Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[ClH:29].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][Cl:34].C(=O)(O)[O-].[Na+]>CN(C=O)C>[ClH:34].[ClH:29].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][N:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17]1
Reactant: CN(C)CCCl
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)CCN1C=Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)=C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (8.5 g, 0.028 mole), 2-dimethylaminoethyl chloride hydrochloride (6.5 g, 0.045 mole) and sodium bicarbonate (18 g, 0.21 mole) in DMF (125 ml) was stirred at 60° C. for two hours. The reaction mixture was concentrated to a slurry which was stirred with water and extracted with ethyl acetate-ether. The organic extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to an oil (8 g) which was converted to the dihydrochloride salt (66 g, 48% d 170° C.) by the addition of ethereal HCl. This material was recrystallized twice from a 20:1 ethyl acetate/methanol solution to yield 3-(2-dimethylaminoethyl)-1-(p-trifluoromethylphenoxy)-3-benzazepine dihydrochloride, d 237°-238° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[CH3:17][Si:18]([CH3:27])([CH3:26])[C:19]#[C:20][C:21](OCC)=[O:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:21](=[O:22])[C:20]#[C:19][Si:18]([CH3:27])([CH3:26])[CH3:17])=[N:6][CH:7]=1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Reactant: Fc1cccc(F)c1Cc1ccc(Br)cn1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C(c1ccc(Br)cn1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-(2,6-difluorobenzyl)pyridine (5.6 g) in THF was added ethyl 3-(trimethylsily)propynoate (4.2 mL) and LHMD (42 mL, 1N in THF) at −78° C. The mixture was warmed to 0° C. and stirred in additional 2 h. The reaction was complete by TLC and quenched with NH4Cl, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and condensed in vacuo. The crude compound was purified by silica gel (hexanes/methylene chloride) to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].CN(C)C=O.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>O.C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:19][C:6]=2[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:8][CH2:9][C:10]1=[O:12]
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Reaction time: 0.33 h

Procedure:
A mixture of 0.1 mole of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° c. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl bromoacetate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloridemethanol and the like to obtain 7-bromo-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:14]([O:16]C)=[O:15])=[N:10][O:11][C:12]=1[CH3:13])=[O:7])[CH3:4]>O.O1CCCC1>[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:14]([OH:16])=[O:15])=[N:10][O:11][C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(C(=O)OC)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)O)noc1C
Reaction time: 12 h
Yield: 70 %

Procedure:
At -15° to -10° C. and under a nitrogen blanket, 4.7 g (0.117 mol) of sodium hydroxide in 80 ml of water was dripped into 25.0 g (0.117 mol) of methyl 4-ethoxycarbonyl-5-methylisoxazole-3-carboxylate in 200 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 12 hours. The solvents were stripped off in a rotary evaporator (bath temperature: 30°-35° C.), the residue was taken up in 250 ml of water, the pH was adjusted to 8-9 with hydrochloric acid, and the mixture was extracted twice, each time with 150 ml of diethylether. The aqueous phase was acidified to a pH of 2 with 6N HCl and extracted four times, each time with 250 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 70%; 1H-NMR (250 MHz; CDCl3); δ=1.42 ppm (t; 3H), 2.80 ppm (s; 3H), 4.59 ppm (q; 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:36])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32](O)=[O:33])=[N:20][C:19]=2[CH3:35])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:46]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Br:31][C:26]1[CH:25]=[C:24]2[C:29]([C:30]3[C:18]([C:14]4[C:13]([CH3:36])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:17]=[CH:16][CH:15]=4)=[C:19]([CH3:35])[N:20]=[C:21]([C:32](=[O:33])[NH2:46])[C:22]=3[NH:23]2)=[CH:28][CH:27]=1
Reactant: Cc1nc(C(=O)O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(NC(=O)OCc2ccccc2)c1C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(NC(=O)OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylic acid (1.10 g, 2.02 mmol), ammonium chloride (0.432 g, 8.08 mmol), BOP (1.16 g, 2.63 mmol), N-methylmorpholine (0.866 mL, 7.88 mmol), and diisopropylethylamine (1.69 mL, 9.70 mmol) in N,N-dimethylformamide (10.0 mL) was stirred at room temperature for 4 h. The reaction mixture was added dropwise to rapidly stirring water (100 mL). After stirring for 60 min., the suspension was filtered under reduced pressure, and the solid was washed with water and dried well under reduced pressure to give benzyl (3-(7-bromo-1-carbamoyl-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenyl)carbamate as a light brown solid. LC/MS M+1=543.4 and 545.4. The reaction mixture was used in the next step without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:9][CH:10]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])=[CH:6][CH:7]=1
Reactant: O=C1CCCCN1
Reactant: Fc1ccccc1-c1ccc(CCCBr)cn1
Product: O=C1CCCCN1CCCc1ccc(-c2ccccc2F)nc1

Procedure:
50 mg (0.17 mmol) of 5-(3-bromopropyl)-2-(2-fluorophenyl)pyridine were reacted with 18.5 mg (0.18 mmol) of piperidin-2-one analogously to example 1d). Yield: 16 mg (31%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C@@H:43]([CH2:54][CH3:55])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])(=O)=O.C(OCC)(=O)C>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C@H:43]([CH2:54][CH3:55])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Reactant: CC[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a solution of N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (52 mg) in acetonitrile (5 mL), potassium carbonate (18 mg) in a powder form was added at room temperature, and the resulting mixture was stirred for 10 minutes. A solution of benzyl (S)-2-trifluoromethanesulfonyloxybutyrate (50 mg) in acetonitrile (2 mL) was added dropwise to the reaction liquor, and the mixture was stirred at the same temperature for 18 hours. Ethyl acetate (50 mL) was added to the reaction liquor, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain a colorless oil (73 mg, 98.3%).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1COCC1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:19][CH:18]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To tributyltin chloride (652 mg, 2.00 mmol, 1.00 equiv) in THF (2 mL) at 23° C. was added 4-methoxyphenylmagnesium bromide (0.50 M in THF, 8.0 mL, 4.0 mmol, 2.0 equiv). After stirring for 1.0 hr at 60° C., the reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl (10 mL), and Et2O (10 mL) was added. The phases were separated and the aqueous phase was extracted with Et2O (2×10 mL). The combined organic phases were washed with brine (10 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by fractional distillation to afford 637 mg of the title compound as a colorless oil (80% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.BrCCBr.[Mg].[Br:19][C:20]1[CH:21]=[C:22]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=2)=O)[CH:23]=[CH:24][CH:25]=1>C1COCC1.COCCOC.C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:21]=[C:22]([C:26]2([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: COCCOC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Brc1cccc(C2(c3cccc(Br)c3)c3ccccc3-c3ccccc32)c1

Procedure:
62.9 g (270 mmol) of 2-bromobiphenyl mixed with 400 ml of THF, 550 ml of toluene, 45 ml of 1,2-dimethoxyethane and 2.6 ml of 1,2-dibromoethane are reacted with 6.6 g (250 mmol) of magnesium to give the corresponding Grignard compound. A solution of 60.0 g (176 mmol) of bis(3-bromophenyl) ketone in 600 ml of THF is added dropwise to the cooled Grignard solution. When the addition is complete, the reaction mixture is heated under reflux for 4 h, the solvent is then removed in vacuo, the residue is dissolved in 700 ml of glacial acetic acid, 10 ml of hydrogen bromide in 30% glacial acetic acid are added, and the mixture is heated under reflux for 6 h. After cooling with stirring, the precipitated solid is filtered off with suction, washed twice with 200 ml of glacial acetic acid each time and three times with 300 ml of ethanol each time and then dried in vacuo. Yield: 69.0 g (145 mmol), 82.1%, 99% pure according to 1H-NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([OH:42])([CH3:41])[CH2:39]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][C:38]([OH:42])([CH3:41])[CH3:39])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CC(C)(O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, substituting 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-methyl-1,2-propanediol in place of 2-ethyl-1-hexanol (yield: 55 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (s, 6H), 3.30 (s, 3H), 4.20 (s, 2H), 4.54 (s, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.98 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (APCI+) m/z 451 (M+H)+; (APCI−) m/z 485 (M+Cl)−; Anal. calc. for C21H20F2N2O5S: C, 55.99; H, 4.47; N, 6.21. Found: C, 56.00; H, 4.48; N, 5.87.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[CH:10]([OH:20])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[CH2:1]([NH:8][C:9](=[O:21])[C:10]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)C(O)c1ccc(O)c(OC)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCCCCNC(=O)C(=O)c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.1 %

Procedure:
Manganese oxide 60% (4.5 g, 31 mmol) was added to a stirred solution of N-heptyl-2-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-acetamide (0.5 g, 1.7 mmol) in chloroform (50 ml) at room temperature. The resulting mixture was stirred at room temperature for 24 hrs. filtered, and centrifuged to remove the remaining of manganese oxide. The filtrate was concentrated in vacuum. The crude product was chromatographed on a silica gel column using ethyl acetate/heptane (2:3) as eluent to provide the title compound (0.15 g, 30% yield) as pale yellow crystals.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:21][CH3:22])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:23]1([C@@H:29]([NH2:31])[CH3:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:23]1([C@@H:29]([NH:31][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][CH3:6])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH3:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(OC)cc(C(=O)N[C@@H](C)C2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a mixture of 5 ml of THF and 0.38 g of 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride were added 0.21 g of (1S)-1-(cyclohexyl)ethylamine and 0.23 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.42 g of N-((1S)-1-cyclohexylethyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 23 of the present invention) represented by the formula:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:15])[CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:14]([O:13][C:7]1[CH:6]=[C:5]([C@H:4]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:17]2)[CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[CH3:15]
Reactant: CCOc1cc([C@@H](CCN)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCNS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 1.1 mmol) and triethylamine (0.3 mL, 2 mmol) in methylene chloride (10 mL) was added methane sulfonyl chloride (0.10 mL, 1.3 mmol) at 0° C. After 3 hrs, the mixture was extracted with methylene chloride (20 mL) and water (20 mL). The organic layer was washed with HCl (1N, 20 mL), sodium hydrogen carbonate (sat 20 mL), brine (20 mL), and dried over MgSO4. The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silca Gel) to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (320 mg, 58% yield): mp, 93-95° C.; 1H NMR (CDCl3) δ 0.89-0.93 (m, 2H, CH2), 1.08-1.10 (m, 2H, CH2), 1.42 (t, J=7 Hz, 3H, CH3), 1.65-1.72 (m, 1H, CH), 2.27-2.32 (m, 2H, CH2), 2.94 (s, 3H, CH3), 2.97-3.06 (m, 1H, CHH), 3.85 (s, 3H, CH3), 3.50 (d, J=17 Hz, 1H, NCHH), 4.04 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=17 Hz, 1H, NCHH), 5.51 (dd, J=6, 9 Hz, 1H, NCH), 5.60-5.62 (m, 1H, NH), 6.8-6.99 (m, 4H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (CDCl3) δ 8.35, 14.76, 16.19, 32.26, 40.24, 40.65, 46.05, 51.12, 55.98, 64.63, 111.50, 112.83, 116.86, 116.94, 117.84, 119.64, 130.31, 133.43, 138.02, 141.44, 148.72, 149.41, 170.07, 172.72; Anal Calcd for C25H31N3O6S+0.35H2O: C, 59.12; H, 6.29; N, 8.27, H2O 1.26. Found: C, 59.42; H, 6.16; N, 8.05, H2O 1.24.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([F:24])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([F:24])[CH:17]=1
Reactant: OCc1ccc(Cl)cc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.72 (1H, d, J=1.6 Hz), 7.07-7.13 (2H, m), 7.33-7.41 (2H, m), 7.51 (1H, d, J=2.0 Hz), 7.95 (1H, s), 8.62 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]([CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[OH:31]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:33]4[CH2:34][CH2:35][CH2:36][C@@H:32]4[C@H:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)[OH:31])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccco1)C1CCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC[C@@H]3[C@@H](O)c3ccco3)sc21

Procedure:
Analogous to the procedures described in Example 2, N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1) is treated with 2-furyl(pyrrolidin-2-yl)methanol (Preparation 4) to afford the title compound
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[C:15]([CH3:21])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:36]1(=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][CH3:12])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:36]3([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:15]([CH3:21])[CH:14]=2)[CH2:22][CH3:23])=[CH:6][C:5]=1[CH3:24]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C
Reactant: O=C1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a −78 C solution of 4-[1-Ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (2.50 g, 7.47 mmol) in THF (80 ml) is added lithium hexamethyldisilazide (8.22 ml, 8.22 mmol, 1.0 M in THF) and stirred at −78 C for 30 min. Cyclopentanone (730 μL, 8.22 mmol) is added and the reaction mixture warmed to room temperature. The reaction is quenched with saturated aqueous NH4Cl (30 ml) and concentrated. The residue is partitioned between EtOAc (300 ml) and 1.0N HCl (50 ml). The aqueous layer is extracted with EtOAc (100 ml). The combined organic layer are washed with water (50 ml), brine (50 ml), dried (MgSO4), concentrated and chromatographed (120 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (2.45 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:25])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([O:25][C:37](=[O:39])[CH3:38])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a 25 mL round-bottom flask equipped with a magnetic stir bar was added 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.65 g, 1.7 mmol), THF (5 mL), triethylamine (0.52 g, 5.1 mmol) and acetic anhydride (0.22 g, 2.2 mmol). To the stirred suspension was then added DMAP (0.002 g, 0.02 mmol). After 1 hour, all reaction components were fully dissolved and the reaction was complete as determined by TLC analysis. To the reaction mixture was added saturated aqueous ammonium chloride (20 mL) and the solution was extracted with ethyl acetate (2×20 mL). The organic fractions were collected, washed with brine (1×20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was further purified by silica gel chromatography, eluting with 2% methanol:DCM to provide acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.404 g, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ ppm 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37-7.34 (m, 3H), 7.25 (td, 1H, J1=2.7 Hz, J2=8.2 Hz), 6.34 (app d, 1H, J=6.3 Hz), 6.17 (ddd, 1H, J1=6.3 Hz, J2=10.2 Hz, J3=16.8 Hz), 5.41 (app d, 1H, J=17.2 Hz), 5.33 (app d, 1H, J=10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); ESMS (m/z): found, 435.