Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[O:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1>O1CCCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:46][CH:43]2[CH2:44][CH2:45][O:40][CH2:41][CH2:42]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCOCC1)C1COCCN1c1nc(Cl)ncc1Br
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a 200 mL round-bottom flask were added 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 2.5 g, 7.75 mmol) and 1-hydroxybenzotriazole (1.257 g, 9.30 mmol) in tetrahydrofuran (30 mL) to give a beige suspension. To this suspension were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.783 g, 9.30 mmol) and tetrahydro-2H-pyran-4-amine (0.802 mL, 7.75 mmol). After 1 hour at 0° C., HPLC showed the reaction was almost complete. The reaction mixture was subsequently partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by normal phase column chromatography (˜50 g silica, 35-100% EtOAc gradient in hexanes) to give the title compound as a white foam (1.8 g, 57.2%).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](ON1C(=O)CCC1=O)=[O:34]>CN(C)C=O>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]([NH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23])=[O:34]
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Reactant: NC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Cc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@@H](c2ccccc2)Cc2ccccc21
Yield: 102.7 %

Procedure:
By conducting the reaction and treatment in the same manner as in Example 12 using 0.2 g of cis-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine 1-acetamide and 0.1 g of succinimido 2 indolecarboxylate dissolved in 5 ml of dimethylformamide and recrystallization from a mixed solvent of ethanol and isopropyl alcohol, 0.18 g of cis-3-(2-indolecarboxamido)-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide 1/2 isopropyl alcohol adduct is obtained, m.p. 204°-216° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 48 h

Procedure:
A flask was charged with methyl 4-hydroxybenzoate (500 mg, 3.29 mmol), copper (II) acetate (895 mg, 4.93 mmol), 4-trifluoromethylphenylboronic acid (2.50 g, 13.15 mmol), and 4 angstrom molecular sieves (500 mg). Dichloromethane (33 mL) and triethylamine (1.83 mL, 13.15 mmol) were added, and the reaction mixture was stirred rapidly, open to air. After 48 h, the reaction mixture was filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 297.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.07-8.05 (m, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.06-7.04 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCCl
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCSc1ccc(O)cc1
Temperature: 80 °C
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, p-hydroxythiophenol (126 g) was dissolved in N,N-dimethylformamide (600 ml) and thereto was added potassium carbonate (152 g). Thereto was added octadecyl chloride (318 g), followed by heating at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water to precipitate a white solid. Thereto was added 5% hydrochloric acid to adjust the pH to acidic state and then, the white solid was filtered off under reduced pressure and then recrystallized from methyl ethyl ketone to obtain the desired product (261 g). Yield 70%; m.p. 95° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: OCc1ccccc1
Product: c1ccc(COc2cncc(N3CCNCC3)n2)cc1
Temperature: 125 °C
Reaction time: 4.5 h
Yield: 90.5 %

Procedure:
A mixture of the product from example 13, step 2 (0.73 g, 3.68 mmol), benzyl alcohol (9.4 g, 87 mmol) and K-t-BuO was stirred at 125° C. for 4.5 h. The reaction mixture was purified by silica gel chromatography (13×5 cm) using CHCl3/MeOH (7:3 followed by 9:1) as eluent. Solvents were evaporated off and the residue was redissolved in ethyl acetate. Filtration and concentration in vacuo furnished 0.90 g (90%) of the title compound as a beige oil. HRMS m/z calcd for C15H18N4O (M)+ 270.1481, found 270.1482. Anal. (C15H18N4O) C, H, N. *This compound was also characterized as its maleate salt: mp 155-156° C. HRMS m/z calcd for C15H18N4O (M)+ 270.1481, found 270.1482. Anal. (C15H18N4O.C4H4O4) C, H, N.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].C(N(CC)CC)C.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), methylene chloride (6 mL), triethylamine (0.348 mL, 2.50 mmol), catalytic 4-dimethylaminopyridine, phenacetyl chloride (0.106 g, 0.626 mmol). m.p. dec. 213° C.; 1H NMR (250 MHz, DMSO-d6) δ3.69 (s, 2 H), 6.85 (s, 1 H), 7.29 (m, 4 H), 7.53 (m, 3 H), 7.83 (m, 2 H), 9.40 (bs, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]([C:11](=O)[CH2:12]Br)=[N:8][CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:9]3[NH:10][C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cnc(C(=O)CBr)[nH]1
Product: CCOc1ccc(-c2nc(-c3ncc(C(=O)O)[nH]3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 5-ethoxycarbonyl-2-(α-bromoacetyl)imidazole and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-imidazolyl)thiazole.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH:5]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1.O>C(OCC)(=O)C>[CH:5]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: O=N[O-]
Reactant: c1ccc2c(C3CC3)cccc2c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Yield: 64 %

Procedure:
Sodium nitrite (30 mL) was slowly added (over 2 hours) to 1-cyclopropylnaphthalene (6.4 g, 38 mmol) stirred at 0° C. The reaction mixture was stirred at 0° C. for an extra 30 min and then slowly poured into ice. Water was added, followed by ethyl acetate. After extraction, the organic layer was washed with aqueous sodium hydroxide (1%) and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-cyclopropyl-4-nitronaphthalene (5.2 g, 64%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].CN(C=O)C>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:22]1[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: COc1ccc2nc(Cl)c(C)cc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc3ccc(OC)cc3cc2C)cc1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 25 %

Procedure:
To a mixture of 2-chloro-6-methoxy-3-methylquinoline (100 mg, 0.482 mmol), 4-(methoxycarbonyl)phenylboronic acid (184 mg, 1.02 mmol), TEA (0.35 mL, 2.41 mmol), and PdCl2(dppf) (35 mg, 0.048 mmol) was added 2 mL of DMF under argon. The mixture was then stirred for 2.5 h at 120° C. in a microwave reactor. The crude mixture was then diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organics were washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield 250 mg of crude material. The crude was purified via column chromatography with a gradient of 5% EtOAc in hexanes to 80% EtOAc in hexanes to yield 37 mg (25% yield) of methyl 4-(6-methoxy-3-methylquinolin-2-yl)benzoate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:28])([O:6][C:7]([CH2:9][C:10]1([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:8])[CH3:5].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][C:7]([O:6][C:4]([CH3:28])([CH3:3])[CH3:5])=[O:8])([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]1=[O:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a suspension of 0.05 g of sodium hydride (60%) in 5 ml of N,N-dimethylformamide was added dropwise a solution of 0.36 g of 3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one in 5 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After stirring the mixture at that temperature for 30 minutes, 0.12 ml of benzyl bromide was added thereto. The whole mixture was stirred for 1 hour and then concentrated. Chloroform was added to the concentrate, and the mixture was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 1-benzyl-3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:11][S:12]([NH:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:13]>>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([CH3:10])=[CH:3][C:2]([C:20]2[CH:21]=[C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])[CH:17]=[CH:18][CH:19]=2)=[CH:7]1
Reactant: Cc1cc(Br)cn(C)c1=O
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: Cc1cc(-c2cccc(NS(C)(=O)=O)c2)cn(C)c1=O

Procedure:
5-Bromo-1,3-dimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): 9.74 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.62 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 3.52 (s, 3H), 3.02 (s, 3H), 2.08 (s, 3H). LCMS (M+H)+ 293.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH2:11][CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCCBr
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCN(CCO)c1ccccc1

Procedure:
A mixture of 101 ml (800 mmol) of freshly distilled N-ethylaniline 14, 71.0 ml (1.00 mol) of 2-bromoethanol, 138 g (1.00 mol) of anhydrous K2CO3 and 8.30 g (50.0 mmol) of anhydrous KI is dissolved in 300 ml of dry n-butanol is refluxed for four days under argon atmosphere and vigorously stirring. After cooling down, the inorganic salts are filtered off and washed with diethylether. The solvents are evaporated under reduced pressure and the crude reaction product is purified by means of a vacuum destillation.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:49]=[CH:50][CH:51]=1)[C:43]([NH:45][CH:46]1[CH2:48][CH2:47]1)=[O:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:46]1([NH:45][C:43]([C:42]2[CH:41]=[C:40]([C:33]3[CH:32]=[CH:31][C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][N:9]([C:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:10]=4)[CH:3]([CH3:4])[CH3:5])=[CH:35][CH:34]=3)[CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:48][CH2:47]1
Reactant: O=C(NC1CC1)c1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(O)(c1ccc(-c2cccc(C(=O)NC3CC3)c2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 46.7 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.40 g), 3-bromo-N-cyclopropylbenzamide (1.53 g) and tetrakis(triphenylphosphine)palladium(0) (0.290 g), the title compound (1.84 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:18])[C@H:5]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[I-:19].[Na+]>C(#N)C>[I:19][CH2:2][O:3][C:4](=[O:18])[C@H:5]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of N-BOC-L-isoleucine chloromethyl ester (19.6 g, 70 mmol) in acetonitrile (300 mL), was added sodium iodide (31.5 g, 210 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 2% MeOH in CH2Cl2), to give 22.6 g of N-BOC-L-isoleucine iodomethyl ester.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[O:18])[CH:10]=[CH:11][C:12]1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2]1([CH:1]=[CH:12][CH:11]=[CH:10][CH2:9][OH:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=CC=Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: OCC=CC=Cc1ccccc1

Procedure:
Analysis by GC and MS showed the major component to have m/e 160. Minor impurities included benzaldehyde and cinnamaldehyde. IR (CHCl3): cm-1 3620 (s), 3430 (br, OH), 3020 (s), 1650 (m), 1620 (m), 1600 (m).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH2:14][C:15]([C:17]4[CH:21]=[CH:20][N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH2:14][C:15]([C:17]4[CH:21]=[CH:20][NH:19][CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(F)ccc2/C1=C1/C=C(c2cc[nH]c2)CO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of (3E)-6-fluoro-3-{4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]furan-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one (Example 33; 90 mg) in a mixture of trifluoroacetic acid (7 mL) and CH2Cl2 (7 mL) was stirred at room temperature for 3 days. The mixture was evaporated to dryness, and re-dissolved in 1:1THF/MeOH (6 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-3-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 40 mg.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([O:19][CH3:20])=[N:10][N:11]([CH2:15][C:16](O)=[O:17])[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH3:29]>ClCCl.O1CCOCC1>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([O:19][CH3:20])=[N:10][N:11]([CH2:15][C:16]([NH2:29])=[O:17])[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(=O)O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
The acid of step (b) above (180 mg, 0.6 mmol) was suspended in dichloromethane (5 ml), and oxalyl chloride (150 μl, 1.72 mmol) was added, resulting in gas evolution. The reaction mixture was stirred at room temperature for 1 hour, under nitrogen. The solvent was then evaporated under reduced pressure and the residue was azeotroped with toluene 3 times. The crude intermediate acid chloride was carried straight through to the next step. It was dissolved in tetrahydrofuran (2 ml), and ammonia 0.5M in dioxane (10 ml) was added. After stirring overnight at room temperature, analysis by TLC showed little product had formed. A further portion of fresh 0.5M ammonia in dioxane (10 ml) was added to the reaction mixture and stirring was continued for another overnight period. The reaction mixture was evaporated and the residue was partitioned between dichloromethane (20 ml) and aqueous sodium bicarbonate (10 ml). The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane (10 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate to provide the title compound (20 mg, 17%).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[CH:19]=[CH:18][C:5]([C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cnccc1C(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1C(=O)c1ccc(-n2ccnc2)cc1

Procedure:
A solution of 4-(4-fluorobenzoyl)-3-carbomethoxypyridine (2.05 g, 7.91 mmol) in 20 mL of DMF is added dropwise to NaH (0.37 g, 9.10 mmol) and imidazole (0.54 g, 7.91 mmol) in 35 mL of DMF. Using the same reaction conditions and workup as those used in Example 13, leads to the recovery of crude product. Chromatographic purification on silica gel (using EtOAc-MeOH, 95:5 as the eluent) gives pure 4-[4-(1H-imidazol-1-yl)benzoyl]-3-carbomethoxypyridine. M.P. 135°-137° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.Br.[CH2:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH2:10][CH3:11].[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>C(#N)C>[Cl:18][CH:19]([Cl:23])[C:20]([N:15]1[CH2:16][CH2:17][N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]1)=[O:21]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCCN1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(C(=O)C(Cl)Cl)CC1
Yield: 96.2 %

Procedure:
21 g (0.15 mol) of potassium carbonate were added in portions to a suspension of 14.5 g (0.05 mol) of 1-n-propyl-piperazine dihydrobromide in 200 ml of acetonitrile. 7.4 g (0.05 mol) of dichloroacetyl chloride were added dropwise to this mixture at room temperature, while stirring. The mixture was subsequently stirred at 20° C. for 5 hours and working up was then effected by a procedure in which the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from a mixture of toluene and petroleum ether. 11.5 g (96% of theory) of 1-dichloroacetyl-4-n-propyl-piperazine were obtained in the form of beige-colored crystals of melting point 88° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(I)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(I)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-(4-iodophenyl)-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.