Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Na+].[Na+].[Na+].[Cl-].[Cl-].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:16]([CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=2)[C:17]([OH:19])=O)=[N:12][CH:13]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][C:30]([C@H:33]([NH2:35])[CH3:34])=[N:31][CH:32]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C@H:33]([NH:35][C:17](=[O:19])[C:16]2[CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH3:7])=[CH:13][N:12]=3)[CH:15]=2)[CH3:34])=[N:31][CH:32]=1
Reactant: C[C@@H](N)c1ccc(F)cn1
Reactant: C=Cc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)N[C@H](C)c2ccc(F)cn2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
To a solution of tri-sodium chloride adduct of 3-(5-methyl-2-pyridinyl)-5-vinylbenzoic acid (2.5 g, 6.0 mmol) in N,N-dimethylformamide (20 mL) were added (1R)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride (1.60 g, 7.5 mmol), EDC (2.02 g, 10.5 mmol), HOAT (0.25 g, 1.8 mmol) and triethylamine (3.36 mL, 24 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→100% ethyl acetate) gave the title compound (1.14 g). MS 362.1 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH2:7][C:8](=[O:11])[CH2:9][CH3:10].[S:12]1[C:16]2[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.C(OCC)(=O)C>CO.CCCCCC>[S:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH2:7][C:8](=[O:11])[CH2:9][CH3:10])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CCC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCC(=O)CNc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.1 %

Procedure:
Sodium acetate (300 mg, 3.66 mmol) and 1-bromo-butan-2-one (0.373 mL, 3.66 mmol) were added to a stirred solution of benzothiazol-6-ylamine (500 mg, 3.328 mmol) in methanol (10 mL) under nitrogen atmosphere. The resulting reaction mass was stirred at room temperature for 24 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was filtered and the solid collected was dried under reduced pressure to afford 250 mg of the product (32% yield).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.Cl.[O:23]1C=CN=C1.CO>O1CCCC1>[C:14]([C:11]1[C:12]([F:13])=[C:6]([OH:5])[C:7]([NH:8][C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:23])=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])(=[O:16])[CH3:15]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: c1cocn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(C)c(C#N)c(NC(=O)C2CC2)c(O)c1F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (1.0 g, 3.49 mmol) was dissolved in tetrahydrofuran (10 ml), aqueous 1 N hydrochloric acid solution (2.0 ml) was added, followed by stirring at room temperature for 19 hours. At this point in time, it was known that a mixture with an oxazole-opened compound is given, and for complete ring opening, methanol (5 ml) was added followed by stirring overnight at room temperature. The solvent was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, followed by fractionation with water.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:28][CH:27]=2)[CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, 1H), 7.70 (d, 1H), 7.65 (d, 2H), 7.45 (d, 2H), 7.28-7.19 (m, 3H), 7.10 (d, 1H), 6.45 (dd, 1H), 3.83 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 350 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:21])[N:11]([CH3:20])[C:12]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:13]=2[CH3:14])=[CH:5][CH:4]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:14][C:13]1[C:12]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[N:11]([CH3:20])[C:10](=[O:21])[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C2=C(C)C3(CCCCC3)N(C)C2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(CBr)C3(CCCCC3)N(C)C2=O)cc1
Temperature: 25 °C

Procedure:
3-(4-Methoxyphenyl)-1,4-dimethyl-1-azaspiro[4.5]dec-3-ene-2-one (881 mg, 3.09 mmol) and N-bromosuccinimide (1.2 eq.) were stirred in 40 mL CCl4 with a catalytic amount of benzoyl peroxide for 3 h at 85° C. After cooling to room temperature the mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4) and evaporated. The 4-bromomethyl-3-(4-methoxyphenyl)-1-methyl-1-azaspiro[4.5]dec-3-ene-2-one thus obtained was dissolved in ethanol (100 mL), CH2Cl2 (20 mL), and ethylamine (70% solution in water, 2 mL), the mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:4]=2[O:3]1.C([Li])CCC.[C:18](=[O:20])=[O:19]>O1CCCC1>[CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([F:11])=[C:10]([C:18]([OH:20])=[O:19])[C:4]=2[O:3]1
Reactant: O=C=O
Reactant: CC1(C)Oc2ccc(F)cc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(F)c(C(=O)O)c2O1

Procedure:
In a flask were placed 29.3 g (0.174 mole) of 2,2-dimethyl-5-fluoro-1,3-benzodioxole and 200 mL of dry tetrahydrofuran, and the resulting solution was cooled to -78° C. To this solution was added dropwise 66.4 mL (0.166 mole) of a 2.5 M solution of n-butyllithium in hexanes. This mixture was stirred at -78° C. for one hour after which a carbon dioxide atmosphere was placed above the reaction mixture. The temperature was allowed to warm to ambient conditions during a 16 hour period while maintaining the carbon dioxide atmosphere. At the conclusion of this period the solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. This mixture was extracted with water, and the water extract was in turn extracted with diethyl ether. The aqueous phase was separated and acidified with hydrochloric acid. The acidified mixture was then extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving 19 g of 2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-ylcarboxylic acid as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nccs1)c1cccc2cc(-c3cccc4cnccc34)ccc12

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (55 mg, 0.18 mmol), 2-aminothiazole (24 mg, 0.23 mmol), DIPEA (0.048 mL, 0.27 mmol) and HATU (0.1 g, 0.27 mmol) were stirred in CHCl3 (1 mL) at room temperature overnight. The solid formed was filtered, rinsed with CHCl3, MeOH and dried under vacuum to give the titled compound as a solid. MS (ESI pos. ion) m/z: 382. (M+H). Calc'd Exact Mass for C23H15N3OS: 381.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.CC1(C)C(C)OB([C:34]2C=N[N:37]([CH:39]3CCN(C(OC(C)(C)C)=O)C[CH2:40]3)[CH:38]=2)O1>>[NH:37]1[CH2:39][CH2:40][CH:1]([N:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([CH2:16][C:17]5[CH:18]=[C:19]6[C:24](=[CH:25][CH:26]=5)[N:23]=[CH:22][CH:21]=[CH:20]6)=[CH:14][N:15]=4)[N:12]=3)[CH:4]=[N:3]2)[CH2:34][CH2:38]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Reactant: CC1OB(c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)OC1(C)C
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C6CCNCC6)c5)nn34)cc2c1

Procedure:
The title compound was prepared in analogy to the synthesis of compound of Example 2, using tert-butyl 4-(4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and with an additional deprotection step before final reduction (tR 1.0 min (conditions 1), MH+=410).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:28][CH:29]=O)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C.Cl.[F:176][C:177]1[CH:182]=[C:181]([CH3:183])[CH:180]=[CH:179][C:178]=1[NH:184]N>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:28]2[C:179]3[C:178](=[C:177]([F:176])[CH:182]=[C:181]([CH3:183])[CH:180]=3)[NH:184][CH:29]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:26][CH:27]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CC=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NN)c(F)c1
Agent: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OC)cc1)[C@H](c1ccc(Cl)cc1)c1c[nH]c2c(F)cc(C)cc12
Temperature: 80 °C

Procedure:
An acetic acid solution (10 ml) of methyl N-{4-[2-(4-chlorophenyl)-4-oxo-1-propylbutyl]benzoyl}-β-alaninate, prepared from INTERMEDIATE 2 as described in EXAMPLE 1, (757 mg, 1.76 mmol), ZnCl2 (3.1M in AcOH, 1.7 ml, 5.27 mol) and 2-fluoro-4-methylphenylhydrazine hydrochloride (374 mg, 2.1 mmol) were heated at 80° C. for 45 minutes. The solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water (2×), brine (2×) and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. Data for the major diastereomer: 1H NMR (500 MHz, CD3CN): δ 9.11 (s, 1H); 7.54 (d, J=8.2 Hz, 2H); 7.48 (d, J=8.5 Hz, 2H); 7.38 (d, J=8.2 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 7.15 (d, J=2.5 Hz, 1H); 7.11 (s, 1H); 7.02-6.97 (m, 1H); 6.59 (d, J=12.3 Hz, 1H); 4.49 (d, J=11.6 Hz, 1H); 3.60 (s, 3H); 3.56-3.48 (m, 3H); 2.52 (t, J=6.8 Hz, 2H); 2.32 (s, 3H); 1.49-1.35 (m, 2H); 1.04-0.90 (m, 2H); 0.69 (t, J=7.4 Hz, 3H). LC1=3.94 min. (M+H)=535. Chiral LC1 (1% to 15% EtOH/heptane over 25 min, 15% EtOH/heptane isocratic>25 min) retention time=28.38 minutes. The material also contains ca 2% by area of the enantiomer. Chiral LC1 (1% to 15% EtOH/heptane over 25 min, 15% EtOH/heptane isocratic>25 min) retention time=26.88 minutes.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Li])CCC.[CH2:21]([N:28]1[CH2:36][CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][C:34]2=[O:37])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.CCCCCC>[CH2:21]([N:28]1[CH2:36][CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][C:34]2([C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[OH:37])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCCC2CN(Cc3ccccc3)CC12
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC2CN(Cc3ccccc3)CC21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.06 cm3 of 3,5bis(trifluoromethyl)bromobenzene in 15 cm3 of dry tetrahydrofuran is added, at -78° C., a solution of 10.9 cm3 of 1.6M butyllithium in hexane. This solution is stirred for 30 minutes at -78° C., and a solution of 1 g of (3aRS,7aSR)-2-benzyl-4-perhydroisoindolone in 5 cm3 of tetrahydrofuran is then run in dropwise. The reaction mixture is subsequently stirred at room temperature for 18 hours, treated with 20 cm3 of water and then extracted with 20 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place, washed with twice 20 cm3 of water, then with 20 cm3 of saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 20 cm3 fractions. Fractions 26 to 37 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.82 g of (3aRS,4RS,7aSR)-2-benzyl-4-[3,5-bis(trifluoromethyl)phenyl]-4-perhydroisoindolol is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[N:3]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=[C:5](/[CH:7]=[CH:8]/[C:9](=O)[CH3:10])[N:6]=1.Cl.[CH3:32][O:33][NH2:34].N1C=CC=CC=1>CCO>[F:1][C:2]1[N:3]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:4]=[C:5]([CH:7]=[CH:8][C:9](=[N:34][O:33][CH3:32])[CH3:10])[N:6]=1
Reactant: CC(=O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)C=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Examples 55 and 56: E-2-Fluoro-4-(3-oxobut-1-enyl)-1-triphenylmethylimidazole in EtOH was treated with O-methylhydroxylamine hydrochloride and pyridine for 18 hours. Solvent was evaporated and 2-fluoro-4-(3-methoxyiminobut-1-enyl)-1-triphenylmethylimidazole isolated by crystallisation as a 3:1 mixture of isomers. The major Z, E-isomer had the following n.m.r. in CDCl3 : 1.96 (s, 3H); 3.9 (s, 3H); 6.48 (d, 1H); 6.6 (s, 1H); 7.04-7.4 (m, 16H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C)=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(OC(=O)c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
While ethyl pyruvate (174 g, 1.5 mol) was being stirred at 0° C., pyridine (120 g, 1.5 mol) was dropped into the ethyl pyruvate. After it was stirred at 0° C. for 10 minutes, benzoyl chloride (210 g, 1.5 mol) was slowly dropped into this mixture. After the temperature of the reaction solution reached room temperature, the reaction solution was stirred for 48 hours. An aqueous solution of saturated sodium hydrogencarbonate and diethyl ether were added to the reaction solution, and an organic layer was separated by use of a separating funnel. Diethyl ether was again added to the aqueous layer and an organic compound was extracted. The obtained organic layer was then mixed with the organic compound, and sodium sulfate was added for dehydration. Thereafter, the sodium sulfate was removed by filtration and the solvent was removed by use of an evaporator under a reduced pressure. The concentrate was distilled under a reduced pressure (1 mmHg, 92 to 102° C.) to give ethyl α-benzoyloxyacrylate (180 g, yield: 54%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:8])[CH3:7].[CH:9]([C:12]1[N:16]=[C:15]([C:17](OCC)=[O:18])[S:14][N:13]=1)([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][C:17]([C:15]1[S:14][N:13]=[C:12]([CH:9]([CH3:11])[CH3:10])[N:16]=1)=[O:18])[CH3:7]
Reactant: CC(N)c1cccs1
Reactant: CCOC(=O)c1nc(C(C)C)ns1
Solvent: Cc1ccccc1
Product: CC(C)c1nsc(C(=O)NC(C)c2cccs2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
(R/S)-1-Thiophen-2-yl-ethylamine (19.05 g, 0.150 mol) is added to a stirred solution of ethyl 3-isopropyl-[1,2,4]thiadiazole-5-carboxylate (25.0 g, 0.125 mol) in toluene (50 ml) and the mixture is heated to 80° C. for 2 hours. A further portion of (R/S)-1-[(2-thienyl)ethyl]amine (10.0 g, 0.08 mol) is added to the mixture, which is heated at 80° C. for a further 2 hours. Then a further portion of (R/S)-1-[(2-thienyl)ethyl]amine (10.0 g, 0.08 mol) is added to the mixture, and stirring is continued for a further 3 hours at 80° C. The solvent is evaporated in vacuo, and the residue is dissolved in methyl tert-butyl ether. The resulting solution is washed two times with 1N hydrochloric acid, dried with magnesium sulphate and the solvent is evaporated in vacuo. The oily residue is dissolved in petroleum ether (50 ml) and, upon agitation, the product crystallises out of the solution. The crystalline product is filtered off, washed with a small amount of petroleum ether and dried, to give (R/S)-3-isopropyl-[1,2,4]thiadiazole-5-carboxylic acid, [1-(2-thienyl)ethyl]amide (22.3 g, 63%) as beige crystals, m.p. 61°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc(F)cc4)CC3)nc2c1
Yield: 90 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.17 (s, 4H), 3.78-3.89 (m, 6H), 4.11-4.15 (m, 4H), 6.88-7.02 (m, 4H), 7.14-7.36 (m, 3H), 7.58-7.62 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17](=[O:34])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:21]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Ba+2].C1COCC1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.[Pd].C(O)(C)C>[CH2:27]([O:26][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17](=[O:34])[CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(C=Cc1cccc(OCc2ccccc2)c1)C=Cc1cccc(OCc2ccccc2)c1
Agent: O=[Cr](=O)=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(CCc1cccc(OCc2ccccc2)c1)CCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogenation of 5.20 g (42.6 mmol) of 1,5-bis-(3-benzyloxy-phenyl)-penta-1,4-dien-3-one prepared in Example E was effected as described in General Method 3 using 0.5 g 5% Pd over BaSO4 and 150 mL of THF under hydrogen atmosphere. The product contained both ketone and alcohol, so the mixture was dissolved in acetone (approximately 200 mL) and treated with 5 mL of 8.0N Jones reagent. The mixture was stirred for 2 hours at room temperature, treated with isopropanol, and filtered through Celite. The filtrate was concentrated, and the residue was triturated with 1:1 hexane:EtOAc to give the title compound. 1H NMR (CDCl3) δ 2.69 (m, 4 H), 2.85 (m, 4 H), 5.03 (s, 4 H), 6.58-6.81 (m, 6 H), 7.18 (m, 2 H), 7.28-7.41 (m, 10 H).
Reaction SMILES: [NH2:1][CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:19][C:20](Cl)=[O:21]>O.C(OCC)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:19][C:20]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:21]
Reactant: NC(CCC(=O)O)C(=O)O
Reactant: O=C(Cl)C=Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CC[C@H](NC(=O)C=Cc1ccco1)C(=O)O
Reaction time: 1 h
Yield: 52 %

Procedure:
In 75 ml of water was suspended 6.5 g of DL-glutamic acid, and 5.2 g of sodium hydroxide was added, after which the resulting mixture was cooled to -10° C. to -7° C., and a solution of 6 g of β-(2-furyl)acrylic acid chloride in 75 ml of diethyl ether was added thereto dropwise over a period of 1 hour. After the addition, the mixture thus obtained was subjected to reaction at the same temperature for 5 hours, after which the aqueous layer was separated and then adjusted to pH 5.5 with diluted hydrochloric acid. The aqueous layer was washed with two 50-ml portions of ethyl acetate, and the aqueous layer was separated. This aqueous layer was adjusted to pH 2 with diluted hydrochloric acid and then extracted with 100 ml of ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 52%) of DL-N-[β-(2-furyl)acryloyl]glutamic acid having a melting point of 174.5°-175.5° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].Br[CH:10]([CH3:14])[C:11](Br)=[O:12].C(N(CC)CC)C>CC(C)=O>[CH3:14][CH:10]1[O:4][C:3](=[O:5])[CH:2]([CH:6]([CH3:8])[CH3:7])[O:1][C:11]1=[O:12]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1OC(=O)C(C(C)C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
5.1 g α-hydroxyisovaleric acid (43 mmol) and 4.85 mL 2-bromopropionyl bromide (45 mmol) were stirred at 75° C. under nitrogen for 12 h. 300 mL acetone and 12 mL anhydrous triethylamine (86 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 500 mL ethyl acetate:hexane mixture (1:1). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.0 (q, 1H), 4.76 (d, 1H), 2.5 (m, 1H), 1.66 (d, 3H), 1.16 (d, 3H), 1.06 (d, 3H). 13C NMR (500 MHz, CDCl3): δ 167.59, 166.16, 79.83, 72.10, 29.24, 18.51, 15.86, 15.79. ELEM. ANAL. Calcd. for C8H12O4: C, 55.81; H, 6.98. Found: C, 55.55; H, 6.99. Yield: 35%.