Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][CH:26]([CH3:28])[C:25]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:24]2)=[O:22])=[CH:16][CH:15]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]2[CH2:27][C:26]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([CH3:28])[C:25]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[N:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(Cc2ccccc2)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
To 2.1 g of diisopropylamine dissolved in 15 ml of tetrahydrofuran and cooled in an ice salt bath was added 8.0 ml of a 2.7 molar solution of n-butyllithium in hexane. After stirring for 5 minutes a solution of 3.4 g of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example G) in 15 ml of tetrahydrofuran was added and the resulting solution stirred for 15 minutes. To this solution was added 1.5 ml of benzyl bromide and, after 5 minutes 1.5 ml of acetic acid was added. The reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo to give 3.90 g of N,3-bis-(4-chlorophenyl)-4-benzyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide, an oil. NMR and IR data were consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][OH:9])[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:9][CH2:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1csc(CCO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(CCO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 2-(4-methylthiophen-2-yl)ethanol (3.0 g, 21.1 mmol) and diisopropylethylamine (4.1 g, 31.7 mmol) in dry DCM (50 mL) at 0° C. was added TBSCl (4.8 g, 32.0 mmol) in dry DCM (20 mL) dropwise and the mixture was then warmed to room temperature gradually. After the alcohol was consumed completely, water (10 mL) was added. The resulting mixture was extracted with DCM (3×100 mL), washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.1 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[C:7]1([N:6]2[C:2]([NH:1][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Nc2ccccc2)n(-c2ccccc2)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
Ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (443 mg) synthesized according to the method described in WO2004/98589, iodobenzene (469 mg), cesium carbonate (1.2 g), tris(dibenzylideneacetone)dipalladium (0) (87 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111 mg) were suspended in toluene (10 mL) and tetrahydrofuran (2 mL), and the mixture was sufficiently deaerated, and stirred at 120° C. for 18 hr under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1), and the obtained solid was washed with a mixed solvent of diisopropyl ether and ethyl acetate to give the title compound as a pale-red solid (yield 345 mg, yield 59%).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]([NH:21][C:22](=[O:24])[CH3:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH2:9][CH2:10][CH3:11])(=[O:5])[CH3:4].[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O.O1CCCC1>[C:3]([O:6][CH2:7][C:8]([NH:21][C:22](=[O:24])[CH3:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH3:11])(=[O:5])[CH3:4]
Reactant: CCCCCCCBr
Reactant: CCCC(CCc1ccccc1O)(COC(C)=O)NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccccc1CCC(CCC)(COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a suspension of sodium hydride (85 mg) in dimethylformamide (5 ml), a solution of 2-acetamido-2-(2-(2-hydroxyphenyl)ethyl)pentyl acetate (0.65 g) in dimethylformamide (5 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution, a solution of heptyl bromide (0.42 g) in tetrahydrofuran (4 ml) was added. The mixture was stirred at the same temperature for 6 hours and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; chloroform-methanol=12:1) to give the subject compound (0.36 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:37])[C:13]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH3:31])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:24]2[CH2:28][NH:27][C:26](=[O:29])[N:25]2[CH3:30])=[CH:17][CH:16]=1)[CH3:10].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:9]([O:11][C:12](=[O:37])[C:13]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH3:31])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH:24]2[CH2:28][N:27]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:26](=[O:29])[N:25]2[CH3:30])=[CH:19][CH:20]=1)[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccccc3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide (0.0.21 mL, 0.174 mmol, d=1.438) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.047 g, 0.116 mmol) and sodium hydride (0.012 g, 0.29 mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 48 h, diluted with ethyl acetate, and washed with 1N HCl and water. The organic layer is dried, concentrated, and used in the next step. MS [EI+] 497 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH2:8][CH2:7][C:6]2=O)[CH3:2].N1C=CC=CC=1.Cl.[NH2:22][OH:23].O>C(O)C.ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH2:8][CH2:7]/[C:6]/2=[N:22]\[OH:23])[CH3:2]
Reactant: NO
Reactant: CCc1ccc2c(c1)C(=O)CCN2C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCc1ccc2c(c1)/C(=N/O)CCN2C
Temperature: 90 °C
Yield: 98 %

Procedure:
To a solution of 6-ethyl-1-methyl-2,3-dihydroquinolin-4(1H)-one (0.32 g) in ethanol (25 mL) were added pyridine (0.53 g) and hydroxylamine hydrochloride (0.59 g). The mixture was heated to 90° C. for two hours with a reflux condensor attatched. The mixture was cooled to room temperature, and the solvent was stripped under reduced pressure. The residue was portioned between water and dichloromethane and the organics were extracted three times. The combined organics were washed once with brine, dried with sodium sulfate, filtered, and concentrated. 0.34 g of the title product were recovered. (98% yield). MS (ESI+) for C12H16N2O m/z 205.02 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(CC(O)=[O:17])C=CC=CC=1.C(OCC1C=CC=CC=1)(=O)C.C(O)C1C=CC=CC=1>>[CH3:1][CH:2]([OH:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Solvent: OCc1ccccc1
Solvent: CC(=O)OCc1ccccc1
Product: CC(O)c1ccccc1

Procedure:
As the third major step toward the formation of styrene, phenylacetic acid synthesized from benzyl acetate, benzyl aldehyde and/or benzyl alcohol is then hydrogenated in the liquid phase to form phenyl ethanol as follows:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[N:13]([O-])=[O:14].[Na+]>>[CH3:11][C:10](=[O:12])[C:9](=[N:13][OH:14])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)C(=NO)C(C)=O
Temperature: 17.5 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
Variant a): In a stirred vessel, 21 l of 20% strength sulfuric acid and 6 kg (60 mol) of acetylacetone were initially charged. The mixture was cooled to about 17° C. and, at 15-20° C., 4.2 kg (60.84 mol) of 40.5% strength aqueous sodium nitrite solution were metered in. The mixture was subsequently stirred at about 17° C. for another 20 minutes and then extracted with 25 l of ethyl acetate. The organic phase was concentrated under reduced pressure, giving 7.42 kg (96% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][C:2]2[CH:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2nc(N[C@H]3CCN(Cc4ccccc4)C3)cc(C)c2c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a mixture of 2-chloro-6-methoxy-4-methylquinoline (1.1 g), Pd2(dba)3 (0.242 g), (±)-BINAP (0.495 g), (S)-1-benzyl-3-aminopyrrolidine (1.1 g), and 1,4-dioxane (88 mL) was added sodium t-butoxide (1.65 g) under nitrogen atmosphere, and the mixture was stirred at 65° C. for 3 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=10:1) to obtain (S)-N-(1-benzylpyrrolidin-3-yl)-6-methoxy-4-methylquinolin-2-amine (1.1 g). (2) (S)-N-(1-Benzylpyrrolidin-3-yl)-6-methoxy-4-methylquinolin-2-amine (1.1 g) was dissolved in methanol (25 mL), followed by addition of 20% Pd(OH)2/C (0.20 g), and the mixture was stirred at 45° C. under hydrogen atmosphere for 5 h. The catalyst was removed by Celite filtration, and then the filtrate was concentrated under reduced pressure to obtain (S)-6-methoxy-4-methyl-N-(pyrrolidin-3-yl)quinolin-2-amine (0.81 g).
Reaction SMILES: [CH:1]1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C(CC)(CC)C#N)=C(F)C=2)CCC[CH2:2]1.[CH:34]1([C:39]([OH:64])([CH2:54][C:55]2[O:56]C(C)(C)O[C:59](=[O:61])[CH:60]=2)[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3([C:51]#[N:52])[CH2:50][CH2:49]3)=[C:44]([F:53])[CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:39]2([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH2:1][CH3:2])([CH2:50][CH3:49])[C:51]#[N:52])=[C:44]([F:53])[CH:43]=3)[CH2:54][C:55](=[O:56])[CH2:60][C:59](=[O:61])[O:64]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCC(C#N)(CC)c1ccc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to step 4 of Example A(97), substituting 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile from step 1 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. 1H NMR (CDCl3) δ: 1.01 (t, J=7.45 Hz, 6H), 1.62-1.90 (br, 8H), 2.03-2.17 (br, 4H), 2.20-2.29 (br, 2H), 2.37 (p, J=9.35 Hz, 1H), 2.75-2.82 (m, 2H), 2.86 (d, J=7.58 Hz, 2H), 3.53 (d, J=2.02 Hz, 2H), 6.94 (dd, J=13.01, 1.64 Hz, 1H), 7.04 (dd, J=7.83, 1.77 Hz, 1H), 7.57 (t, J=8.21 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[O+][O-].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>CC(C)=O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[C:10]([CH3:24])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]3[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(O)cc3)c12
Agent: O=[O+][O-]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenol (0.260 g, 0.668 mmol) was reacted with K2C(O3 (0.120 g, 0.868 mmol) and methyl bromoacetate (0.133 g, 0.868 mmol) in acetone (5 ml) to give the product (0.271 g, 0.587 mmol, 88%) as a viscous oil. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 3.71 (s, 3H), 4.84 (s, 2H), 5.29 (s, 2H), 6.84 (d, J=7.0 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.11 (t, J=7.3 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.31-7.35 (m, 5H), 7.41 (t, J=7.2 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H); [ESI(+)], m/z 462 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)=[C:5]([Br:7])[N:6]=1.C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=1.[Cl-].[Li+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Br:7][C:5]1[N:6]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[S:3][C:4]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1sc(Br)nc1Br
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(Br)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 120 °C

Procedure:
A mixture of 2,4-dibromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole (13.62 g, 31.01 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (11.1 g, 37.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.792 g, 1.550 mmol), copper(I) iodide (1.772 g, 9.302 mmol) and lithium chloride (3.944 g, 93.02 mmol) in 1,4-dioxane (569 mL, 7290 mmol) was degassed and filled with argon three times. The mixture was sonicated for 20 min and then heated at 120° C. for 5 h. The reaction mixture was dry loaded onto a silica gel column and purified by chromatography to afford N-(4-(4-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide as an orange solid. LCMS (AA) ES+ 494, 496.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Yield: 89.7 %

Procedure:
4-Biphenylsulfonic acid (3.0 g, 12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g of crude 4-biphenylsulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9](=[N:20]C(OCC)=O)[N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)=[O:7])=[CH:4][C:3]=1[N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1.Cl[Si](C)(C)C>ClCCCl>[Cl:1][C:2]1[CH:27]=[C:26]2[C:5]([C:6](=[O:7])[NH:8][C:9]([N:10]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]3)=[N:20]2)=[CH:4][C:3]=1[N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1
Reactant: CCOC(=O)N=C(NC(=O)c1ccc(Cl)c(N2CCc3ccccc3C2)c1)n1cc(C(=O)OCC)cn1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCc5ccccc5C4)cc3c(=O)[nH]2)c1
Yield: 37 %

Procedure:
A solution of 1-{[4-chloro-3-(3,4-dihydro-1H-isoquinolin-2-yl)-benzoylamino]-ethoxycarbonylimino-methyl}-1H-pyrazole-4-carboxylic acid, ethyl ester (1.2 g, 2.4 mmol), DCE (5 mL) and chlorotrimethylsilane (2.8 mL, 22 mmol) was heated to 110° C. for 16 h in a sealed tube. The vessel was cooled in an ice bath for 1 h, and the resulting precipitate was collected by filtration, washed with cold DCE, and dried under vacuum to provide the titled compound (0.40 g, 19%). MS (ESI): mass calcd. for C23H20ClN5O3, 449.9; m/z found, 450.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH3:39])(=O)=O>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:39])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Product: COC[C@@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 27.7 %

Procedure:
Using (S)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (530 mg) described in Example 274 and methyl tosylate (203 mg) and by the reaction and treatment in the same manner as in Example 36, the title compound (151 mg) was obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][C:12](=O)[CH2:11][NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>O1CCCC1>[CH2:1]([C@H:8]1[CH2:9][NH:10][CH2:11][CH2:12][NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)[C@H](Cc2ccccc2)N1
Agent: B
Solvent: C1CCOC1
Product: c1ccc(C[C@H]2CNCCN2)cc1
Yield: 40.3 %

Procedure:
To a suspension of (S)-3-benzyl-2,5-dioxopiperazine (2.284 g, 11.18 mmol) in tetrahydrofuran (20 mL) was added borane-tetrahydrofuran complex (49 mL, 1.0 M solution in THF, 49 mmol) at room temperature. The resulting mixture was refluxed for several hours before it was quenched with methanol at 0° C. After concentration in vacuo, the residue was treated with 10% sodium hydroxide aqueous solution, which was extracted with dichloromethane thoroughly. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford white crystals, which were washed with ether to yield (S)-2-benzylpiperazine (795 mg, 40.3%).
Reaction SMILES: [Cl:1][C:2](=[CH2:10])[C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O>[Cl:1][C:2](=[CH2:10])[C:3]([CH3:9])([CH3:8])[C:4]([OH:6])=[O:5]
Reactant: C=C(Cl)C(C)(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(Cl)C(C)(C)C(=O)O
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (33 g, 0.2 mol) and NaOH (9.6 g, 0.24 mol) in water (200 mL) was heated at reflux for 5 h. The mixture was cooled to ambient temperature and extracted with ether. The organic layer was discarded. The aqueous layer was acidified with cold 20% HCl solution and extracted ether (200 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give 3-chloro-2,2-dimethyl-but-3-enoic acid (21 g, 70%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.90 (brs, 1 H), 5.37 (dd, J=2.4, 6.8 Hz, 2 H), 1.47 (s, 6 H).
Reaction SMILES: [CH3:1][C@H:2]([C:7](=O)[C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=1)[CH2:3][C:4](O)=[O:5].O.[NH2:25][NH2:26]>C(O)C>[CH3:1][C@@H:2]1[C:7]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:14][C:10]=3[CH:9]=2)=[N:26][NH:25][C:4](=[O:5])[CH2:3]1
Reactant: C[C@@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@H]1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
177 mg (572 μmol) (S)-3-methyl-4-oxo-4-(2-phenyl-benzoxazol-6-yl)-butyric acid are combined with 10 ml of ethanol and 350 μl (7050 μmol) hydrazine hydrate. The reaction mixture is refluxed for 3 h. The solvent is eliminated by rotary evaporation in vacuo and the residue is separated through silica gel (eluant cyclohexane/EA).