Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:32]([CH3:35])(=[O:34])=[O:33])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:3]=[CH:4][C:5]=3[S:32]([CH3:35])(=[O:33])=[O:34])[C:21]2=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 214e, racemic (2′S,3R,4′S)-2′-[5-bromo-2-methylsulfonyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 37.2 %

Procedure:
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.7 g, 3.7 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (816 mg, 4.4 mmol), Pd(Ph3P)2Cl2 (200 mg), and aq Cs2CO3 solution (4 mL, 2M) in 1,4-dioxane (30 mL) was stirred and heated to reflux for 2 h. When the reaction was over, the mixture was washed with water and extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (614 mg, 37%). LC-MS Method 2 tR=1.075 min, m/z=447.1; 1H NMR (CDCl3): δ=1.38 (m, 1H), 1.47 (d, 3H), 1.73 (m, 2H), 1.98 (m, 2H), 2.20 (m, 1H), 2.31 (m, 2H), 2.94 (m, 1H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63 (m, 1H), 6.67 (m, 1H), 6.87 (m, 2H), 7.05 (m, 2H), 7.31-7.41 (m, 6H), 7.48 (m, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.S(OC)(O[CH3:25])(=O)=O>C1COCC1>[CH3:25][O:3][C:4](=[C:16]([C:17]#[N:18])[C:19]#[N:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(CC(O)=C(C#N)C#N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(Cc1ccc(OC)c(OC)c1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 60% NaH (5.7 g, 0.14 mol) in THF (150 ml) at -78° C. under argon was added dropwise (1-hydroxy-(3,4-dimethoxyphenylethylidene))malononitrile (34.6 g, 0.14 mol) in THF (100 ml) over 1.25 hours. The reaction mixture was stirred for 2 hours and dimethyl sulfate (26.9 g, 0.21 mol) in THF (50 ml) was added over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvents were removed in vacuo and the residue was partitioned between ether and water. The organic layer was separated and the aqueous layer was extracted with ether (3×150 ml). The ether layers were combined and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ether (6/4) to afford crude (1-methoxy-(3,4-dimethoxyphenylethylidene))malononitrile as a gold oil.
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H](C(O)=O)CCC(=O)[OH:6].[CH2:28]1[CH2:33][CH2:32][CH:31]([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:30][CH2:29]1>O1CCCC1>[CH:37]1([NH:36][C:35]([NH:34][CH:31]2[CH2:30][CH2:29][CH2:28][CH2:33][CH2:32]2)=[O:6])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Yield: 78 %

Procedure:
Fmoc-D-Glu-OH (59.8 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (THF) (324 mL). DCC (40.1 g, 1.2 eq) was then added while stirring in ice-water bath. The reaction mixture was allowed to warm to r.t and stirring was maintained for additional 8 h to produce 1,3-dicyclohexylurea (DCU). The precipitates were filtered off, and washed with small amount THF. Dry ammonia gas was then bubbled through the filtrate which was stirred in a NaCl salt-ice bath. The reaction was completed after 1.5 h when no more white solid was precipitated. Still standing for 30 min, small amount MeOH was added to dissolve the solid. The mixture was cooled in an ice-water bath again. Then 2.0 N HCl was added carefully and slowly to adjust pH to 2-3. The solvent was evaporated under vacuum. The resulting solid was dissolved in AcOEt and then washed with diluted HCl, saturated aqueous NaHCO3 solution, and H2O sequentially. The organic layer was separated and combined, then dried with MgSO4 overnight, filtered and evaporated under vacuum. Then residue was recrystallized with ethylacetate-cyclohexane system. After filtration, 46.5 g target product was obtained with a yield of 78%. m.p.=204˜205° C., [α]=−4.2° (C=10 mg/mL, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([N:34]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)=[O:4].C1COCC1.Cl>Cl.CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([NH2:34])[CH:27]=1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Yield: 101.2 %

Procedure:
Concentrated HCl (12M, one drop) is added at 0° C. to a mixture containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (60 mg, 0.08 mmol) in MeOH (5 mL). Added THF (2 mL) followed by a second drop of 12M HCl and warmed reaction mixture to ambient temperature. The reaction is quenched by pouring the reaction mixture onto a 1:1 mixture of CH2Cl2/aqueous NaHCO3 and the layers are separated. The aqueous phase is washed with CH2Cl2 and then the combined organic phase is washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue is chromatographed on silica gel (CH2Cl2 to 4% MeOH/CH2Cl2) to provide 42 mg (93%) of the title compound. 1H NMR (300 MHz, CDCl3) δ2.98 (dd, J=12.5, 3.5 Hz, 1H), 3.60 (d, J=16.8 Hz, 1H), 3.69 (d, J=15.3 Hz, 1H), 3.79 (s, 3H), 3.98 (m, 1H), 4.21-4.31 (m, 2H), 4.44 (br s, 2H), 5.36 (d, J=15.3 Hz, 1H), 6.47 (dd, J=8.0, 1.4 Hz, 1H), 6.54 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.5, 1.8 Hz, 1H), 7.80-7.86 (m, 3H) ppm; MS (ISP loop): m/z 519 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCOCC3)cc21
Yield: 87.6 %

Procedure:
Morpholine (0.06 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 100 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of a solid. The solid was purified by column chromatography (chloroform/methanol 99:1). The appropriate fractions were combined to give 0.17 g of the title compound as a solid.
Reaction SMILES: CN.[C:3](N1C=CN=C1)([N:5]1C=CN=[CH:6]1)=[O:4].[CH2:15]([C@:17]1([C:42]#[N:43])[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[N:23]=2)[C:18]1=[O:41])[CH3:16].O>O1CCCC1>[C:42]([C@@:17]1([CH2:15][CH3:16])[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:3]([NH:5][CH3:6])=[O:4])[CH2:37][CH2:36]4)=[CH:33][CH:34]=3)[N:23]=2)[C:18]1=[O:41])#[N:43]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCN(C(=O)NC)CC4)cc3)n2)C1=O
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 2 M methylamine in tetrahydrofuran (0.28 mL) were added 1,1′-carbonyldiimidazole (91 mg) and tetrahydrofuran (3.0 mL) in an ice bath, and the mixture was stirred at the same temperature for 10 min. To the reaction mixture was added (3R)-3-ethyl-2-oxo-1-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)pyrrolidine-3-carbonitrile (200 mg) obtained in Example 220, and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the obtained purified product (290 mg) in ethanol (3 mL) was added 1 M hydrochloric acid (0.64 mL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (220 mg)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:21][C:20](=[O:23])[N:19]([CH2:28][C:27]#[CH:26])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C#CCBr
Reactant: O=C(CCl)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A solution of 3.6 g (11.0 mmol) of 3-chloro-2-[3-(2-chloroacetylamino)-4-hydroxyphenyl]-5-trifluoromethylpyridine in 50 ml of anhydrous dimethylformamide was added dropwise at 0° C. to a suspension of 0.4 g (12 mmol) of sodium hydride (80% strength in mineral oil) which had been freed of mineral oil and 50 ml of anhydrous dimethylformamide. After stirring for 15 minutes, 1.3 g (11.0 mmol) of propargyl bromide were added dropwise to this mixture. The reaction mixture was then slowly allowed to warm to about 20° C. room temperature, stirred for a further three hours and then poured into 500 ml of ice water. The aqueous phase was extracted three times with 200 ml of ethyl acetate each time. The combined organic phases were washed twice with a little water, dried over sodium sulfate and then concetrated. Chromatographic purification of the residure on silica gel (eluent: cyclohexane/ethyl acetate 4:1) gave 1.9 g (47%) of colorless crystals of m.p.: 136-137° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)cc(Cl)c3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)cc(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.4 g (78%) of a white solid: mp 144.5-147.0° C.; IR (diffuse reflectance) 2982, 2972, 1748, 1690, 1456, 1411, 1373, 1366, 1352, 1252, 1222, 1202, 1159, 1115, 824 cm; MS (EI) m/z 440 (M+), 442, 440, 386, 384, 310, 300, 298, 86, 84, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.15; H, 6.04; N, 6.37.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[Br:28]Br>C(Cl)(Cl)(Cl)Cl>[Br:28][CH:13]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10]2)=[O:26]
Reactant: BrBr
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(Br)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC

Procedure:
To a solution of 1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (37 g, 0.1 mol, Chemistry and Biology 2000, 7, 979) in carbon tetrachloride (300 mL) is added bromine (16.0 g, 0.1 mol) at such a rate to obtain a continuous discoloration of the reaction mixture. After the addition is complete (about 10 minutes), the reaction mixture is evaporated under reduced pressure to obtain 2-bromo-1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:17][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(-c2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)cc1-c1ccccc1
Yield: 99.3 %

Procedure:
A mixture of 4-methyl-2-phenylbenzoic acid (1.66 g, 7.82 mmol), prepared as in Example 227B, N-bromosuccinimide (1.40 g, 8.21 mmol) and 2,2′-azobisisobutyronitrile (25 mg) in carbon tetrachloride (30 mL) was stirred at reflux for 1 hour. The reaction mixture was poured into ethyl acetate and extracted with water (3×) and brine, dried, filtered, and concentrated in vacuo to give 4-bromomethyl-2-phenylbenzoic acid (2.26 g).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(C)cc1

Procedure:
A suspension of 300 g of p-methylcinnamic acid (J. Chem. Soc., Chem. Comm., 471, 1976) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled and filtered to give as a white solid, p-methylcinnamic acid methyl ester, mp 55°-56° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[CH3:1][S:2]([O:16][CH:14]([CH3:15])[CH2:13][CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: CC(O)CCC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(CCC1CCCCC1)OS(C)(=O)=O
Yield: 107.5 %

Procedure:
A solution of 3.53 g methanesulfonyl chloride in 100 mL methylene chloride was added to a solution of 4.38 g 4-cyclohexylbutan-2-ol in 200 mL methylene chloride. The reaction mixture was stirred over night. Aqueous work-up yielded 7.06 g (96%) of a colourless oil.
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[NH:18][N:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=2)[CH:9]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH:7](/[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[NH:18][N:17]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:15]=2)[CH:9]=1)=[CH:23]\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccnc(-c2cc(C(F)(F)F)n[nH]2)c1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(-c2cc(/C=C/c3ccccc3)ccn2)[nH]n1
Reaction time: 6 h

Procedure:
Ligand L1 was synthesized employing a modified literature procedure,[4] in which solid tert-BuOK (1.19 g, 10.56 mmol) was added to a solution of 4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-5-yl) pyridine (0.30 g, 1.32 mmol) and benzaldehyde (0.4 mL, 3.96 mmol) in anhydrous DMF (100 mL). The resulting mixture was stirred 6 h at 100□ under nitrogen. The solvent was then evaporated, and product was dissolved in water titrated by 2 M HCl until pH 3˜4. The insoluble solid was filtered on a sintered crucible and recrystallized from hot ethylacetate (EA), filtered, and washed with methanol to obtain the desired product L1 as a beige solid (0.22 g, 51%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:31])[CH:28]=4)[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(OCC)C>[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]([OH:31])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:28]=4)[CH2:23][CH2:22]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: Brc1ccccn1
Solvent: CCOCC
Product: OC(c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)c1ccccn1
Yield: 56.1 %

Procedure:
2-Bromopyridine (0.16 ml), 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.5 g) and diethyl ether employed as the solvent were treated as in Example 93 to give the title compound (0.344 g) as a yellow oil (yield: 56.1%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[C:27](=[O:28])[C@@H:26]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH2:25][O:24][C:23]4[CH:43]=[CH:44][CH:45]=[CH:46][C:22]3=4)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH3:10]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:27](=[O:28])[C@@H:26]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH2:25][O:24][C:23]3[CH:43]=[CH:44][CH:45]=[CH:46][C:22]2=3)[N:11]([CH2:9][CH3:10])[CH:12]=1
Reactant: CCn1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Yield: 90.8 %

Procedure:
A solution of N-chlorosuccinimide (NCS, 17.2 mg, 129 μmol, Eq: 1.00) in DMF (2 mL) was added dropwise to a solution of tert-butyl (S)-1-((S)-5-((1-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (67 mg, 129 μmol, Eq: 1.00) in DMF (12 mL) at 0° C. After 2 h at 0° C. the mixture was diluted with sat. NaHCO3 and extracted with EtOAc. The combined extracts were washed with H2O, concentrated and the residue was purified by preparative TLC to give tert-butyl (S)-1-((S)-5-((3-chloro-1-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 91%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH:8]2)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.O>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccncc1)n2Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the compound obtained in Example 31 (1) (0.4 g) in N,N-dimethylformamide (160 ml), 60% sodium hydride (0.065 g) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 20 minutes, followed by addition of 4-fluorobenzyl bromide (0.2 ml), and the mixture was stirred at 15 to 30° C. for 15 hours. The reaction solution was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 0.3882 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:31][CH2:30]3)=[O:18])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)N3CCN(c4ccc(F)cc4)CC3)o2)c(C)[nH]c1=O
Yield: 98 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-carboxylic acid and (4-fluoro-phenyl)-piperazine to afford the title compound (98% yield). LC/MS: RT 2.9 min; m/e 410 (M+H).