Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8](Br)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(OC(C)(C)C)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:25](B(CC)CC)[CH3:26].[CH2:32]1COC[CH2:33]1>>[CH:1]1([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH2:32][CH3:33])[CH:15]=2)[CH2:26][CH2:25]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N(Br)Cc1ccccc1
Reactant: CCB(CC)CC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCc1cccc(CNC2CC2)c1

Procedure:
The Boc-bromobenzyl amine 10 (26.8 g, 94.03 mmol), and PddfPdCl2 (816 mg, 0.38 mmol, 0.004 eq) were mixed together in anhydrous THF (300 mL) and aqueous K3PO4 (100 mL of 2.0 M). To this red solution was added triethylborane (100 ml of 1.0 M in THF, 100 mmol). The solution turned black and was refluxed for 4 hours. GC/MS indicated the reaction was complete. The solution was poured into a separatory funnel and the aqueous layer separated. The organic layer was collected and solvent removed to a volume of 100 mL. Ethyl acetate/ hexanes (300 mL of 1:1) were added and the solution was extracted with 1N HCl (1×100 mL), sodium bicarbonate (2×100 mL) and brine (1×100 mL). The solution was dried over sodium sulfate and vacuum filtered through a bed of silica gel (125 ml of silica). The solvent was removed at reduced pressure to afford 20.6 grams of 11 as light yellow oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3C=CC=C[C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:14][CH2:15][CH2:16][C:17]([C:7]1[O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=2[CH:8]=1)=[O:18]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)c1cc2ccccc2o1

Procedure:
Using dibenzofuran and 3-chloropropionyl chloride, the same procedure as in Reference Example 2 was followed, to yield the title compound as a colorless crystal having a melting point of 116° to 118° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]3[CH2:26][C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[CH:24][C:23]3=[O:35])[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9]2)[CH2:4][O:3]1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[CH:24][C:23]2=[O:35])[CH2:16][CH2:17][C:18]([F:20])([F:19])[F:21])=[N:9]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CCC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (210 mg, 0.39 mmol), methanol (5 mL) and p-toluenesulfonic acid hydrate (17 mg). This mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire, 40 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (140 mg, 71%) as a white foam: HR-ES-MS m/z calculated for C21H21N4O5ClF3 [M+H]+ 503.1304, observed 503.1300; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.88-2.46 (m, 4H), 3.20-3.33 (m, 2H), 3.68-3.82 (m, 1H), 3.86 (dd, J=13.4, 7.2 Hz, 1H), 4.09 (dd, J=13.4, 3.9 Hz, 1H), 4.32 (d, J=18.1 Hz, 1H), 4.53 (m, J=18.1 Hz, 1H), 4.72 (t, J=5.4 Hz, 1H), 4.78 (dd, J=9.1, 5.1 Hz, 1H), 4.83 (s, 1H), 4.94 (d, J=5.1 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 7.33-7.40 (m, 1H), 7.42-7.57 (m, 3H), 7.66 (d, J=8.2 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:11][CH2:21][CH2:20][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A suspension of 2,3-Dihydroxy-benzoic acid methyl ester (336 mg, 2 mmol) and cesium carbonate (1.56 g, 4.8 mmol) in DMF was stirred at room temperature for 0.5 h. 1,2-Dibromoethane (0.224 ml, 2.6 mmol) was added to the DMF solution. The mixture was stirred at 80 C for 4 h, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product. It was chromatographed on silica gel with EtOAc/hexane (20%-40%) as eluent to afford 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester as a white solid. (223 mg, 1.14 mmol, 57.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12].ClC1C=CC=CC=1N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccccc1Cl
Solvent: O
Solvent: N#CCC#N
Solvent: Nc1ccccc1Cl
Product: NC1=NN=C(N)C1=NNc1ccccc1Cl
Yield: 29 %

Procedure:
This compound was prepared using 102 mg (0.5 mmol) of 2-[(2-chlorophenyl)-hydrazono]malononitrile, which was derived from 2-chloroaniline (105 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 34 mg (29%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]2[C:15](=O)[O:14][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH4+:23].[OH-].Cl.O>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][C:11]([C:15]([NH2:23])=[O:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [NH4+]
Reactant: Cc1ccc(NN=C2N=C(c3ccccc3)OC2=O)cc1C
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(-n2nc(C(N)=O)nc2-c2ccccc2)cc1C
Yield: 76.9 %

Procedure:
Three grams (0.01 mole) of 4-(3,4-dimethylphenylhydrazono)-2-phenyl-oxazoline-5-one (R1 =3--CH3, R2 =4--CH3 and R3 =H in the formula II) was suspended in 16 ml of acetone. To the resulting suspension, 1.57 ml of 29% solution of NH4OH (0.013 mole) was added dropwise at room temperature. After refluxing for 25 minutes, heating was stopped and 1.57 ml of concentrated hydrochloric acid was added dropwise. The resulting mixture was again refluxed for 5 minutes. 42 ml of water was then added to the reaction mixture, and obtained crystal was filtered out, washed with acetone containing water and dried. The thus treated crystal was recrystallized from a mixture of 8.8 ml of ethanol and 3 ml of water to obtain 2.25 g of almost colorless crystal, m.p. 169°-170° C., with a yield of 76.9%.
Reaction SMILES: C(O[C:6]([C:8]1[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:11]2[CH2:12][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>O>[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:6]([C:8]2[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:11]3[CH2:12][CH:13]([CH2:15][O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:31]1
Reactant: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(COc1ccccc1)O2
Reactant: Cn1ccc(N)n1
Solvent: O
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(COc1ccccc1)O2

Procedure:
The title compound was prepared in a similar manner as described for Example 200 from 4-isopropoxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214c) and 1-methyl-3-aminopyrazole. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H) 7.28-7.32 (m, 3 H) 7.05 (s, 1 H) 6.93-7.00 (m, 3 H) 6.89 (s, 1 H) 6.84 (s, 1 H) 5.19-5.27 (m, 1 H) 4.64-4.72 (m, 1 H) 4.20-4.26 (m, 1 H) 4.11 (dd, J=9.98, 4.67 Hz, 1 H) 3.82 (s, 3 H) 3.35 (dd, J=16.42, 9.35 Hz, 1 H) 3.11 (dd, J=16.55, 6.95 Hz, 1 H) 1.36 (d, J=5.81 Hz, 6 H); LCMS for C23H25N3O4 m/z 408.20 (M+H)+; Anal. Calcd. for C23H25N3O4.0.50 H2O: C, 66.33; H, 6.29; N, 10.09; Found: C, 66.29; H, 6.05; N, 9.87.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.[NH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:15][CH:16]1[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:26])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC1Cc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
5-Chloroindole-2-carboxylic acid (196 mg, 1 mmol) was dissolved in DMF (5 mL) containing 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem. 28, 1985, 1511–16; 162 mg, 1 mmol), EDCI (192 mg, 1 mmol) and HOBT (135 mg, 1 mmol). The mixture was stirred at ambient temperature for approximately 18 h before being partitioned between water and EtOAc. The organics were washed with water, saturated aqueous NaHCO3, saturated brine and dried over MgSO4; then filtered and evaporated to afford the title compound (212 mg, 66%) as an amorphous white solid.
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[C:21]([CH2:2][S:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH:22]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chilled mixture of 1-chloromethanesulfonyl-naphthalene (19.7 g, 81.8 mmol) and 1-fluoro-4-nitrobenzene (8.7 mL, 82 mmol) in dry THF (197 mL) was dropwise added 1.0M potassium t-butoxide in THF (205 mL, 205 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 1.5 hours. Glacial acetic acid (16 mL, 280 mmol) was then added. After stirring at ambient temperature for 1 hour, 40 minutes, the reaction mixture was concentrated and partitioned in warm ethyl acetate and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. The solid residue was stirred in ether, filtered and dried at 82° C. in vacuo for 1 hour. This yielded 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene as a brown/rust-colored solid (19.9 g, 70.6%): MP: 155-160° C.; Mass Spectrum (−EI, [M−H]−) m/z 344. 1HNMR (300 MHz, DMSO-d6): δ8.50-8.52 (m, 1H), 8.33 (d, 1H, J=8.30 Hz), 8.06-8.14 (m, 2H), 7.97 (dd, 1H, J=7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1H), 7.23-7.26 (m, 1H), 5.23 ppm (s, 2H). Elemental Analysis for C17H12FNO4S: Calcd: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.
Reaction SMILES: [Si]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])(C(C)(C)C)(C)C.F.C(=O)(O)[O-:33].[Na+]>C(#N)C>[OH:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][C:20](=[O:33])[CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: F
Agent: [Na+]
Solvent: CC#N
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of crude 20-tert-butyldimethylsilyloxy-7β-methyl-5α-4-azapregnane (25.2 gms) in acetonitrile (300 mL) was added an aqueous solution of hydrofluoric acid (12 mL). After stirring for 8 hr at room temperature, the reaction mixture was cooled to 0° C. and saturated sodium bicarbonate solution was slowly added. The mixture was extracted with methylene chloride (3×500 mL) and the combined extracts washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the title compound (22.3 gms) which was used without purification in the subsequent reaction.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([C:18]2[CH2:19][C@@H:20]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([CH:24]=2)[CH2:22][CH2:21]3)[CH:9]=1.[C:43]1([C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][N:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:52]3[CH:51]=[N:50][C:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:54][CH:53]=3)=[C:12]2[N:11]=[C:10]([C:18]2[CH2:19][C@@H:20]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([CH:24]=2)[CH2:22][CH2:21]3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2

Procedure:
This compound was prepared from (1R,5S)-tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate and 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, following essentially the similar procedures given in Preparative Example 1-1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[OH:8][S:9]([O-:11])=[O:10].[OH-].[Ca+2:13].[OH-]>>[CH:5]1[C:4]([OH:7])=[CH:3][CH:2]=[C:1]([S:9]([O-:11])(=[O:10])=[O:8])[CH:6]=1.[CH:5]1[C:4]([OH:7])=[CH:3][CH:2]=[C:1]([S:9]([O-:11])(=[O:10])=[O:8])[CH:6]=1.[Ca+2:13]
Reactant: O=S([O-])O
Reactant: Oc1ccccc1
Agent: [Ca+2]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccc(O)cc1

Procedure:
While 1000 g of a phenol sulfonic acid aqueous solution at a concentration of 5% was stirred at room temperature, calcium hydroxide was gradually added to reach a pH of about 6. The mixture was continuously stirred for a while. Then, this was filtered with 0.4 micrometer glass filter to obtain a calcium phenolsulfonate aqueous solution, which was then spray-dried to obtain powders of calcium phenolsulfonate.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH:17]=[CH2:18].CC(C)C=CN1CCCC(C(C)=O)=C1>>[Br-:15].[CH2:18]([N+:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH:17]=[CH2:16]
Reactant: O=C(c1ccccc1)c1cccnc1
Reactant: C=CCBr
Agent: CC(=O)C1=CN(C=CC(C)C)CCC1
Product: C=CC[n+]1cccc(C(=O)c2ccccc2)c1
Product: [Br-]

Procedure:
3-Benzoyl pyridine was reacted with 1-bromo-2-propene according to the procedure of Part (a) of Example 4 to give 1-(2-propenyl)-3-benzoyl pyridinium bromide as a tan coloured crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35].N1C(C)=CC=CC=1C>ClCCl.CCOCC>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@@H:4]([C:3]([OH:2])=[O:30])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:24][CH:25]=1)=[O:35]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)C(=O)O)CCCC2)cc1
Reaction time: 4 h
Yield: 29.1 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (66 mg, 0.17 mmol) and 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmol) were dissolved in 5 mL of dichloromethane and 2,6-lutidine (50 μL, 0.43 mmol) were added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with 1 N HCl, water, and saturated NaHCO3 and was dried (MgSO4). The crude product was dissolved in methanol (4 mL) and treated with 4 N NaOH (0.1 mL). After 2 hours, the excess base was quenched with acetic acid (0.1 mL), the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min. The peak eluting at 79% acetonitrile was concentrated and lyophilized to give 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (28.2 mg), HR-FABMS: obs. mass 591.1445. Calcd. mass 591.1430 (M+Na).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O.CN(C)C=O>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[N:7]([CH3:16])[C:6]3=[O:17])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cn1c(=O)c2ccccc2n(CCCBr)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(=O)c2ccccc2n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-bromopropyl)-3-methyl-2,4(1H,3H)-quinazolinedione (1.68 g), 1-diphenylmethylpiperazine (1.56 g), anhydrous potassium carbonate (2.33 g) and N,N-dimethylformamide (8 ml) was stirred for 3 hours at 60° C. After cooling, water was added to the reaction mixture and then the mixture was extracted twice with chloroform. The chloroform layer was washed with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oily residue. This oily residue was dissolved in methanol and then conc.hydrochloric acid solution was dropwise added to the solution to give a crystal, which was collected by filtration, washed with water and dried. This crude crystal was recrystallized from a mixture of methanol and water, to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-3-methyl-2,4(1H,3H)quinazolinedione.2HCl.0.5H2O (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][CH3:35])=[CH:25][C:24]=1[Br:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][O:30][C:26]3[CH:25]=[C:24]([Br:36])[C:23]([NH2:22])=[C:28]([Br:29])[CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Reactant: CNCCCOc1cc(Br)c(N)c(Br)c1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCCOc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-1-chloropropane, N-[3-(4-amino-3,5-dibromophenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[C:17](N)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][C:28]([C:31]([OH:33])=O)=[N:29][CH:30]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[C:16]([NH:40][C:31]([C:28]3[N:29]=[CH:30][C:25]([Br:24])=[CH:26][N:27]=3)=[O:33])=[CH:17][CH:18]=[C:19]([Br:21])[CH:20]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)cc(Br)c2)COC1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)ccc2NC(=O)c2ncc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[(R)-5-(3-Amino-5-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (33 mg, 0.082 mmol), 5-bromo-pyrimidine-2-carboxylic acid (18 mg, 0.090 mmol) and HOBT (16 mg, 0.106 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (10.54 mg, 0.082 mmol) and EDC (17 mg, 0.090 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated column chromatography (cyclohexane/ethyl acetate) to yield the title compound as a tan foam. MS: 569 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine