Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C(O)C>[CH3:3][C:2]1[C:12]([CH3:11])=[N:1][C:2]2[C:12](=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)[N:13]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)c(C)nc2c1
Yield: 203.8 %

Procedure:
Ethyl 3,4-diaminobenzoate (500 mg, 2.77 mmol) and diacetyl (238 mg, 2.77 mmol) were dissolved in ethanol (20 ml), and the mixture was heated under reflux. One hour after, diacetyl (30 mg) was added thereto, and the mixture was heated under reflux. After the mixture was heated under reflux for 2.5 hours in total, the reaction solution was poured into water, and the precipitate was separated by filtration and washed with water. By through circulation drying for 15 hours, the title compound (650 mg, quantitative) as a light-brown powder was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:9][N+:10]([O-])=O.[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[NH2:10][CH2:9][CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(Nc1ccc2c(C(C[N+](=O)[O-])c3ccccc3F)c[nH]c2c1)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: NCC(c1ccccc1F)c1c[nH]c2cc(NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of benzyl 3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-ylcarbamate (0.600 g, 1.384 mmol), zinc (1.358 g, 20.76 mmol), and ammonium chloride (1.111 g, 20.76 mmol) in tetrahydrofuran (30 mL) and methanol (30.0 mL) was stirred at room temperature for 2 hr. The insoluble material was removed by suction filtration through CELITE®. The filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL), washed with 10% NaHCO3 solution (25 mL) and brine (25 mL), and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.586 g, 1.322 mmol, 95% yield) as a pale white solid.
Reaction SMILES: [C:1]1([C@@H](NC(=O)C[C@H](O)C[C@H](O)/C=C/C2N(C(C)C)C3C(C=2C2C=CC(F)=CC=2)=CC=CC=3)C)C=CC=CC=1.[OH-].[Na+:40].[CH:41]1([C:44]2[C:53](/[CH:54]=[CH:55]/[C@@H:56]([OH:64])[CH2:57][C@@H:58]([OH:63])[CH2:59][C:60]([OH:62])=[O:61])=[C:52]([C:65]3[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=3)[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)CC1.Cl>>[Na+:40].[F:71][C:68]1[CH:69]=[CH:70][C:65]([C:52]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH:44]([CH3:1])[CH3:41])[C:53]=2/[CH:54]=[CH:55]/[C@@H:56]([OH:64])[CH2:57][C@@H:58]([OH:63])[CH2:59][C:60]([O-:62])=[O:61])=[CH:66][CH:67]=1
Reactant: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)N[C@@H](C)c2ccccc2)c(-c2ccc(F)cc2)c2ccccc21
Reactant: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
can be prepared from (E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide by hydrolysis with sodium hydroxide according to the procedure described above for the preparation of (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid. After completion of the hydrolysis, excess sodium hydroxide is neutralised by addition of hydrochloric acid and the solvent is evaporated under reduced pressure. As a work-up variant, the residue is dissolved in water at 60-70° C. and the solution is allowed to cool down to room temperature. Crystallisation occurs. The formed suspension is cooled down to 5° C., stirred for several hours at this temperature to complete the crystallisation and the product is isolated by filtration. (E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt is obtained as beige to yellow crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1cccc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(N)c1

Procedure:
A mixture of (3-aminophenyl)acetic acid (5.0 g, 33 mmol), methanol (150 ml), and c.H2SO4 (10 ml) was heated at reflux overnight. The solvent was evaporated in vacuo and the residue taken up in water (50 ml) and ethyl acetate (200 ml). Solid Na2CO3 was added until the solution was pH 10. The layers were separated and the aqueous layer was extracted again with ethyl acetate (250 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a brown oil. 5.0 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:29]3[C:30]4[C:26](=[CH:25][C:24]([O:23][CH3:22])=[CH:32][CH:31]=4)[CH:27]=[CH:28]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: COc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and 5-methoxy-1H-indole (0.085 g, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:16])([O-:12])=[O:11]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Product: COc1cccc(NC(=O)c2ccccc2[N+](=O)[O-])c1
Yield: 85 %

Procedure:
Using m-anisidine (2.03 g, 16.5 mmol) and 2-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.47 g (84.9%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[NH2:11][OH:12]>C(O)C>[OH:12][N:11]=[C:7]([NH2:8])[C:6]1[CH:9]=[CH:10][C:3]([CH2:2][OH:1])=[N:4][CH:5]=1
Reactant: N#Cc1ccc(CO)nc1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc(CO)nc1
Yield: 98 %

Procedure:
A solution of 6-(hydroxymethyl)nicotinonitrile (ChemPacific, 0.698 g; 5.2 mmol) and 50% aqueous hydroxylamine (1.6 mL) in ethanol (10 mL) was heated at 80° C. for 3 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and evaporated in vacuo. The resultant solid was washed with MeCN and dried to afford the title product (0.850 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 9.79 (1 H, s), 8.79 (1 H, d, J=2.2 Hz), 8.05 (1 H, dd, J=8.2, 2.3 Hz), 7.49 (1 H, d, J=8.2 Hz), 5.98 (2 H, s), 5.56-5.40 (1 H, m), 4.60 (2 H, d, J=4.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([Li])CCC.[Cl-].[NH4+]>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2)C1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 1-t-butoxycarbonyl-3-piperidinecarboxylic acid (458 mg, 2.00 mmol), sodium hydride (88 mg, 2.20 mmol, 60% oil suspension), oxalyl chloride (0.22 ml, 2.50 mmol) and catalytic amount of dimethylformamide (0.20 ml) in dichloromethane (16 ml) was stirred at 0° C. After stirring for 30 min, aniline (0.20 ml, 2.20 mmol) which was treated with n-butyl lithium (1.45 ml, 2.30 mmol, 1.59 M in hexane) in tetrahydrofuran (4 ml) was added to the reaction mixture at 0° C. After additional 30 min, saturated ammonium chloride was added and the whole reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (hexane-ethyl acetate) gave 1-t-butoxycarbonylpiperidine-3-carboxanilide (437 mg, 71%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)=[CH:13][CH:12]=1)C.[OH-].[Na+].O>C1COCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][CH:13]=2)[CH2:19][CH2:20]1)[CH3:25]
Reactant: CCOC(=O)c1ccc(CN2CCN(CC)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCN(Cc2ccc(CO)cc2)CC1
Temperature: 0 °C
Yield: 71.1 %

Procedure:
To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 4.61 g of crude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask and THF (60 mL) was added on cooling. A solution of 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to 0° C., 10% NaOH solution was added, and then water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78% yield. To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to the −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at −78° C. The solution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.8 g, 47.52 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then, solvent was removed to give crude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).
Reaction SMILES: [C:1]([O:4][C:5]([C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:6])(=[O:3])[CH3:2].[H][H].C(OC(/C=C\C1C=CC=CC=1)C)(=O)C>C1COCC1.F[B-](F)(F)F.C1([Rh+]C2CCCCC=CC=2)CCCCC=CC=1>[C:1]([O:4][CH:5]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: C=C(C#Cc1ccccc1)OC(C)=O
Reactant: [H][H]
Agent: C1=CCCCCC([Rh+]C2=CC=CCCCC2)=C1
Agent: CC(=O)OC(C)/C=C\c1ccccc1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(=O)OC(C)CCc1ccccc1

Procedure:
This reaction was performed as in Example 1 with bis(cyclooctadienyl)rhodium tetrafluoroborate (10 mg; 0.025 mmol; 0.02 equiv), R,R-1,2-bis(2,5-dimethylphospholano)benzene (6, R"=CH3 ; 9 mg; 0.03 mmol; 0.024 equiv) and 4-phenylbut-1-en-3-yn-2-yl acetate (3b; 233 mg; 1.25 mmol) in 10 mL of degassed THF until hydrogen uptake ceased to afford 0.25 g of crude product. 1H NMR analysis indicated Z-4-phenyl-3-buten-2-yl acetate (5b) as the sole product, and reduction of the olefin to afford 4-phenyl-2-butyl acetate followed by chiral GC analysis and comparison to the racemate and authentic R-4-phenyl-2-butyl acetate indicated 97.8% ee for R-Z-4-phenyl-3-buten-2-yl acetate. Further investigation indicated a bimodal reduction, with 4-phenylbut-1-en-3-yn-2-yl acetate initially chemoselectively and enantioselectively reduced to 4-phenylbut-3-yn-2-yl acetate (4b), which was then more slowly reduced to Z-4-phenyl-3-buten-2-yl acetate (5b).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Total protein assays were done using a Pierce BCA kit (Rockford, Ill.). Tryptophan racemase assays with the mutant enzyme were performed in triplicate using the wild-type enzyme prepared in the same manner as a positive control. The assays contained per mL: 30 mM L-tryptophan, 50 mM potassium phosphate pH 8, 10 μM PLP, and approximately 200 μg of racemase protein in a cell free extract. Zero, 20 minute, 1 hour, and overnight samples were collected, treated with 2% formic acid, filtered, and diluted 1:10 for analysis using the chiral amino acid method described in Example 1. At the 20 minute time point, the Y396C mutant produced approximately 264 ppm D-tryptophan, as compared to 761 ppm for the wild-type enzyme. At 1 hour, the mutant produced an average of 444 ppm D-tryptophan, as compared to 1110 ppm for the wild-type enzyme. The overnight samples contained 2300 ppm D-tryptophan, whereas the wild-type enzyme had reached equilibrium by producing approximately 3000 ppm D-tryptophan.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:32](OCC)(=O)C>CN(C)C=O.O>[CH3:32][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=2)=[C:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C)ccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(Cc2c(-c3ccccc3)n(C)c3cc(C)ccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (100 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (min. 55% in oil, 13 mg) under ice-cooling, and this mixture was stirred at room temperature for 30 minutes. Then, methyl iodide (0.026 mL) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (35.3 mg). 1H-NMR (CDCl3) δ ppm: 2.51 (3H, s), 3.62 (3H, s), 4.02 (3H, s), 4.36 (2H, s), 6.88-6.95 (1H, m), 7.12-7.20 (2H, m), 7.29 (1H, d, J=8.0 Hz), 7.33-7.49 (5H, m), 7.58 (1H, t, J=7.8 Hz), 7.88-7.95 (1H, m).
Reaction SMILES: [CH:1]([C:3]1[S:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)=O.Cl.[NH2:15]O>>[C:1]([C:3]1[S:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)#[N:15]
Reactant: O=Cc1cc2[nH]c(C(=O)O)cc2s1
Reactant: NO
Agent: Cl
Product: N#Cc1cc2[nH]c(C(=O)O)cc2s1

Procedure:
2-Formyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid was treated with hydroxylamine hydrochloride according to Procedure G.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>>[ClH:18].[CH3:17][O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COCCN1CCNCC1
Yield: 74 %

Procedure:
1-(2-Methoxyethyl)piperazine-4-carboxylic acid tert-butyl ester (1.39 g) obtained from Referential Example 96 was dissolved in 4N HCl-dioxane (20 mL). The resultant solution was stirred at room temperature for 3 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and ethanol was added to the residue, and then the solvent of the resultant mixture was evaporated. Ethanol and ether were added to the residue, and the precipitated solid was recovered by filtration, to thereby give the title compound (900 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27].[CH:30]1([NH:36][C:37]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:42]2[CH2:43][CH2:44][CH:39]([C:37]([NH:36][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:38])[CH2:40][CH2:41]2)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27]
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(N3CCC(C(=O)NC4CCCCC4)CC3)c(F)cc2c1=O
Yield: 10.5 %

Procedure:
200 mg (0.44 mmol) of the compound of Example 70A and 138 mg (0.66 mmol) of 4-(cyclohexylamino)carbonylpiperidine (for preparation see WO 2003031397) are heated with 91 μl (0.66 mmol) of triethylamine in 4 ml of DMSO at 120° C. for 7 h. After cooling, the entire reaction mixture is separated by preparative HPLC (method 6). 30 mg of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[CH3:17]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][C:4]([F:16])([F:15])[F:3])=[CH:7][CH:8]=1)([CH3:17])=[CH2:13]
Reactant: CS(C)=O
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C(C)c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 60% sodium hydride (1.96 g, 49 mmol) was added DMSO (20 ml) dropwise at 0° C. and the mixture was stirred at 80° C. for 30 minutes. After cooling the mixture to 0° C., a solution of methyltriphenylphosphonium bromide (17.5 g, 49 mmol) in DMSO (60 ml) was added dropwise at 0° C. and stirred at ambient temperature for 45 minutes. Then, to this mixture 1-[4-(trifluoromethoxy)phenyl]ethanone (5 g, 24.5 mmol) was added dropwise at ambient temperature and stirred at ambient temperature for 1 hour. The reaction was quenched with a small amount of acetone and diluted with hexane and water. The resulting precipitates were filtered and the organic layer was separated. After evaporation of the solvent, the residue was washed with hexane and concentrated in vacuo to afford 5.1 g (quant.) of the title compound as a colorless oil
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)=O.[NH2:13][C:14](=[S:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:20][CH:2]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)cs1

Procedure:
1.35 g of the compound from Example 1A having a purity of 68% (5.37 mmol) are heated under reflux in 25 ml of ethanol, a solution of 0.72 g (5.37 mmol) of ethyl amino(thioxo)acetate and 10 ml of ethanol is added dropwise and the mixture is heated under reflux for 18 hours. The reaction mixture is concentrated and the residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1), and 1.94 g of the title compound having a purity of 57% (100% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C:7](=[CH2:9])[CH2:6][N:5]1C(OCC1C=CC=CC=1)=O>[Pd].CO>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][NH:5]1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CC(C)CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
180 mg of 10% palladium on carbon were added to a solution of 1.80 g (6.5 mmol) of (S)-1-benzyloxycarbonyl-4-methylideneproline methyl ester [obtained as described in Preparative Example 8(i)′ above] in 50 ml of methanol, and the resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure to afford 0.93 g (quantitative yield) of the title compound as a pale yellow oil.