Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH:31]2[CH2:39][CH3:40])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:39]([CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]1[C:28]([C:24]1[N:25]=[CH:26][N:27]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:23]=1)=[O:29])[CH3:40]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: CCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1Cc2ccccc2N1C(=O)c1cc(N2CCC(N3CCc4cc(OC)ccc4NC3=O)CC2)ncn1

Procedure:
110 mg (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 103 mg (0.36 mmol) (6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone and 0.14 mL (0.80 mmol) DIPEA in 3.0 mL DMF were stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]([O:32][C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][N:39]=[C:40]3[N+:43]3C=CC=CC=3)=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH3:31])=[O:27])=[CH:21][CH:20]=1.O>C(CN)O>[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[CH:28]([O:32][C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][N:39]=[C:40]3[NH2:43])=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=1
Reactant: CCCC(Oc1ccc2ccnc(-[n+]3ccccc3)c2c1)C(=O)Nc1ccc(N2CCCCC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: NCCO
Product: CCCC(Oc1ccc2ccnc(N)c2c1)C(=O)Nc1ccc(N2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
The crude 1-(7-{1-[4-(2-oxopiperidin-1-yl)phenylcarbamoyl]butoxy}-isoquinolin-1-yl)pyridinium toluene4-sulfonate obtained in this way is dissolved in 4 ml of ethanolamine, and the mixture is stirred at room temperature for 42 hours. The reaction mixture is introduced into water and extracted with ethyl acetate. The organic phase is evaporated, and the residue is chromatographed on a silica-gel column, giving N-[4-(2-oxopiperidin-1-yl)phenyl]-2-(1-aminoisoquinolin-7-yloxy)pentanamide (“AA”) as a colourless solid; ESI 433.
Reaction SMILES: [ClH:1].O1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=3[O:20][CH3:21])[CH2:8][CH2:7]2)[O:5]CC1>C(O)=O>[ClH:1].[O:5]=[C:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[O:20][CH3:21])[CH2:10][CH2:11]1
Reactant: COc1c(NC2CCC3(CC2)OCCO3)ccnc1C
Agent: Cl
Solvent: O=CO
Product: COc1c(NC2CCC(=O)CC2)ccnc1C

Procedure:
27.3 g of 4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-methoxy-2-methylpyridine hydrochloride are stirred with 400 ml of formic acid for 4 hours. The residue which remains after concentrating in vacuo is dissolved in methylene chloride and shaken with 2N NaOH. The methylene chloride phase is concentrated, the residue is dissolved in ether and the hydrochloride is precipitated by addition of ethereal HCl. 14 g=90%; m.p.: 115° to 120° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[N:22]1([C:20]([C:6]2([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH2:29][CH2:30]3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C(N1CCOCC1)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(N1CCOCC1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 1-[9-(4-bromo-butyl)-9H-xanthen-9-yl]-1-morpholin-4-yl-methanone and 2-piperazin-1-yl-quinoline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43](=[O:59])[C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43](=[O:59])[C:44]2[CH:45]=[CH:46][C:47]([C:2]3[CH:3]=[C:4]4[C:10]([C:11]5[CH:12]=[CH:13][C:14]([C:15](=[O:16])[NH2:17])=[CH:18][CH:19]=5)=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:48][CH:49]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(N)=O)cc3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cnc4[nH]cc(-c5ccc(C(N)=O)cc5)c4c3)cc2)CC1
Yield: 46 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzamide (Intermediate CA, 200 mg, 0.425 mmol), 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (212 mmg, 0.51 mmol) and dichlorobis(triphenylphosphine)palladium (II) (15 mg, 0.021 mmol) were combined in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) and reacted in a microwave reactor at 150° C. for 10 min. The mixture was filtered, water was added, extracted with EtOAc and purified by silica gel chromatography using 0-8% MeOH:DCM. The title compound was obtained in 46% yield (102 mg). 1H NMR (DMSO-d6, 300 MHz): δ 12.2 (bs, 1H), 8.63 (d, J=1.1 Hz, 1H), 8.54 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 7.98 (bs, 1H), 7.96 (d, J=5.1 Hz, 2H), 7.89 (m, 4H), 7.54 (d, J=4.9 Hz, 2H), 7.32 (bs, 1H), 3.6 (bs, 2H), 3.4 (bs), 1.41 (s, 9H).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].Br[C:34]1[S:35][CH:36]=[CH:37][N:38]=1>C(N(CC)CC)C.C(#N)C>[CH3:10][C:7]1[S:6][C:5]([C:4]#[C:3][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1
Reactant: Brc1nccs1
Reactant: Cc1ccc(C#C[Si](C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C#Cc2nccs2)s1
Yield: 41.8 %

Procedure:
In a manner similar to Step E of Example 3, the reaction of 7.96 gram (0.0410 mole) of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne, 1.23 gram (3.9×10-4 mole) of tetrabutylammonium fluoride, and 2.6 gram (0.045 mole) of potassium fluoride in 120 ml of triethylamine and 40 ml of acetonitrile with 6.39 grams (0.0390 mole) of 2-bromothiazole yielded 3.35 grams of 1-(5-methylthien-2-yl)-2-(thiazol-2-yl)ethyne as an oil.
Reaction SMILES: C(O[C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:8]=[N:7]1)C.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].O>CCOCC>[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH:30][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:8]=[N:7]1)[CH3:25]
Reactant: CCOC(=O)Cn1ncc(-c2ccccn2)c1-c1ccccc1
Reactant: CCN(CC)CCCN
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccccn2)c1-c1ccccc1
Yield: 43.1 %

Procedure:
A solution of 10 g (0.032 mol) of ethyl 5-phenyl-4-(2-pyridinyl)pyrazole-1-acetate of example 1 in 15 mL (0.095 mol) of 3-(diethylamino)propanamine was heated at 100° for 3 hr. The excess amine was stripped in vacuo and the residue distributed between water and ether. The ether solution was dried over MgSO4, stripped and applied to 350 g of silica gel in a small amount of methylene chloride. The column was eluted with 20:1 acetone-triethylamine and a light yellow oil was obtained that crystallized upon triturating with cyclohexane to yield 5.4 g of product, mp 82°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C1C(=O)N([Br:21])C(=O)C1.OS(O)(=O)=O>O>[Br:21][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:13]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc2c(c1Br)CCCC2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a suspension of 6-methoxy-1-tetralone (2.0 g, 11.4 mmol) and NBS (2.0 g, 11.4 mmol) in H2O (30 mL) was added conc. H2SO4 (1.2 mL, 22.7 mmol) at rt. The reaction was stirred at 60° C. for 3 h. The mixture was filtered, and concentrated. Purification by prep-HPLC gave 1.2 g (41%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.13-2.18 (2H, m), 2.61 (2H, t, J=6.0 Hz), 3.03 (2H, t, J=6.0 Hz), 3.97 (3H, s), 6.88 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz). [M+H] Calc'd for C11H11BrO2, 255, 257. Found, 255, 257.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a room temperature solution of 4-bromo-1-fluoro-2-nitrobenzene (3.3 g, 15 mmol) and 4-fluorophenylamine (1.42 mL, 15 mmol) in anhydrous acetonitrile (20 mL) was added N,N-diisopropylethylamine (2.9 mL, 16.5 mmol) and the mixture was warmed to 90° C. After 24 hours, the mixture was concentrated in vacuo and the crude material was purified by column chromatography over silica gel eluting with 0-20% ethyl acetate in hexanes to afford 4.7 g of (4-bromo-2-nitrophenyl)-(4-fluorophenyl)amine as an orange oil which solidified on standing. MS m/z 311/313 (MH+).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[C:1]1([CH:7]([CH3:11])[C:8]([Cl:19])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(O)=S)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C(=S)Cl)c1ccccc1

Procedure:
In a 500 ml. three-necked reaction flask containing 45 g (247 mmol) of 2-phenylthiopropionic acid (as prepared in example 21) in 280 ml. of anhydrous benzene equipped with a magnetic stirrer, a reflux condenser connected with a wash-bottle containing H2SO4 there are added carefully by a cock-funnel with pressure compensation, 32 g (270 mmol) of thionyl chloride. The mixture is gradually heated until reflux with vigorous stirring. When gas evolution is completed, the solvent is evaporated and the residue is purified by distillation under reduced pressure (106° C/4 mm) to yield 2-phenylthiopropionic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][CH:39]([NH:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH3:40]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][CH:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)NCCCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCCNC(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1-methylethyl)-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.02 (m, 6H), 1.68 (m, 2H), 2.32 (m, 3H), 2.46 (m, 1H), 2.66 (m, 1H), 2.82 (m, 1H), 3.11 (m, 1H), 3.46 (m, 1H), 6.35 (d, J=8.8 Hz, 1H), 7.11 (m, 1H), 7.24 (m, 2H), 7.46 (m, 2H), 7.55 (m, 2H), 8.02 (m, 1H), 8.11 (d, J=7.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([OH:26])=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].Cl.CN(C)CCCN=C=NCC.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([NH:48][S:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:47])=[O:46])=[O:26])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[C:7]2[CH3:21]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2c(Cl)ccc(OCC(=O)NS(=O)(=O)c3ccccc3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetic acid (0.050 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.037 g), benzenesulfonamide (0.030 g), and 4-(N,N-dimethylamino)pyridine (0.005 g) in dichloromethane (5.0 mL) was stirred at room temperature 1 hour. The mixture was purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (1:19 by volume), followed by trituration with cyclohexane containing a small amount of diethyl ether to afford title compound as a buff solid, 0.020 g.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:17]4[CH2:18][CH2:19][N:14]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:15][CH2:16]4)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(-c2oc3ccc(CC(=O)O)cc3c2SC)cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2oc3ccc(CC(=O)N4CCN(c5ccccc5)CC4)cc3c2SC)cc1OC
Reaction time: 16 h
Yield: 554 %

Procedure:
Triethylamine and 12.992 mg of 1-phenyl-piperazine (0.080 mM) were added to the solution containing 35 mg of 3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid (35a; 0.068 mM) dissolved in 2 ml of dichloromethane. The reaction mixture was stirred for 16 hours and the remaining solvent was removed. The remaining residue was purified with Silica gel column chromatography with a mobile phase (dichloromethane:methanol=20:1) to obtain white solid type of 2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone (37a; 223 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:1]([Cl:4])=[O:2])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Oc1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of phosgene in toluene (20% w/w, 2.2 mL, 4.2 mmol), cooled in an ice bath, was added dropwise a solution of 60 (321 mg, 1.9 mmol) in 2 mL of toluene. The mixture was stirred in the same bath, which was left to come to room temperature on its own. After 18 h, the mixture was concentrated in vacuo to give 61, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 5.28 (s, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>CCO>[OH:2][N:1]=[C:7]([C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH3:3])[NH2:8]
Reactant: NO
Reactant: COc1ccccc1C#N
Solvent: CCO
Product: COc1ccccc1C(N)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
Hydroxylamine (Fluka 55458; 50% in water; 11.28 mL; 187.76 mmol; 5 eq.) was added to a solution of 2-methoxybenzonitrile (Alrich 231231; 4.59 mL; 37.55 mmol; 1 eq.) in EtOH (50 mL) and the resulting mixture was stirred at room temperature for 16 hours then at 55° C. for 24 hours. The solvent was then evaporated and the resulting colourless oil was further dried under high vacuum to give a white solid. The latter was triturated in n-hexane, filtered and dried to afford the title compound (6.29 g, quantitative) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[BH3-]C#N.[Na+].[Cl:23][C:24]1[C:25]([CH2:34][CH:35]=O)=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[C:29]#[N:30]>C(Cl)Cl>[Cl:23][C:24]1[C:25]([CH2:34][CH2:35][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[CH:10]=3)[CH2:2][CH2:3]2)=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: COc1cc(CC=O)c(Cl)cc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (90 mg, 0.190 mmol) and NaBH3CN (24 mg, 0.380 mmol) in 20 mL DCM was added 5-chloro-2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.190 mmol) and the mixture was stirred at RT overnight. Concentrated, and the residue was purified by prep-TLC to give 5-chloro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, MeOD) δ ppm 7.82 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.50˜7.53 (m, 2H), 7.20 (s, 1H), 5.35 (s, 2H), 3.95 (s, 3H), 3.23˜3.26 (m, 6H), 3.10˜3.16 (m, 8H), 3.00˜3.03 (m, 2H). MS m/e 441 (M+1)+. (0.094 μM)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 4-bromobenzyl bromide (5 g, 20 mmol) and phenol (2.26 g, 24 mmol) was added potassium carbonate (8.29 g, 60 mmol). This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (4.69 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>CN(C)C=O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1cccc(CCl)c1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 82.4 %

Procedure:
To 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1 were tetrahydrofuran (3 mL) and a 5N sodium hydroxide aqueous solution (22.4 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 3-methoxybenzyl chloride (21.0 mg, 0.13 mmol), which was stirred for 12 hours at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and this residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (35.1 mg, 81%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][CH:28]=[N:29]3)=[CH:24][CH:23]=2)[CH:16]=1>C(Cl)Cl>[N:29]1[C:30]2[C:25](=[CH:24][CH:23]=[C:22]([O:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:6]4[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:12])[F:14])=[CH:10][C:5]=4[OH:4])[CH:16]=3)[CH:31]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Solvent: ClCCl
Product: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7-[6-(2-methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline, (Example 190), (1.1 g, 2.5 mmol) in CH2Cl2 (25 mL) at −78° C. was added borontrifluoride diethyl etherate (0.95 mL, 7.6 mmol, Aldrich). The reaction mixture was allowed to warm to 0° C. over 1 h and then left to stir at room temperature for 16 h. The reaction mixture was quenched with satd NaHCO3 at 0° C. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuum. The crude yellow solid was suspended in MeOH, collected by filtration, washed with MeOH, and dried under high vacuum to give the title compound as a light-yellow solid. MP: 210.5–212.3° C. MS (ESI, pos. ion) m/z: 384 (M+1), 382 (M−1). Anal. Calcd for C20H12F3N3O2: C, 62.67; H, 3.16; N, 10.96; F, 14.87. Found: C, 62.85; H, 3.18; N, 11.02; F, 14.57.