Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:18])[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](O)=[O:22].C1CCC(N=C=NC2CCCCC2)CC1.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:19][CH2:20][C:21]([O:18][CH:16]([CH3:17])/[CH:15]=[CH:14]/[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:22]
Reactant: CC(O)/C=C/c1cccc(Oc2ccccc2)c1
Reactant: O=C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(/C=C/c1cccc(Oc2ccccc2)c1)OC(=O)CCl
Reaction time: 0.08 h
Yield: 99.2 %

Procedure:
The product from step (b) (12.01 g) and chloroacetic acid (5 g) were taken up in methylene chloride, DCC (15 g) was added, and the mixture stirred for 5 minutes. DMAP (0.5 g) was then added, causing the mixture to boil, and the mixture stirred for 1 hour. Ether (200 ml) was then added, the mixture filtered, and the filtrate washed with satd. aqu. NaHCO3, 2 M aqu. HCl, and satd. aqu. NaCl, dried over MgSO4 and stripped. The residue was taken up in ether/pet.ether (1:1, 100 ml). filtered, and stripped to give the desired product (15.7 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[S:44]1[CH:48]=[C:47]([CH2:49][N:50]2[C:58]3[C:53](=[CH:54][C:55]([NH2:59])=[CH:56][CH:57]=3)[CH:52]=[N:51]2)[N:46]=[CH:45]1>ClCCCl>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:59][C:55]1[CH:54]=[C:53]3[C:58](=[CH:57][CH:56]=1)[N:50]([CH2:49][C:47]1[N:46]=[CH:45][S:44][CH:48]=1)[N:51]=[CH:52]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2cscn2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol), triphenylphosphine (603 mg, 2.3 mmol) and carbon tetrachloride (2.2 ml, 23 mmol) in 1,2-dichloroethane (5 ml) was stirred at 45° C. for 2 hours. 1-(1,3-Thiazol-4-ylmethyl)-1H-indazol-5-amine (184 mg, 0.8 mmol) was added and the solvents were evaporated under vacuum. Acetonitrile (5 ml) was added. The mixture was stirred at 75° C. for 2 hours. After cooling, the solvents were evaporated under vacuum. The residue was diluted in 6N methanolic ammonia and the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 3% to 5% methanol in DCM) to give the title compound as a beige foam (215 mg, 60%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.80 (s, 2H), 6.81 (d, 1H), 6.93 (s, 1H), 7.48 (m, 2H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.08 (s, 1H), 8.43 (s, 1H), 8.62 (s, 1H), 8.78 (s, 1H); Mass spectrum 474.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([OH:19])[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH:12]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)CCC(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CCC(OS(C)(=O)=O)c1ccccc1)OS(C)(=O)=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Stir methanesulfonyl chloride (2.94 g, 25.7 mmol) in dichloromethane (40 mL) in a flask that has been purged with nitrogen. Cool the mixture to −20° C. and add 1-phenyl-hexane-1,4-diol (2.0 g, 10.3 mmol) dissolved in dichloromethane (5 mL), and triethylamine (3.13 g, 30.9 mmol). After 2 h of stirring at −20° C., quench with saturated aqueous NH4Cl solution and concentrate to a quarter of the volume. Dilute with EtOAc, and wash with saturated NaHCO3 solution, water, and brine. Dry the organic portion over Na2SO4, filter, and concentrate to obtain 3.0 g (83%) of the title compound. Use with no further purification. 1H NMR (400 MHz, CD3OD): δ 7.37-7.24 (m, 5H), 4.69-4.59 (m, 1H), 4.21-4.14 (m, 1H), 3.01 (s, 3H), 2.73 (s, 3H), 1.91-1.55 (m, 6H), 0.96-0.88 (m, 3H).
Reaction SMILES: N#N.C([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=C.[C:14](OCC=C)(=O)[C:15](C)=C.C(O)(=O)C1C=CC=CC=1.C(OC(=O)C(C)=C)CCCCCCCCCCC>C(OC(=O)C)C.O1CCCC1>[CH:14]([C:7]1[CH:6]=[CH:5][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[CH2:15]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: C=CCOC(=O)C(=C)C
Agent: C=C(C)C(=O)OCCCCCCCCCCCC
Agent: N#N
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccccc1C(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 500 ml. 2-necked flask fitted with a thermometer, and a reflux condenser connected to a N2 source, was introduced a mixture of 3.5 g of 4-vinylbenzoic acid (Aldrich Chemical Co. , 3 g of allyl methacrylate, 150 ml tetrahydrofuran and 150 ml ethylacetate. The mixture was stirred to dissolve the benzoic acid compound. Next was added 93.5 g of laurylmethacrylate. The flask was purged with N2 and heated at 70° C. for 10 minutes. The flask was purged again with N2 and 1 g of 2,2-azobisisobutyronitrile (AIBN) was added all at once and heated at 70° C. under a N2 blanket. This was continued for a period of 8 hours. The resulting polymeric solution was cooled to room temperature and diluted with twice its volume with Isopar™ G and filtered to remove insoluble materials (About 125 mg of homopolymer of VBA acid remained on the filter paper). The clear filtered polymeric solution was further diluted with Isopar™ G to 4.1 liters and was subjected to distillation under reduced pressure until about 500 ml of the distillate was collected in the receiving flask. The distillate was mainly ethylacetate, tetrahydrofuran and Isopar™ G).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH:12]1[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15](=[O:25])[N:14]([CH3:26])[CH2:13]1>>[CH3:26][N:14]1[CH2:13][CH:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15]1=[O:25]
Reactant: CNc1ccccc1
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Product: CN1CC(CCN(C)c2ccccc2)c2nc3ccccc3n2C1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 15 mL of N-methylaniline was added 3.5 g (0.0133 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one. The reaction mixture was heated to 90° C. (oil bath) for 2 days, and the excess N-methylaniline removed in vacuo at 80° C., 0.5 mm Hg. The residue was dissolved in 100 mL of CH2Cl2, washed with 2×100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to high vacuum (0.5 mm, Hg) at 85° C. for 2 hr, and then crystallized from iso-octane/toluene to give 2.3 g (52%) of analytically pure crystals, mp 130°-31° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][C:16](=[O:20])[NH:17]2)=[C:13]([Cl:21])[N:12]=1.CO.[CH3:24]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[Cl:21][C:13]1[N:12]=[C:11]([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[CH:24]2)[N:19]=[C:18]2[C:14]=1[NH:15][C:16](=[O:20])[NH:17]2
Reactant: COC(OC)OC
Reactant: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CS(C)=O
Product: N#Cc1ccc2ncn(-c3nc(Cl)c4[nH]c(=O)[nH]c4n3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a solution of crude 4-amino-3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile (1.23 mmol) in anhydrous DMSO (10 mL) was added methanol (150 mL), followed by anhydrous trimethylorthoformate (5 mL) and p-toluene sulfonic acid (100 mg) and the reaction mixture was stirred under Ar at room temperature for 3 h (LC-MS monitoring). The solvent was removed in vacuo and the residue redissolved in 7 mL of DMSO, then 40 mL of water were added. The pink solid formed was filtered under vacuo using a fine porosity Buchner filter funnel, washed with water, then dried in the vacuum oven at 60° C. to give 0.26 g of the desired product (67% yield on 2 steps). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.24 (s, 1H), 9.00 (s, 1H), 7.91 (d, 1H), 7.69 (d, 1H); MS (EI) m/z 312.2 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.O>CN(C=O)C>[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:29]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OC1CCCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(O)C4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73.8 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 3-hydroxypiperidine (168 mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4—(3-hydroxypiperidino-methyl)phenyl]-3—(4-methylphenyl)cinnamamide (Compound 67) (174 mg) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[C:32]([NH:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)(=[O:34])[CH3:33]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(OCCN)c3Cl)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of 8-[3-(2-aminoethoxy)-2,6-dichlorobenzyloxy]-2-methylquinoline (11 mg) in dichloromethane were added pyridine (3.46 g) and acetic anhydride (4.47 mg), and the mixture was stirred for 30 minutes. The reaction mixture concentrated, and the reside was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1, V/V) to give 8-[3-(2-acetamidoethoxy)-2,6-dichlorobenzyloxy]-2-methylquinoline (6 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:13][S-:14].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][S:14][CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)C1(CCBr)CCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
To a solution of 1-(2-bromoethyl)cyclopentane carboxylic acid methyl ester (2.0 mmol, 472 mg) in DMF (5 mL) was added sodium thiomethoxide (2.65 mmol, 186 mg). The reaction mixture was stirred for 15 h at room temperature and was poured into water (30 mL). The organic compound was extracted into diethyl ether (2×20 mL). The combined extracts were washed with a saturated solution of sodium chloride (50 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford 334 mg (82%) of a colorless oil. HR MS C10H18O2S): Obs mass, 202.1024. Calcd mass, 202.1028 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[NH2:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:10]=[C:9]1[NH:25][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(N)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(NC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 124 (200 mg, 0.593 mmol), triethylamine (0.082 mL, 0.583 mmol), 4-dimethylaminopyridine (10 mg), and 4-fluorobenzoyl chloride (0.063 mL, 0.533 mmol) in dichloromethane (2 mL) is stirred at RT for 0.5 h. The solution is diluted with dichloromethane and washed with NaHCO3, brine, and then dried (MgSO4). The mixture is filtered, the filtrate evaporated, and residue purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 123 mg of the product 125. 1H NMR (CDCl3) δ 10.00 (s, 1 H), 8.50-8.35 (m, 2 H), 7.20-6.85 (m, 12 H), 6.55-6.40 (m, 2 H), 1.20 (s, 9 H); MS: m/z 460 (M++1).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH:14]1([C:19]([OH:21])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.Cl.[NH2:24][C:25]1[CH:57]=[CH:56][C:28]([O:29][C:30]2[CH:31]=[CH:32][C:33]3[N:37]=[C:36]([CH2:38][O:39][C:40]4[CH:53]=[CH:52][C:43]([CH2:44][CH:45]5[S:49][C:48](=[O:50])[NH:47][C:46]5=[O:51])=[CH:42][CH:41]=4)[N:35]([CH3:54])[C:34]=3[CH:55]=2)=[CH:27][CH:26]=1>CN(C)C=O>[O:50]=[C:48]1[NH:47][C:46](=[O:51])[CH:45]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([O:39][CH2:38][C:36]3[N:35]([CH3:54])[C:34]4[CH:55]=[C:30]([O:29][C:28]5[CH:56]=[CH:57][C:25]([NH:24][C:19]([CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18]6)=[O:21])=[CH:26][CH:27]=5)[CH:31]=[CH:32][C:33]=4[N:37]=3)=[CH:53][CH:52]=2)[S:49]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(O)C1CCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCC4)cc3)cc21

Procedure:
A reaction was conducted by a similar procedure to that described in Example 58 using triethylamine (0.32 ml), ethyl chloroformate (0.08 ml), cyclopentanecarboxylic acid (0.09 ml), anhydrous N,N-dimethylformamide (8 ml) and 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg). The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. To the residue was added water and ethyl acetate and the insoluble material was isolated by filtration to afford the title compound (236 mg, white powder, mp 227-228° C.).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)(Cl)=O.C(O)(=O)C(CCC)CCC.[NH2:25][C:26]([NH2:28])=[O:27]>C(#N)C>[CH2:3]([CH:2]([CH2:6][CH2:7][CH3:8])[C:1]([NH:25][C:26]([NH2:28])=[O:27])=[O:9])[CH2:4][CH3:5]
Reactant: NC(N)=O
Reactant: CCCC(CCC)C(=O)Cl
Agent: CCCC(CCC)C(=O)O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCCC(CCC)C(=O)NC(N)=O

Procedure:
Valproyl chloride (0.057 mol), prepared by coupling of thionylchloride and valproic acid according to a published method [24], was dissolved in dry acetonitrile (50 ml), and the resulting solution was slowly added to a boiling solution of urea (0.14 mole) in dry acetonitrile (100 ml) and allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The products were purified by crystallization from ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:14](=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[CH:12][CH:11]=3)=[N:27][CH:28]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(-c2ccnnc2)cc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnnc2)cc1)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(pyridazin-4-yl)phenyl)acetic acid 37-4 (43 mg, 0.2 mmol), 5-phenylpyridin-2-amine (41 mg, 0.24 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (117 mg, 0.3 mmol) in DMF (1 mL) was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The crude product was purified by reverse phase HPLC to give N-(5-phenylpyridin-2-yl)-2-2(4-pyridazin-4-yl)phenyl)acetamide 37 as white solid. MS m/z 367.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.45-9.44 (m, 1H), 9.22 (dd, 1H, J1=1.2 Hz, J2=11.2 Hz), 8.44 (d, 1H, J=2.4 Hz), 8.29 (d, 1H, J=8.8 Hz), 7.92 (dd, 1H, J1=16.8 Hz, J2=2.4 Hz), 7.70-7.66 (m, 3H), 7.56-7.51 (m, 4H), 7.46-7.43 (m, 2H), 7.39-7.35 (m, 1H), 3.85 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:75])([F:74])[F:73])[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[O:63]=[C:62]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55](=[O:64])[N:54]1[CH2:53][C@@H:52]([NH:51][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[C:2]([F:1])[CH:3]=1)[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:74])([F:73])[F:75]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (66 mg, 0.3 mmol), PyBrOP (169 mg, 0.37 mmol) and diisopropylethyl amine (263 μL, 1.5 mmol) in DCM (3 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (105 mg, 0.3 mmol)[prepared according to Preparation 3]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (112 mg, 68%) as a white solid: LC-MS (ES) m/z=551 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:20]([O:22]C)=O)[CH:4]=1)[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C(OCC)(=O)C>[CH2:1]([C:3]1[S:7][C:6]2[N:8]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:37][CH:38]=3)[C:9](=[O:19])[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:20]([OH:22])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(NC(=O)CCCc2ccccc2)s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a mixture of methyl 5-ethyl-2-[(4-phenylbutanoyl)amino]thiophene-3-carboxylate (15 g) and N,N-dimethylformamide (150 mL) was added 60% sodium hydride (2.17 g), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added 4′-(bromomethyl)biphenyl-2-carbonitrile (14.8 g), and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After purification by silica gel column chromatography, the obtained residue was dissolved in tetrahydrofuran (200 mL), potassium tert-butoxide (5.3 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.89 g, 22%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[I:22]C1C=CC(C=O)=CC=1>>[I:22][C:7]1[CH:6]=[CH:5][C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(I)cc2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 52 but using 4-iodobenzaldehyde in place of 3-iodobenzaldehyde. Solid (12.7 g, 57%);