Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:32][O:31][CH2:29][CH3:30])=[O:13])=[C:4]([CH3:18])[CH:3]=1
Reactant: CCON
Reactant: Cc1cc(Br)ccc1Nc1cnccc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCONC(=O)c1ccncc1Nc1ccc(Br)cc1C
Reaction time: 2 h
Yield: 77 %

Procedure:
3-[(4-Bromo-2-methylphenyl)amino]isonicotinic acid 2b (320 mg, 1.04 mmol) was dissolved in 15 ml dry DMF followed by the addition of DIPEA (2.08 mmol, 373 μl), ByBOP (1.25 mmol, 651 mg) and O-ethylhydroxylamine hydrochloride (2.08 mmol, 203 mg). The mixture was stirred for 2 h and the volatiles were removed in vacuo. The crude material was purified by flash chromatography using silica gel and a gradient of 0-5% methanol in DCM as eluent to give 280 mg (800 μmol; 77% yield) of pure desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:18][C:11]3[N:12]=[CH:13][N:14]=[C:15]([S:16][CH3:17])[C:10]=3C=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2].CSC1C2N=C(C=O)SC=2[N:30]=CN=1.CSC1C2C=C(C=O)SC=2N=CN=1>>[CH2:1]([N:3]1[C:7]([C:8]2[S:18][C:11]3[N:12]=[CH:13][N:14]=[C:15]([S:16][CH3:17])[C:10]=3[N:30]=2)=[C:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Reactant: CSc1ncnc2sc(C=O)nc12
Agent: CSc1ncnc2sc(C=O)cc12
Product: CCn1cnc(-c2ccccc2)c1-c1nc2c(SC)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carbaldehyde (Intermediate 77) in place of 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 15). Yellow solid (103 mg, 58%);
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][O:13][C:8]=3[CH:7]=2)[CH2:2]1.[CH3:22][CH:23]([NH2:25])[CH3:24]>C(O)C>[C:14]1([CH:11]2[CH2:10][C:9]3[CH:20]=[CH:21][C:6]([O:5][CH2:4][CH:3]([OH:1])[CH2:2][NH:25][CH:23]([CH3:24])[CH3:22])=[CH:7][C:8]=3[O:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C2COc3cc(OCC4CO4)ccc3C2)cc1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2c(c1)OCC(c1ccccc1)C2

Procedure:
5.0 g 1,2-epoxy-3-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane and 2.5 cm3 2-propylamine were boiled in 40 cm3 ethanol for 2 hours. After evaporating the mixture and triturating the residue with water, the base 1-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-3-(1-methylethylamino)-2-propanol was obtained, from which forming salt following the process of example 5 (a) 5.5 g of the maleate was obtained (m.p. 171°-173° C.).
Reaction SMILES: [CH2:1]([CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][CH:9]1[C@H:20]([N:24]1[CH:28]=[C:27]([CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[N:26]=[C:25]1[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:30][CH2:29][C:27]1[N:26]=[C:25]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:24]([C@@H:20]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:18])[C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=[C:13]([Cl:19])[CH:12]=3)[CH:21]([CH3:23])[CH3:22])[CH:28]=1
Reactant: Cc1ccc(-c2nc(CN3C(=O)c4ccccc4C3=O)cn2[C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
To N-{1-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-chromen-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-ylmethyl}-phthalimide (0.50 g, 0.78 mMol) in EtOH (15 mL) was added hydrazine monohydrate (0.12 mL, 2.5 mMol). The reaction was stirred at RT for 72 h, filtered through a pad of Celite® to remove the insoluble precipitate, rinsed with EtOH and evaporated to dryness. Purification by flash chromatography on silica gel [5-10% (5% NH4OH in MeOH)/CH2Cl2] gave the title compound (364 mg, 91%) as a white solid foam: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.37 (m, 6H), 7.15 (m, 3H), 6.71 (d, J=1.7 Hz, 1H), 6.69 (s, 1H), 5.00 (d, J=10.9 Hz, 1 H), 4.07 (d, J=15.5 Hz, 1H), 3.92 (d, 1H), 3.88 (d, 1H), 2.72 (br s, 2H), 2.65 (m, 1H), 2.49 (s, 3H), 2.48 (d, J=15.5 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.30 (d, J=6.7 Hz, 3H); MS (ES) m/e 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].C[O-].[Na+]>CO>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]3[OH:20])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 4-[(4-ethylthiophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.3 g) in methanol (10 mL) was added sodium methoxide (28% methanol solution, 0.13 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.87 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:43]([Mg]Br)[CH3:44].Cl>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][N:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH2:43][CH3:44])[CH2:30][CH2:29]1
Reactant: CC[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)CC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.0 g) was dissolved in tetrahydrofuran (10 mL), ethylmagnesium bromide (1.7 mL, 3.0 M diethyl ether solution) was added dropwise, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])/[C:10](/[CH3:19])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])/[C:10](/[CH3:19])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: C/C(=C\c1cccc(O)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C/C(=C\c1cccc(Oc2ccnc(C#N)c2)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 68.6 %

Procedure:
(E)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-hydroxyphenyl)-2-methylacrylamide (1.0 g, 2.81 mmol), 4-chloropicolinonitrile (428 mg, 3.09 mmol) and cesium carbonate (2.75 g, 8.43 mmol) were combined and stirred in DMF. The reaction mixture was heated at 100° C. overnight and then cooled to rt. The mixture was filtered to remove cesium carbonate, the collected precipitate was washed with EtOAc, and the combined filtrate was concentrated. Purification by column chromatography (SiO2, 0-80% EtOAc in hexanes) provided the title compound (883 mg). LCMS, FA: Rt=2.15 min, [MH+ 458.0].
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43])=[O:35]>C1COCC1>[CH3:43][C:37]1[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=1[C:34](=[O:35])[CH2:33][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: Cc1ccc(C(=O)CBr)c(C)c1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(C)cc1C
Yield: 21.6 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (60 mg, 0.19 mmol), with triethylamine (130 uL, 0.94 mmol, 5.0 eq), and 2-bromo-2',4'-dimethylacetophenone (52 mg, 0.23 mmol, 1.2 eq) in THF (7 mL), provided a crude product. A portion of the product was purified by preparative TLC to provide 19 mg (21%) of L-isoleucine, N-[1-(2-(2,4-dimethylphenyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([OH:26])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39]O)=[CH:35][CH:34]=1>>[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:25][C:24]([C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)=[O:26])=[CH:35][CH:34]=1
Reactant: OCc1ccncc1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)OCc3ccncc3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid and 4-pyridinemethanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15]CC)=[O:14])=[O:9].[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([OH:15])=[O:14])=[O:9]
Reactant: CCOC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Yield: 91.5 %

Procedure:
Ethyl 2-[3-(2-thienyl)acrylamido]benzoate (150 mg, 0.50 mmol) prepared in Example 2 was dissolved in methanol (3 ml) while warming, and 1N-aqueous NaOH (1.8 ml, 1.80 mmol) was added dropwide under stirring. The mixture was stirred at 70° C. for 1 hour. After the reaction, methanol was removed, and the residue was treated with water under ice cooling and acidified (to pH 4) with 10% HCl. The precipitated solid were collected on a filter, washed with water, and dried to give white solids of the title compound (125 mg, yield, 92%), which were recrystallized from the mixed solvent of methanol and water. m.p., 215°-216° C.
Reaction SMILES: Cl.FC1C=CC(NN)=CC=1.Cl[C:12]1[CH:13]=[C:14]([N:19]2[C:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Cl)[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20]2)[CH:15]=[CH:16][C:17]=1[F:18]>>[F:30][C:28]1[CH:29]=[C:24]([C:23]2[N:19]([C:14]3[CH:13]=[CH:12][C:17]([F:18])=[CH:16][CH:15]=3)[N:20]=[C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: NNc1ccc(F)cc1
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)cc2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 8A and 4-fluorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 23.0 g (44% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.C(NC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(Br)C=2)C=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Brc1cncc(-c2cc(NCc3ccccc3)nc(-c3ccccn3)c2)c1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Product: c1ccc(CNc2cc(-c3cncc(-c4cnn(C5CCNCC5)c4)c3)cc(-c3ccccn3)n2)cc1

Procedure:
This compound is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with Benzyl-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 1.25).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10]C=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.I[Cl:22].C(OCC)(=O)C.Cl[CH2:30][Cl:31]>>[Cl:22][C:3]1[C:2]([OH:1])=[C:30]([Cl:31])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]([C:12]([F:15])([F:14])[F:13])[O:8]2
Reactant: ClCCl
Reactant: ClI
Reactant: CCOC(=O)C1=Cc2cc(O)ccc2OC1C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2c(cc(Cl)c(O)c2Cl)OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 1.0 g (3.5 mmol) of ethyl 6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 10 mL of anhydrous dichloromethane was added a solution of 1.5 mL (30 mmol) of iodomonochloride in 5 mL anhydrous dichloromethane. The resulting brown solution was stirred at room temperature for one hour. The reaction was added to 50 mL of ethyl acetate. The organic solution was washed with sat. sodium sulfite solution three times, washed with brine three times and dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 0.8 g (64%) of a yellow solid: 1H NMR (CDC3/300 MHz) 8.00 (s, 1H), 7.01(s, 1H), 5.81(s, 1H), 5.70(q, J=6.6 Hz, 1H), 4.38(m, 2H), 1.40(t, J=7.2 Hz, 3H); MS (ESI+) 357.0 (M+1, 100).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:21])C(=O)C1>>[Cl:21][C:5]1[N:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:8][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCc1cnc(C(=O)OCC)[nH]1
Product: CCCc1[nH]c(C(=O)OCC)nc1Cl
Yield: 73.5 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-propyl-1H-imidazole-2-carboxylate obtained in Example (46b) (1.01 g, 5.54 mmol) and NCS (0.74 g, 5.50 mmol), to obtain 876 mg of the title compound as a white solid (73%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13].COC1C=CC([NH2:44])=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:44][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=2[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13])[CH:4]=1
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: COc1ccc(N)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
1-Hydroxy-N-[4-(2,4-di-t-pentylphenoxy)-butyl]-2-naphthamide was coupled with a diazotized p-anisidine ##STR29## The azo group of the compound thus prepared was then reduced with sodium dithionite (Na2S2O4) to the corresponding amine.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH:3]=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=O>>[O:22]([C:18]1[CH:17]=[C:16]([CH2:14][CH2:13][CH2:3][C:2]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)([CH3:5])[CH3:1])[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Product: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
In the same manner as described in Synthesis Example 2, the equivalent mixture of α, α-dimethyl-(4-chlorophenyl)acetaldehyde and 3-phenoxyacetophenone was treated to give 1-(3-phenoxyphenyl)-4-(4-chlorophenyl)-4-methylpentane.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:20](C(OC(C)(C)C)=O)[N:19]=2)=[O:16])=[CH:13][N:14]=1>O1CCOCC1>[CH2:1]([NH:8][C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[NH:20][N:19]=2)=[O:16])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)c2cnc(Br)s2)cc1-c1ccc(F)cc1
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccc(F)cc2)[nH]n1)c1cnc(NCc2ccccc2)s1
Temperature: 85 °C
Reaction time: 24 h
Yield: 106.4 %

Procedure:
Benzylamine (0.1 mL, 0.87 mmol) was added to a solution of tert-butyl 3-(2-bromothiazole-5-carboxamido)-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate (160 mg, 0.43 mmol) in dioxane (3 mL). The resulting solution was stirred at 85° C. for 24 hrs. The solvent was evaporated and the crude product was purified by column (0-10% MeOH/AcOEt gradient), yielding 2-(benzylamino)-N-(5-(4-fluorophenyl)-1H-pyrazol-3-yl)thiazole-5-carboxamide (180 mg, 90%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:29][CH:28]=1.ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][CH:32]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(NC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 68.3 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl) propanoic acid (5 g) and ethyl 4-aminophenylacetate (2.36 g) were condensed in a mixed solvent of dichloromethane (100 ml) and acetonitrile (10 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.27 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol/acetonitrile (10/1) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(3-indolyl)propanamide (4.86 g).
Reaction SMILES: [OH:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30]>C1C=CC=CC=1>[OH:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]=1[O:1][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)[Si](OCCc1cccc(CC2=C(O)CCC2=O)c1)(C(C)C)C(C)C
Reactant: CC(C)CO
Solvent: c1ccccc1
Product: CC(C)COC1=C(Cc2cccc(CCO)c2)C(=O)CC1
Yield: 81 %

Procedure:
A mixture containing 46 (0.294 g, 0.757 mmol), paratoluensolfonic acid (0.005 g), i-butanol (1.0 mL) and benzene (4.0 mL) was heated to reflux for 12 h. The reaction mixture was then concentrated and the residue so obtained was purified by silica gel column chromatography using 5% of methanol in dichloromethane as eluent, obtaining the desired compound. Yield: 81%.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([N:31]2[CH2:30][CH2:29][N:28]([C:26]([N:23]3[CH2:22][CH2:21][N:20]([C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[F:13])[CH2:25][CH2:24]3)=[O:27])[CH2:33][CH2:32]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(N1CCNCC1)N1CCN(c2ccncc2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
Phenylsulphonyl chloride (0.38 g) was added to a mixture of 1-[(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine dihydrochloride (0.65 g) and triethylamine (1.5 ml) in dichloromethane (30 ml) at 5° C. The solution was stirred at 5° C. for 1 hour and at ambient temperature for 18 hours. The solution was evaporated to dryness. The residue was dissolved in dichloromethane (100 ml), and the solution was washed with water (3×10 ml), dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (N32-63) using 0.1-0.3% methanol in dichloromethane as eluent. Recrystallisation from ethyl acetate/isohexane gave 1-phenylsulphonyl-4-[1-(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine (0.49 g), as an off-white solid mp 143-145° C: NMR (CDCl3): 3.05 (t, 4H), 3.25 (t, 4H), 3.40 (m, 8H), 6.70 (dd, 1H), 7.60 (m, 3H), 7.78 (s, 2H), 8.20 (dd, 2H); m/z 434 (M+1).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH2:45][CH2:44][CH3:43]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1H), 7.55-7.58 (m, 2H), 7.27-7.38 (m, 6H), 6.09-6.11 (m, 1H), 4.77 (s, 4H), 4.08-4.14 (m, 2H), 3.58-3.68 (m, 2H), 2.39-2.51 (m, 2H), 2.34 (dt, J=19.8, 7.3 Hz, 2H), 1.46-1.62 (m, 2H), 0.88-0.93 (m, 3H); MS (ESI(+)) m/e 390 (M+H)+.