Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](OCC)=[O:29])=[C:22]([O:33][CH3:34])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(C1CCC(C2C=C(NC(=O)C(OC)C3C=CC(C(O)=O)=C(OC)C=3)C=CC=2)CC1)(C)(C)C.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[C:22]([O:33][CH3:34])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)cc1OC
Agent: COc1cc(C(OC)C(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-ethoxycarbonylmethyloxy-3-methoxyphenylacetamide (240 mg), which is an intermediate of Example 72, is dissolved in ethanol, and thereto is added sodium borohydride (35 mg), and the mixture is stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution is added thereto, and the mixture is extracted with chloroform. The extracted is washed with water, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (110 mg).
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7](C(OC)=O)=[CH:6][C:5]=1C1C2C(=CC=CC=2)N=CC=1)([O-])=O.CO.CO[C:27]1[CH:32]=CC(C(C=O)C=O)=C[CH:28]=1>[Pd].CC(O)=O>[N:1]1[C:4]2[N:8]([CH:7]=[CH:6][CH:5]=2)[CH:28]=[CH:27][CH:32]=1
Reactant: COc1ccc(C(C=O)C=O)cc1
Reactant: COC(=O)c1cc(-c2ccnc3ccccc23)c([N+](=O)[O-])[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1cnc2cccn2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 253.9 %

Procedure:
A mixture of methyl 5-nitro-4-quinolin-4-yl-1H-pyrrole-2-carboxylate (23, 90 mg, 0.3 mmol), Pd/C (5%, 45 mg), and MeOH (15 mL) was stirred under argon for 5 min, then under hydrogen for 40 min before removal of the catalyst by filtration through celite. To the orange color filtrate was added 2-(4-methoxyphenyl)malondialdehyde (54 mg, 0.3 mmol) followed by AcOH (2 mL). The resulting reaction mixture was stirred overnight at 82° C., then cooled to rt, quenched with sat. NaHCO3, and extracted with ethyl acetate and CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (90:10) to give 25 as a yellow solid (90 mg, 73%). 1H NMR (DMSO-d6, 500 MHz) δ 9.80 (d, J=3.0 Hz, 1H), 8.97 (d, J=5.0 Hz, 1H), 8.87 (d, J=3.0 Hz, 1H), 8.10 (m, 1H), 8.04 (s, 1H), 7.80 (m, 1H), 7.75 (d, J=5.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.61 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H); mp 230-231° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][CH2:16][C:17]2[C:25]3[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][CH:18]=2)[CH2:10][CH2:9]1.O>C1COCC1.[OH-].[Na+]>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][CH:18]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(CCCc2c[nH]c3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
LAH (2.6 g, 68 mmol) was added dropwise to a suspension of 3-[3-(4-methylpiperazin-1-yl)-3-oxo-propyl]-1,5,6,7-tetrahydroindol-4-one (5 g, 17 mmol) in THF (300 mL). The mixture was then refluxed overnight. The mixture was then cooled and 2.6 mL each of water followed by a few drops of 15% NaOH was added. The reaction was stirred at room temperature for 30 min and then filtered to remove insolubles. The filtrate was concentrated to give 4.5 g (100%) of 3-[3-(4-methylpiperazin-1-yl)propyl]-4,5,6,7-tetrahydro-1H-indole.
Reaction SMILES: [Cl-].[NH4+].C(O)C.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:15][CH2:16]2)=[O:21])=[CH:27][CH:26]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3)CC2)c(C)c1
Yield: 109.7 %

Procedure:
4-Nitrobenzoic acid (2 g), 1-(2,4-dimethylphenyl)piperazine (2.28 g), and 1-hydroxybenzotriazole 1 hydrate (1.62 g) were dissolved in N,N-dimethylformamide (30 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate/diisopropyl ether and the insoluble material was collected by filtration to give [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g). Then, ammonium chloride (3.71 g) and iron (2.68 g) were added to a solution of ethanol (61 mL) and water (17 mL), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g) was added with stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was filtered off, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (4.17 g). To the obtained crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1 g) were added itaconic acid (0.42 g), water (5 mL), 1,2-dimethoxyethane (2 mL) and acetic acid (5 mL), and the mixture was stirred with heating under reflux for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate, and the precipitate was collected by filtration to give the title compound (508 mg).
Reaction SMILES: [C:1]([OH:14])(=[S:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]1[O:17][CH2:16]1>C(O)C>[C:1]([S:13][CH:16]([OH:17])[CH3:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(O)=S
Reactant: C1CO1
Solvent: CCO
Product: CCCCCCCCCCCC(=O)SC(C)O
Reaction time: 8 h

Procedure:
Thiolauric acid (15 g) is dissolved in dry ethanol (50 ml) and thereto is added a solution of ethylene oxide (15 ml) in cold dry ethanol (20 ml) and the mixture is allowed to stand at room temperature overnight. The solvent is distilled off under reduced pressure and the resulting residue is recrystallized from petroleum ether to give colorless scales of S-lauroylmercaptoethanol (8 g), m.p. 45° - 46° C (SH test with DTNB: negative).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=3[N:15]=2)=[C:5]([O:21][CH2:22][O:23][CH3:24])[CH:4]=1.[Br:25]N1C(=O)CCC1=O.N#N>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:25][CH2:20][C:16]1[C:14]2[N:15]=[C:11]([C:6]3[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:21][CH2:22][O:23][CH3:24])[O:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(C)cccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Temperature: 0 °C
Yield: 66 %

Procedure:
A mixture of 5 (1.39 g, 4.23 mmol), N-bromosuccinimide (0.75 g, 4.23 mmol) and AIBN (33 mg, 0.2 mmol) in CCl4 (70 mL) was refluxed for 15 hours under a flow of dry N2 gas. The reaction mixture was cooled to 0° C. and the precipitate was removed by filtration while maintaining the temperature at 0° C. After the solvent was evaporated, the residue was washed with small amount of ethanol several times to afford a pinkish solid 6 (1.14 g, 66%): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2oc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2oc1=O

Procedure:
4-Hydroxy-2-oxo-6-(4-trifluoromethyl-phenyl)-2H-chromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester and 4-(trifluoromethyl)phenylboronic acid under conditions analogous to example 3-a. MS ESI(+) m/e: 365 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].ClC[CH2:40][S:41]([CH3:44])(=[O:43])=[O:42]>ClCCl.O>[CH3:40][S:41]([CH2:44][CH2:6][N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)(=[O:43])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Reactant: CS(=O)(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
203 a) To a solution of 4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.50 g, 1.6 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.2 mL, 16 mmol). The mixture was stirred at room temperature for 2 hours then the volatiles were evaporated. The residue was dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (0.60 g, 1.8 mmol), sodium iodide (25.0 mg, 0.167 mmol) and 1-chloro-2-methanesulfonyl-ethane (0.26 g, 1.8 mmol) were added. The mixture was heated at 50° C. for 18 hours then cooled to room temperature and water (30 mL) was added. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×20 mL) and saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered and evaporated. 1-(2-Methanesulfonyl-ethyl)-4-(3-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine was isolated as an orange viscous oil (0.381 g, 75%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.23 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.23 (s, 1H), 3.27 (s, 2H), 3.23 (t, J=6.5 Hz, 2H), 3.07-3.01 (m, 5H), 2.82 (t, J=5.5 Hz, 2H), 2.61 (br s, 2H). MS=311 (MH)+.
Reaction SMILES: N[C@H:2](C(O)=O)CC(C)C.[Mg+2].[Cl-].[Cl-].[Cl-].[K+].[CH3:15][C:16]1([CH3:38])S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)[N:18]2[C@H:17]1[C:35]([OH:37])=[O:36].O=C[C@H]([C@@H]([C@@H](CO)O)O)O>>[NH2:18][C@H:17]([C:35]([OH:37])=[O:36])[C:16]([CH3:38])([CH3:2])[CH3:15]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [K+]
Product: CC(C)(C)[C@H](N)C(=O)O
Reaction time: 7.5 h

Procedure:
A gene encoding the leucine dehydrogenase from B. stearothermophilus is subjected to mutagenesis by error-prone PCR according to the method of May et al. The error-prone PCR is performed in a 100 CL reaction mixture containing 0.25 ng of plasmid DNA as template dissolved in PCR buffer (10 mM TRIS, 1.5 mM MgCl2, 50 mM KCl, pH 8.3), and also containing 0.2 mM of each dNTP, 50 pmol of each primer and 2.5 units of Taq polymerase. Conditions for carrying out the PCR are as follows: 2 minutes at 94 CC; 30 cycles of 30 sec 94 CC, 30 sec 55 CC; 2 minutes at 72 CC. The PCR product is double digested with Nco I and Bgl II and subcloned into pBAD/HisA vector which has been digested with the same restriction enzymes. The resulting leucine dehydrogenase mutant library is transformed into an E. coli host strain LMG194 and plated on LB agar supplied with 100 μg/mL ampicillin. Individual transformants are inoculated into 96-well master plates containing 0.2 mL LB Broth with 100 μg/mL ampicillin, and growth is allowed to take place for 8-16 hours at 37 CC with shaking at 200 rpm. Each well in each master plate is then re-inoculated by a replica plating technique into a new second stage 96-well plate pre-loaded with the same growth media plus 2 g/L of arabinose, and growth is allowed to continue for 5-10 hours at 37 CC with shaking at 200 rpm. The second stage plates are then centrifuged at 14,000 rpm for 20 minutes, and the supernatant is decanted. The cell pellet in each well is washed with 200 CL of water. The washed cell pellet is suspended in 30 CL of B-Per. After mixing, the suspension of cells in B-Per reagent is allowed to stand for 10 minutes at room temperature, and a solution having the following composition is then added to each well in the plate:
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]12[CH2:16][C@@:15]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[C:14](=[O:34])[N:6]1[C@H:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[O:8][CH2:9]2)=[O:4]>C(O)(C)(C)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C@:5]12[CH2:16][C@@:15]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:17]([OH:19])=[O:18])[C:14](=[O:34])[N:6]1[C@H:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[O:8][CH2:9]2)=[O:4]
Reactant: COC(=O)[C@@]12CO[C@@H](C(C)(C)C)N1C(=O)[C@](Cc1ccccc1)(C(=O)OCc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: COC(=O)[C@@]12CO[C@@H](C(C)(C)C)N1C(=O)[C@](Cc1ccccc1)(C(=O)O)C2
Yield: 98.7 %

Procedure:
Compound 11 (250 mg, 0.54 mmol) was dissolved in t-butanol (10 mL), then 20% Pd(OH)2/C (90 mg) was added, and the mixture was hydrogenated at 1 bar and room temperature overnight. The catalyst was filtered off, and the solvent was removed under vacuum to give the product 13 (200 mg, 100%): mp >133° C. (decomp.; from hexane/EtOAc); [α]D+9.1° (c 0.4 CHCl3); IR (KBr) 3141, 2973, 1736, 1718 cm−1; 1H NMR δ7.33-7.14 (m, 5H), 6.5 (br, 1H), 4.84 (s, 1H), 4.80 (d, 1H, J=8.7 Hz), 3.77 (s, 3H), 3.54-3.38 (m, 3H), 2.67 (d, 1H, J=14.7 Hz ), 2.43 (d, 1H, J=14.7 Hz), 0.93 (s, 9H); 13C NMR δ179.77, 172.03, 171.80, 134.52, 130.02, 128.50, 127.70, 97.94, 74.25, 69.22, 60.24, 53.09, 42.94, 35.34, 35.15, 24.93; MS m/z (%) 331 (0.3), 274 (36), 58 (72), 43 (100). Anal. (C20H25NO6) Calcd: C, 63.99; H, 6.71; N, 3.73. Found; C, 64.33; H, 6.47; N, 3.57.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:11][C@@H:12]1[CH2:20][C@@H:15]2[O:16][C:17](=[O:19])[CH2:18][C@@H:14]2[C@H:13]1[CH:21]=[O:22])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:3]([O:11][C@@H:12]1[CH2:20][C@@H:15]2[O:16][C:17](=[O:19])[CH2:18][C@@H:14]2[C@@H:13]1[CH2:21][OH:22])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1C[C@@H]2[C@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reaction time: 0.42 h
Yield: 68.7 %

Procedure:
To a suspension of sodium borohydride (650 mg, 17.1 mmol) in methanol (20 mL) at 0° C. (bath temperature) was added a solution of (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-2H-cyclopenta[b]furan-2-one-4-carboxaldehyde (1) (3.5 g, 12.8 mmol) as a solution in 1:1 methanol:methylene chloride (40 mL). After 25 min, saturated citric acid was added cautiously (60 mL), the mixture was extracted with ethyl acetate (3×40 mL), the combined organic layers were washed with water (2×80 mL) and saturated brine (2×80 mL), dried (magnesium sulfate), filtered, and concentrated to afford 2 (2.43 g, 69%).
Reaction SMILES: C(OC[N:10]1[C:14](=[O:15])[CH:13]([CH3:16])[N:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([CH3:37])=[CH:35][C:34]([CH:38]5[CH2:40][CH2:39]5)=[CH:33][N:32]=4)[CH2:27][CH2:26]3)=[O:24])=[C:19]([F:41])[CH:18]=2)[C:11]1=[O:42])C1C=CC=CC=1.C(O)=O>CO.[C].[Pd]>[CH:38]1([C:34]2[CH:35]=[C:36]([CH3:37])[C:31]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:12]5[CH:13]([CH3:16])[C:14](=[O:15])[NH:10][C:11]5=[O:42])=[CH:18][C:19]=4[F:41])=[O:24])[CH2:26][CH2:27]3)=[N:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)cc2F)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)NC(=O)C3C)cc2F)CC1
Yield: 18.8 %

Procedure:
3-Benzyloxymethyl-1-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methylimidazolidine-2,4-dione (270 mg) described in Example 536 was dissolved in methanol (20 mL), formic acid (0.36 ml) and 10% palladium carbon catalyst (108 mg) were added, and the mixture was stirred with heating under reflux for 16 hr. The reaction mixture was cooled, the catalyst was removed by celite filtration, and the solvent was evaporated. To the residue were added methanol and 0.5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature. The reaction solution was neutralized with acetic acid, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (40 mg).
Reaction SMILES: [C:1](/[C:9](=C(/OC)\C)/[C:10]#[N:11])(=O)[C:2]1C=CC=CC=1.[F:16][C:17]1[CH:31]=[CH:30][C:20]([C:21](/[C:23](=[C:26](/OC)\[CH3:27])/[C:24]#[N:25])=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:31]=[CH:30][C:20]([C:21](/[C:23](=[C:26](/[NH:11][CH2:10][CH2:9][CH2:1][CH3:2])\[CH3:27])/[C:24]#[N:25])=[O:22])=[CH:19][CH:18]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Product: CCCCN/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
By replacing the 2-benzoyl-3-methoxycrotononitrile employed in Example 16 with an equimolar amount of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile, there is obtained the title compound in equally good yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:11]([P:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].[Cl-].C([PH+](CC)CC)C>C1(C)C=CC=CC=1>[Cl-:1].[Cl:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][P+:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: CCP(CC)CC
Reactant: ClCc1ccccc1CCl
Agent: CC[PH+](CC)CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC[P+](CC)(CC)Cc1ccccc1CCl

Procedure:
To a mixture of α,α'-dichloro-o-xylene (15.0 g, 86.0 mmol) in toluene (200 ml) was added triethylphosphine (6.3 ml, 43.0 mmol) under argon gas. The reaction mixture was stirred for several days at room temperature under argon after which time the triethylphosphonium chloride salt had crystallized out of solution. The crystals were filtered and washed with toluene (3×50 mL) and pentane (3×50 mL) and dried: 1H NMR (CDCl3) δ 1.15-1.26 (dt, 9H), 2.58-2.69 (m, 6H), 4.39-4.44 (d, 2H), 4.87 (s, 2H), 7.31-7.34 (dd, 2H), 7.43-7.46 (dd, 1H), 7.50-7.54 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH2:21]C(=O)C)=[CH:15][C:14]=3[CH3:26])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:28]=1.[OH-:29].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH2:21][OH:29])=[CH:15][C:14]=3[CH3:26])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:28]=1
Reactant: [OH-]
Reactant: CC(=O)CC(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)CO)ccc1C(=O)N1CCCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Chloro-1-[2-methyl-4-(2-acetylacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) is dissolved in tetrahydrofuran (7 ml), and thereto is added a 5N aqueous sodium hydroxide solution (0.5 ml), and the mixture is stirred at room temperature for two hours. The reaction solution is neutralized with a 2N hydrochloric acid, and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered, and concentrated. To the resulting residue is added n-hexane/ethyl acetate (1:1), and the mixture is washed, filtered, and the obtained powder is dried to give 7-chloro-1-[2-methyl-4-(2-hydroxyacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as white powder.
Reaction SMILES: CN(C=O)C.[C:6]([C:8]1([NH:11][C:12](=[O:40])[C@H:13]([CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[NH:14][C@@H:15]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9]1)#[N:7].Br[C:42]1[CH:47]=[CH:46][C:45]([CH:48]([OH:53])[C:49]([F:52])([F:51])[F:50])=[CH:44][CH:43]=1.C(=O)(O)[O-].[Na+]>C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:6]([C:8]1([NH:11][C:12](=[O:40])[C@H:13]([CH2:35][C:36]([F:39])([CH3:37])[CH3:38])[NH:14][C@@H:15]([C:20]2[CH:21]=[CH:22][C:23]([C:42]3[CH:47]=[CH:46][C:45]([CH:48]([OH:53])[C:49]([F:51])([F:52])[F:50])=[CH:44][CH:43]=3)=[CH:24][CH:25]=2)[C:16]([F:19])([F:18])[F:17])[CH2:9][CH2:10]1)#[N:7]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(C(O)C(F)(F)F)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 80 °C

Procedure:
A stream of nitrogen was passed through a solution of DMF (4 mL), N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-L-leucinamide described in step 3 of example 1 (150 mg), 1-(4-bromophenyl)-2,2,2-trifluoroethanol from step 1 in example 3 (92 mg) and 2 M Na2CO3 (750 μL) for 15 minutes followed by the addition of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex (1:1) with dichloromethane (12 mg). The mixture was warmed to 80° C. for 3 hours under nitrogen. The mixture was cooled to room temperature, poured into ice (20 g) and saturated aqueous sodium bicarbonate (20 mL) and extracted with 50% ethyl acetate in diethyl ether (3×50 mL). The combined extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using ethyl acetate and hexanes (20 to 50%) as eluent, followed by trituration using diethyl ether and hexanes to yield the title compound.