Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[CH3:34][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:19][CH:20]=2)[N:4]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 36 %

Procedure:
The thus obtained methyl {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate was dissolved in THF (6 mL) and treated with 1N NaOH (3 mL). The biphashic reaction mixture was stirred at room temperature for 14 hours and then Et2O was added. The organic layer was siphoned off and the remaining aqueous layer was neutralized with 6N HCl. The separated solids was collected by suction, triturated with diisopropyl ether, and filtered to give {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.047 g, 36% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N3CCOCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 50.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with morpholine (11 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane and allowed to react overnight. The reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 28 mg of the title compound as a colorless solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34]([OH:36])=O.CCN(C(C)C)C(C)C.[CH:46]1([C:52]2[CH:53]=[CH:54][C:55]([O:72][CH3:73])=[C:56]([C:58]3[N:59]=[C:60]([NH:63][C:64]([CH:66]4[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]4)=[O:65])[S:61][CH:62]=3)[CH:57]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[CH:46]1([C:52]2[CH:53]=[CH:54][C:55]([O:72][CH3:73])=[C:56]([C:58]3[N:59]=[C:60]([NH:63][C:64]([CH:66]4[CH2:67][CH2:68][N:69]([C:34]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][N:28]=5)=[O:36])[CH2:70][CH2:71]4)=[O:65])[S:61][CH:62]=3)[CH:57]=2)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCNCC2)n1
Reactant: O=C(O)c1cnccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)c3cnccn3)CC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
0.32 g of BOP, 0.08 g of pyrazinecarboxylic acid and then 0.37 mL of DIPEA are added, at a temperature of 0° C., to a solution of 0.25 g of the compound prepared in step 1.2 in 3 mL of acetonitrile. The medium is stirred at room temperature for 12 hours and then concentrated. The medium is taken up in EtOAc and washed 3 times with 10% Na2CO3 solution and then with saturated NaCl solution. After drying over MgSO4, the solution is concentrated and then purified by flash chromatography to give 0.23 g of a dark yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.[C:37]1([C:43]2[NH:47][C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C2C(=CC=C3C=2N=NC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu](I)I>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][C:9]([N:47]2[C:46]4[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=4[N:44]=[C:43]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:8][CH:7]=3)[CH:3]=1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3cc(Br)ccc3c(-c3ccc4ccccc4c3)c2c1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(-c3ccc4ccccc4c3)c3cc(-n4c(-c5ccccc5)nc5ccccc54)ccc3c(-c3ccc4ccccc4c3)c2c1
Yield: 35.6 %

Procedure:
5.9 g (10 mmol) of 2,6-dibromo-9,10-di(2-naphthyl)anthracene, 2.2 g (11 mmol) of 2-phenyl-1H-benzimidazole, 0.19 g (1.0 mmol) of copper iodide, and 3.6 g (2.0 mmol) of 9,10-phenanthroline were dissolved into a 2 M solution of cesium carbonate in dimethylformamide (DMF), and the whole was refluxed under heating for 48 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered. The filtrate was poured into 1 L of 10-mass % hydrochloric acid, and the whole was extracted with methylene chloride. An organic layer was taken out and dried with magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resultant solid was purified by means of silica gel column chromatography to obtain 2.5 g of a pale yellow solid (36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][N:26]=[N+:27]=[N-:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 240 h
Yield: 97.9 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-bromobutyl]-benzenesulfonamide (0.505 g, 1.12 mmol) in THF/H2O (8/2, 10 mL) was added sodium azide (0.363 g, 5.58 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 10 days. The mixture was extracted with ether (3×20 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.455 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzenesulfonamide as a colorless oil in 98% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[C:35]#[CH:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH:36]=[CH:35][C:34]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCC
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25.0 g (53.2 mmol) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester and 10.8 mL (106 mmol, 2 equivalents) of ethyl propiolate in 200 mL of dry tetrahydrofuran at 1° C. was treated with 53.2 mL (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M) over 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was displaced with toluene at reduced pressure, and the toluene solution was washed with water and brine, diluted to 600 mL with toluene, stirred with 90 g of silica gel for three hours, filtered, and concentrated to 25.14 g (83%) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid benzyl ester as an orange oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.I[CH2:16][CH2:17][CH2:18][CH3:19].Cl>CN(C=O)C>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Yield: 86.1 %

Procedure:
A suspension of sodium hydride (34.1 g, 1.42 mol) in 300 mL of DMF was stirred in an ice/methanol bath and a solution of 3-indolecarboxylic acid (55.0 g, 0,374 mol) in 250 mL DMF was added dropwise over 45 minutes. The mixture was stirred for 30 minutes and then 100 mL of additional DMF was added. The mixture was cooled to 0° C. and 1-iodobutane (8.79 g, 40.8 mL, 0.359 mol) was added. The mixture was stirred for approximately 12 hours. The mixture was then poured in 2.0 L of ice water, acidified with 1N hydrochloric acid, extracted 3 times with ethyl acetate, washed twice with water and then dried over magnesium sulfate. The mixture was concentrated and the residue mixed with diethylether. Filtration gave 1-butylindole-3-carboxylic acid (62.74 g, 0.309 mol) as a white powder.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccccc1OC)c1ccccc1

Procedure:
A mixture of 130 g (1.05 m) guaiacol, 243 g (1 M) ethyl α-bromophenylacetate, 150 g of potassium carbonate and 1.5 L of acetone was refluxed for 96 hours, cooled and filtered. The solvent was removed at reduced pressure and the residue dissolved in toluene. After washing with dilute sodium hydroxide, then water, the solvent was removed and the residue distilled. The fraction boiling at 158-163°/0.4 mm was collected, weight 263 g.
Reaction SMILES: [N:1]1([C:7](=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:7](=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.2 %

Procedure:
Methyl 6-morpholin-4-yl-6-oxohexanoate (4.60 g) obtained in Reference Example 84(1) is dissolved in methanol (20 ml), and thereto is added a solution of sodium hydroxide (1.61 g) in water (8 ml). The mixture is stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure and the residue is neutralized with 2 N hydrochloric acid. The residue is concentrated under reduced pressure and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is concentrated under reduced pressure to give the title compound (4.11 g).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[C:46]1([C:52]2[O:60][C:59]3[C:54](=[N:55][CH:56]=[CH:57][C:58]=3[O:61][C:62]3[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=3)[CH:53]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCOCC1>[C:46]1([C:52]2[O:60][C:59]3[C:54](=[N:55][CH:56]=[CH:57][C:58]=3[O:61][C:62]3[CH:63]=[CH:64][C:65]([NH:66][C:10]([C:7]4[C:6](=[O:13])[N:5]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:4]([CH2:3][C:2]([OH:1])([CH3:20])[CH3:21])[C:8]=4[CH3:9])=[O:12])=[CH:67][CH:68]=3)[CH:53]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(-c5ccccc5)oc34)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
To a 10 mL sealed tube with stirbar was added 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (57.62 mg; 0.20 mmol; 1.20 eq.), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (63.15 mg; 0.25 mmol; 1.50 eq.). The tube was sealed and flushed with N2. To this mixture was added dioxane (3.00 ml) and N,N-diisopropylethylamine (0.14 ml; 0.83 mmol; 4.00 eq.) and the mixture was stirred at room temperature for 1 h. To the reaction mixture was then added 4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline (50.00 mg; 0.17 mmol; 1.00 eq.) and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (50% EtOAc/hex 10 column vol.; 50-100% 10 column vol.) to afford a beige solid (14 mg, 15%). (HPLC (method F): 88%, RT: 6.27 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.84 (s, 1H), 8.35 (d, J=5.6, 1H), 7.98-7.90 (m, 2H), 7.73 (d, J=9.0, 2H), 7.70 (s, 1H), 7.60-7.50 (m, 4H), 7.49-7.43 (m, 2H), 7.35 (d, J=7.4, 2H), 7.30 (d, J=9.0, 2H), 6.71 (d, J=5.5, 1H), 4.85 (s, 1H), 3.86 (s, 2H), 2.80 (s, 3H), 0.97 (s, 6H); MS (m/z) 575 [M+H]+, RT: 3.7 min.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:15]>N1C=CC=CC=1>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]=2[S:1][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:15]1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1ccc(C(=O)O)c(S)c1
Solvent: c1ccncc1
Product: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Yield: 42.9 %

Procedure:
A mixture of 2-mercaptoterephthalic acid (2.0 g, 10 mmol), 2-cyanopyridine (1.3 g, 11 mmol) and pyridine (10 ml) was refluxed for 8 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from methanol-diisopropylether to give the titled compound (1.22 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6](Cl)[CH:7]=1.BrC1C=CC([F:25])=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:25]
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: Fc1ccc(Br)cc1Cl
Product: O=C(Cc1ccccc1)c1ccc(F)c(Cl)c1
Yield: 20 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-2-chloro-1-fluorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 17 (110 mg, yield 20.0%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:14][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1nc2ccc(CO)cc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(CBr)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (2-methyl-1,3-benzoxazol-6-yl)methanol (66.5 mg, 0.408 mmol) in toluene (1 mL) were added carbon tetrabromide (135 mg, 0.408 mmol) and triphenylphosphine (106 mg, 0.408 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was directly applied to silica gel, and concentrated to dryness to give 6-(bromomethyl)-2-methyl-1,3-benzoxazole as an oil. To the obtained oil (92.0 mg, 0.408 mmol) were added DMF (4 mL), N-[1-(5-hydroxy-1-benzofuran-2-yl)ethyl]acetamide (30.0 mg, 0.136 mmol) obtained in Reference Example 38 and potassium carbonate (37.8 mg, 0.274 mmol), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was directly purified by basic silica gel column chromatography (hexane:ethyl acetate-4:1 to 3:7), and the solvent was evaporated. The residue was triturated with a small amount of ethyl acetate and diethyl ether to give the title compound (17.8 mg, yield 36%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22][C:21]2=[O:31])[CH2:12][CH2:11]1)([O-])=O.[Sn](Cl)Cl.C(OC(C)C)(C)C>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22][C:21]2=[O:31])[CH2:12][CH2:11]1
Reactant: O=c1[nH]c(=O)n(CCCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)c2ccccc12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: Nc1ccccc1N1CCN(CCCCn2c(=O)[nH]c(=O)c3ccccc32)CC1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of 1-[4-{4-(2-nitrophenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione (90 mg) in ethanol (8 ml) was added tin(II) chloride (159 mg) at 80° C. After stirring for 1 hour at the same temperature, the reaction mixture was quenched with ice and saturated aqueous sodium bicarbonate, and extracted with chloroform. The organic extract was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated to give an amorphous. 1-[4-{4-(2-Aminophenyl)piperazin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione (31 mg) was obtained by crystallization of the amorphous from diisopropyl ether.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([CH3:38])([O:39][C:40]1[CH:45]=[CH:44][C:43]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:2][CH:3]=3)[O:8][C:9]=2[CH3:25])=[CH:42][CH:41]=1)[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Yield: 47 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-(2-biphenyl-4-yl --methyl-oxazol-4-yl)ethyl ester (14.9 g, 34.3 mmol), 2-(4-hydroxyphenoxy)-2-methyl propionic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691 (6.15 g, 27.4 mmol) and Cs2CO3 (12.0 g, 36.8 mmol) was heated at 55° C. in DMF (110 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (600 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (6.25 g, 47%) as a colorless, viscous oil: Rf=0.48 in 35% ethyl acetate/hexanes; 1H NMR (500 MHz, CDCl3) δ8.05-8.03 (m, 2H), 7.67-7.64 (m, 4H), 7.46 (m, 2H), 7.38 (m, 1H), 6.83-6.77 (m, 4H), 4.22 (q, J=9.2 Hz, 2H), 4.18 (t, J=8.8 Hz, 2H), 2.97 (t, J=8.8 Hz, 2H), 2.37 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=9.2 Hz, 3H).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3cccc(Cl)c3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3cccc(Cl)c3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 73 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (100.0 mg, 45%).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH:34]CC(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][OH:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: NNC(=O)CO
Product: Cc1cc(C2CCC2)c(-c2nnc(CO)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 152 but using 2-hydroxyacetohydrazide in place of acetohydrazide. m/z (ES+) 456 (M+H)+.