78° C. under nitrogen and 1.8 M phenyllithium (2 mL, 3.6 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 30 min for 1 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and stripped. The crude product was purified by chromatography on silica (60 g) with 5% ethyl acetate in heptane (1 L), then 7.5% (2 L) to afford 6 (1.14 g, 100%). This material contains a minor impurity and it was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35].C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH:38]=[CH2:39])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol) were dissolved in 6 ml dichloromethane. 85 μl (2 molar equivalents) triethylamine and 65 μl (2 molar equivalents) of allyl chloroformate were added. The reaction mixture was stirred at 20° C. for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95/5 volume ratio) to provide 70 mg (yield=51%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH:11]([CH3:12])[CH3:13])[N:10]=1)[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCNc1nc(C(C)C)co1
Product: CCCCN(C(=O)C(C)C)c1nc(C(C)C)co1

Procedure:
2-(N-Butylamino)-4-isopropyloxazole was acylated with isobutyryl chloride as described in Example 9.
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:15][C:11]1[NH:12][C:13](=[O:14])[CH:8]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:9][C:10]=1[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Product: CC1=C(c2ccncc2)SC(Nc2ccccc2)C(=O)N1

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one and aniline were reacted to give the titled compound as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:27])[CH:11]([NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:12][CH2:13][CH3:14])[N:6]=[CH:5]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[F:25][C:20]1[CH:19]=[C:18]([CH2:17][C:16]([NH:15][CH:11]([CH2:12][CH2:13][CH3:14])[C:10]([NH:9][C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH:8]=2)=[O:27])=[O:26])[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCO)cn1
Solvent: c1ccncc1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCOS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide (1 equiv) was dissolved in pyridine and treated with methansulfonyl chloride (2.2 equiv) at 0° C. The reaction was warmed to rt and stirred for 4 h, quenched with sodium bicarbonate, and extracted with methylene chloride. The extracts were dried and concentrated to provide methanesulfonic acid 2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethyl ester which was used without further purification.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]([CH3:31])[CH:19]=4)=[CH:17][C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>>[C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]([CH3:31])[CH:19]=4)=[CH:17][C:10]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNc5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 11.4 %

Procedure:
Phenyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is prepared as described in Example 179a and, starting with 0.120 g of phenyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a, and 0.95 cm3 of 5N potassium hydroxide. 0.010 g of phenyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[H-].[Na+].Cl[C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:18][C:14]=2[N:15]=[CH:16][N:17]=1.O>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[N:17][CH:16]=[N:15][C:14]=3[O:18][C:19]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=1
Reactant: N#CCCCCCO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCC#N)c23)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Dissolve 850 mg (3.8 mmol) 6-hydroxyhexanenitrile [obtained according to Eur. J. Med. Chem. 36 (4), 303-311 (2001)] in 15 ml DMF, add, at 0° C., 180 mg 60% sodium hydride (dispersion in mineral oil; approx. 4.5 mmol) and stir the mixture for 1 h at room temperature. Next, add 1.26 g (3.8 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir the mixture overnight at 120° C. After cooling, add water to the mixture and extract with ethyl acetate. Dry the organic phase, and concentrate by evaporation. Purify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 2:1→cyclohexane/ethyl acetate 1:2). 1.05 g (68% of theor.) of an orange-coloured oil is obtained, which is used as raw product in further reactions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH:18]([CH2:34][CH3:35])[C:17]1=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH:18]([CH2:34][CH3:35])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 2-[3-ethyl-4-(2-nitrobenzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 32, (5.3 g, 10. mmol) in anhydrous THF (10 mL) is added 1.0 M borane-tetrahydrofuran complex (32.0 mL) at −20° C. The reaction mixture is stirred at this temperature overnight. Methanol (3 mL) is added to the reaction mixture at −20° C. and the solution is allowed to stir for twenty minutes. Additional methanol (6 mL) is added and the reaction mixture is allowed to warm to room temperature. The solvent is removed in vacuo and the product is purified over silica (EtOAc/Hexane: 1:1) to afford 4.1 g (68% yield) of the desired product. 1H NMR (CDCl3, δ): 8.04–7.98m, (1H), 7.80–7.72 (m, 3H), 7.61–7.52 (m, 4H), 7.45–7.38 (m, 2H), 7.28 (d, J=9.6 Hz, 1H), 3.78 (t, J=6.0 Hz, 1H), 3.64 (d, J=11.0 Hz, 1H), 3.50 (s, 3H), 3.48 (t, J=7.2 Hz, 1H), 3.24–3.10 (m, 2H), 3.10–2.95 (m, 1H), 2.90 (t, J=11.0 Hz, 1H), 2.66 (d, J=2.4 Hz), 2.38–2.20 (m, 1H), 1.61–1.48 (m, 1H), 1.48–1.32 (m, 1H), 0.58 (t, J=9.6 Hz, 3H); ); 13C NMR, δ 171.7, 148.0, 135.9, 134.2, 133.7, 132.4, 132.0, 130.9, 128.0, 127.7, 127.6, 126.2, 125.6, 124.4, 69.0, 56.4, 53.8, 51.3, 47.0, 41.9, 35.2, 22.2, 10.7.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:19][C:6]1([CH2:5][CH2:4][OH:3])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 31.20 g (108.50 mmol) of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxy-1-piperidinecarboxylate (WO 02/16352) in 150 ml of tetrahydrofuran is added dropwise to a suspension of 4.12 g (108.50 mmol) of lithium aluminium hydride in 150 ml of tetrahydrofuran. The mixture is stirred at room temperature for 2 hours and is then worked up as described in Example 2 (step 2.4).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[C:36]=1[Cl:43]>ClCCl>[Cl:43][C:36]1[C:37]([CH2:41][CH3:42])=[N:38][CH:39]=[CH:40][C:35]=1[NH:34][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCc1nccc(N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Yield: 26.2 %

Procedure:
2.97 g (10.0 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 20 ml of dichloromethane, and the solution was cooled to a temperature of from -10° to 0° C. Then, 2.30 g (12.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto, and the mixture was stirred at a temperature of from -10° to 0° C. 30 minutes later, 1.57 g (10.0 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was gradually returned to room temperature with stirring and further stirred for 16 hours at room temperature. Then, 10 ml of dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 1.14 g of the desired product as colorless cotton-like crystals (melting point: 124.5° to 125° C.).
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[C:29](O)(=[O:32])[CH2:30][OH:31].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:30](=[O:31])[CH2:29][OH:32])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CO)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (110 mg) in dimethylformamide (6 ml) were added, under argon, glycolic acid (19 mg), diisopropylethylamine (32 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 159 mg). Then diisopropylethylamine (64 mg) was added once again to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-{3-[2-(1-glycoloylpiperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl methanesulphonate (15 mg, 12%).
Reaction SMILES: C(Br)Br.C(=O)(O)[O-].[Na+].[CH3:9]N(C)C=O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([NH:20][C:21](=[S:23])[S-:22])=[CH:16][CH:15]=1.[NH4+]>O>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([N:20]=[C:21]2[S:22][CH2:9][S:23]2)=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC(=S)[S-])cc1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: BrCBr
Solvent: O
Product: Cc1ccc(N=C2SCS2)cc1
Temperature: 12 °C
Reaction time: 4 h

Procedure:
In a suitable reaction vessel is mixed 6,090 grams of methylene bromide, 1,955 grams of sodium bicarbonate and 13.2 liters of dimethylformamide. The mixture is cooled to 12°C. and maintained between 12°C. and 20°C. while adding powdered ammonium p-tolyldithiocarbamate in small portions over about a 2-hour period. After stirring for an additional 4 hours at room temperature, the mixture is poured into a separatory funnel and diluted with an equal volume of water. The lower oily phase is separated and the upper aqueous DMF phase is extracted three times with 3.5 liter portions of ethylene chloride. The combined organic phase is washed with water and filtered. In a suitable vessel, the washed ethylene chloride mixture is diluted with an additional 36 liters of ethylene chloride, cooled to 10°C. to 15°C., and well stirred while adding 3,690 ml. of 37% aqueous solution of hydrochloric acid. After the mixture comes to room temperature, the solids are collected by filtration and washed with ethylene chloride and then methyl ethyl ketone. The air-dried hydrochloride salt of 2-p-tolylimino-1,3-dithietane, amounting to 3,432 grams, is finely pulverized and mixed with 14.5 liters of water. The mixture is cooled and about 2800 ml. of ammonium hydroxide is added over about 30 minutes to give a final acidity of pH 8. The solids are collected by filtration, washed with water, and air-dried to give 2,566 grams of 2-p-tolylimino-1,3-dithietane, melting point 54.5°C. to 55.0°C. The infrared spectrum shows C=N absorption at 1640 cm.-1.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1>>[CH3:7][C:8]1[O:9][C:10]([CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])=[CH:11][CH:12]=1
Reactant: Cc1ccco1
Reactant: C=CC(=O)OC
Product: COC(=O)C=Cc1ccc(C)o1
Yield: 26 %

Procedure:
The reaction and post treatment were carried out in the same manner as described in Example 21 except that 30 ml of 2-methylfuran was used instead of 30 ml of furan, the amount of methyl acrylate was changed to 1.015 g and the reaction temperature was changed to 200° C. From a fraction eluted with benzene/hexane (4/1) was obtained 0.51 g of methyl β-(5-methyl-2-furyl)acrylate (2) (the yield was 26%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CN(C)C=O>CCCCC>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCC
Solvent: CN(C)C=O
Product: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Yield: 37 %

Procedure:
A mixture of 34.56 g (0.25 mol) of 4-fluoroacetophenone, 32.6 g (0.3 mol) of chlorotrimethylsilane, 60.6 g (0.6 mol) of triethylamine and 100 ml of dimethylformamide was refluxed overnight, cooled, and diluted with 200 ml of pentane. This mixture was washed successively three times with 300 ml of cold 5% aqueous sodium bicarbonate, with cold 1.5 N hydrochloric acid, and with 5% aqueous sodium bicarbonate, dried and distilled to give 19.44 g of 1-(4-fluorophenyl)vinyloxytrimethylsilane as a colorless liquid: bp 55°-57° C. (0.12 mm); 19F NMR (CFCl3) δ-114.1 ppm (m); 1H NMR (CFCl3) δ 0.25 ppm (s, 9H), 4.35 ppm (d,J=1.5 Hz, 1H), 4.77 ppm (d,J=1.5 Hz, 1H), 6.9 ppm (m, 2H) and 7.5 ppm (m, 2H). Anal. Calcd. for C11H15FOSi: C, 62.82; H, 7.19; Found: C, 62.97; H, 7.31.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:16][C:13]1[O:12][C:11]([C:8]2[N:7]=[C:6]3[C:2]([C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:17])([F:29])[F:30])[CH:21]=4)=[CH:3][O:4][C:5]3=[CH:10][CH:9]=2)=[N:15][N:14]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Product: Cc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3n2)o1
Yield: 57 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using [3-(trifluoromethoxy)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 57%) was obtained as colorless crystals.