Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7]N)=[CH:3][CH:2]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[C:14]([CH3:29])([CH2:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13]1>>[CH3:11][N:12]1[CH2:17][C:16]2[C:3]3[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][C:4]=3[N:7]3[C:15]=2[C:14]([CH3:29])([CH2:19][CH:20]=[C:21]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13]1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)C(C)(CCC(=O)c2ccccc2)C1
Agent: Cl
Product: Cc1ccc2c(c1)c1c3n2C(c2ccccc2)=CCC3(C)CN(C)C1

Procedure:
A solution of p-tolylhydrazine.HCl (13 mg, 0.084 mmol) and 1,3-dimethyl-3-(3-oxo-3-phenyl-propyl)-piperidin-4-one (22 mg, 0.084 mmol) in ethanolic-HCl (5 mL) was stirred at 84° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was basified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×15 mL), organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to obtain 2,3a,10-trimethyl-6-phenyl-2,3,3a,4-tetrahydro-1H-indolo[3,2,1-ij][1,6]naphthyridine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]([O:19]CC)=O)[CH2:6]1)(=[O:4])=[O:3].[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>CCO.CO>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:17](=[O:19])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]2
Reactant: CCOC(=O)COc1cccc2c1CCN(S(C)(=O)=O)C2
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(cccc2OCC(=O)NCC(O)CN2CCc3ccccc3C2)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
A mixture of ethyl 2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetate (140 mg, 0.447 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (184 mg, 0.89 mmol) in EtOH (0.2 mL) was stirred at 120° C. for 30 min under microwave conditions. The mixture was diluted with MeOH and purified by prep-HPLC to afford N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetamide (53.5 mg, 25%). 1H NMR (400 MHz, MeOD) δ 0.84 (s, 1H), 7.29-7.15 (m, 5H), 6.80 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.41 (s, 2H), 4.35-4.17 (m, 3H), 3.54 (t, J=6.1 Hz, 2H), 3.48-3.38 (m, 4H), 3.17-3.04 (m, 4H), 2.98 (t, J=6.0 Hz, 2H), 2.92 (s, 3H). LCMS (m/z): 474.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1.O>C1COCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[NH:1][CH2:2]/[CH:3]=[C:4]2\[CH2:5][CH2:6][CH2:7][C:8]3[C:13]\2=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[CH:20][CH:19]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1ccc2c(c1)C(=CCN)CCC2
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(=O)NC/C=C2\CCCc3ccc(OC)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 1-(2-aminoethylidene)-7-methoxy-1,2,3,4-tetrahydronaphthalene (3.0 g, 14.8 mmol) in THF (20 ml) was gradually added dropwise, under ice cooling, 4-methoxyphenyl isocyanate (2.2 g, 14.8 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was then poured into water. The organic layer was subjected to extraction with 10% methanol/chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=6:4), followed by recrystallization from ethyl acetate/methanol to give the above-titled compound (2.8 g, yield 54%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2cccc(CC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a mixture of methyl 2-[3-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]acetate (1.10 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5.0 mL) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and water and dilute hydrochloric acid were added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.85 g, 80%) of 2-[3-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)=[O:9])=[CH:4][CH:3]=1.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[C:16]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])[S:15][C:14]=23)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ncn3ccsc23)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3ccc(C)nc3)c2s1

Procedure:
The title compound (606 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 447 mg of 7-(6-methylpyridin-3-yl)carbonylimidazo[5,1-b]thiazole, 0.552 ml of tri-n-butylstannyl chloride, and 3.2 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([C:11]2[C:15]([F:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)[C:8]([Cl:22])=[CH:7][C:6]=1[Cl:23].[C:25](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>>[CH3:1][O:2][N:3]=[C:4]([O:24][CH3:25])[C:5]1[CH:10]=[C:9]([C:11]2[C:15]([F:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)[C:8]([Cl:22])=[CH:7][C:6]=1[Cl:23]
Reactant: CONC(=O)c1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CON=C(OC)c1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl

Procedure:
Using 0.5 g (1.3 mmol) of N-methoxy-2,4-dichloro-5-(5-difluoromethoxy-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzamide, 0.21 g (1.6 mmol) of potassium carbonate and 0.20 g (1.6 mmol) of dimethyl sulfate and following the procedure described in Example 1, 0.17 g of the desired produce of value was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:38]=1>CN(C=O)C>[C:49]([O:48][C:46]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:38]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a stirring solution of 437.3 mg 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (0.95 mmol) in 10 mL DMF at 0° C. is added 2.09 mL (1.04 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2. The reaction is allowed to warm to RT, then cooled back down to 0° C., and 325 mg (1.04 mmol, 1.1 equiv) 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is then added in one portion. The reaction is allowed to warm to RT, and is stirred an additional 20 min. The reaction is then concentrated, diluted with H2O, and the aqueous layer is extracted with ethyl acetate (3×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 1:1-2:1 ethyl acetate:hexanes) to afford 487 mg of the title compound as a pale yellow foam: 1H NMR (CDCl3, 400 MHz) δ8.58 (s, br, 2H), 8.01 (d, 1H, J=8.4), 7.93 (d, 1H, J=7.8), 7.47 (t, 1H, J=7.5), 7.38-7.26 (m, 4H) 7.26-7.11 (m, 4H), 6.94 (dd, 2H, J=8.7, 11.8), 4.94 (m, 1H), 4.39 (s, br, 1H), 4.32 (dd, 1H, J=4.9, 8.5), 4.16 (d, 1H, J=16.6), 3.83 (s, 3H), 3.80 (m, 1H), 3.52 (dd, 1H, J=5.1, 16.5), 1.62 (s, 9H), 1.03 (d, 6H, J=6.9); low resolution MS (FAB)m/e 689 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([CH:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)=O)[CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(C(=O)N2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCC(CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidine-1-carbonyl]-cyclohexanone (27 mg, 0.070 mmol) was dissolved in 1 mL of THF and excess lithium aluminum hydride (27 mg, ca. 10 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 0.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 4-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-ylmethyl]-cyclohexanol, 188, (16 mg, 61%) was obtained. Data for this compound: MS 372 (M++1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([F:40])[CH:34]=3)=[N:24]2)[CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:41][C:42]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])[CH3:43].N1C=CN=C1>CN(C)C=O.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([O:39][Si:45]([C:42]([CH3:44])([CH3:43])[CH3:41])([CH3:47])[CH3:46])[CH:38]=3)=[N:24]2)[CH3:22])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(O)cc(F)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(F)cc(O[Si](C)(C)C(C)(C)C)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one (Example 72, 726 mg, 1.343 mmol) was dissolved in N,N-Dimethylformamide (7.5 ml), followed by the addition of TBDMSCl (405 mg, 2.69 mmol) and imidazole (366 mg, 5.37 mmol). The mixture stirred for 3 hrs at rt, then further 0.3 eq of TBDMSCl and imidazole were added to achieve full reaction completion The reaction was diluted with DCM (100 ml) and washed twice with 0.5M HClaqueous (50 ml), filtered through a phase separator, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and EtOH to give the title compound (635 mg, 72.2%) as pinky foam.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2ccccc2Cl)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1onc(C(=O)c2ccccc2Cl)c1NC(=O)CBr
Reaction time: 1 h

Procedure:
Bromoacetylbromide (42 g, 210 mmoles) was added slowly to a mixture of (4-amino-5-methylisoxazol-3-yl)-2-chlorophenylmethanone of Example IIIb (24.8 g, 105 mmoles) in dichloromethane (300 ml) with 2N sodium carbonate (200 ml) and saturated sodium bicarbonate (500 ml) at 5° C. After stirring for 1 hour, the mixture was diluted with dichloromethane (400 ml) and water (400 ml). The organics were washed with water, saturated sodium chloride, dried (sodium sulfate) and evaporated to give 36 g of an oil. The residue (5.2 g) was flash chromatographed (25% ethyl acetate:hexane) to yield 4.5 g (85%) of an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][NH2:6])=[O:4].C(=O)(O)[O-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1.O>[C:14]([NH:6][NH:5][C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethyl-propionic acid hydrazide (2.32 g, 20 mmol), sodium bicarbonate (1.68 g, 20 mmol) in tetrahydrofuran and water (1:1, 40 mL) was added acetyl chloride (1.56 g, 20 mmol) dropwise. The mixture was stirred overnight and concentrated in vacuo. The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give a white solid. The solid was recrystallized from tetrahydrofuran and hexane (1:8) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.14 (m, 9 H) 1.83 (s, 3 H) 9.28 (br s, 1 H) 9.53 (br s, 1 H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC.[O:28]1[C:32]2=[CH:33][C:34]3[C:35]([C:40]#[N:41])=[CH:36][NH:37][C:38]=3[CH:39]=[C:31]2[O:30][CH2:29]1>C1(C)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:37]2[C:38]3[CH:39]=[C:31]4[O:30][CH2:29][O:28][C:32]4=[CH:33][C:34]=3[C:35]([C:40]#[N:41])=[CH:36]2)=[CH:3][CH:4]=1
Reactant: N#Cc1c[nH]c2cc3c(cc12)OCO3
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cc(C#N)c3cc4c(cc32)OCO4)cc1

Procedure:
A mixture of p-iodoanisole (85 mg, 0.36 mmol), anhydrous K3PO4 (102 mg, 0.48 mmol), CuI (4.6 mg, 0.024 mmol) and N,N′-Dimethyl cyclohexane-1,2-diamine (14 mg, 0.096 mmol) was added to 5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (45 mg, 0.24 mmol), prepared as described by the method of example 1A, step A, in anhydrous toluene (0.4 mL). After heating at reflux for 24 h, the solvent was evaporated under vacuum. The residue was dissolved with CH2Cl2 (5 mL) and the mixture was filtered. The filtrate was concentrated to afford crude product, which was purified by silica gel chromatography using EtOAc/petroleum ether (1:4) as eluent to yield 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:40]([C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=2)=[O:41])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCN)CCCC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCNC(=O)c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[2-[[(3-trifluoromethylphenyl)-carbonyl]amino]ethyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-aminoethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester and 3-trifluoromethylbenzoyl chloride using the general method described in example 205 to give a 99% yield of a white solid. HR MS C33H32Cl2N3O5): Obs. mass, 700.1596. Calcd. mass, 700.1569 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])=[CH:9][CH:8]=[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[CH2:28]([O:30][CH2:31][C:32](Cl)=O)[CH3:29].C(N(CC)CC)C>>[CH2:28]([O:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:29]
Reactant: Nc1cnc2cc(-c3ccccc3)ccc2c1NCCCN1CCCC1=O
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCN1CCCC1=O
Yield: 56.7 %

Procedure:
1-[3-(3-Amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (2.21 g, 6.13 mmol) was treated with ethoxyacetyl chloride (0.95 mL, 8.76 mmol) according to the methods described in Parts C and D of Examples 152-156. Triethylamine (8.6 mmol) was added in Part C. The product from Part D was purified by column chromatography on silica gel (eluting with acetone and then chloroform:methanol in a gradient from 95:5 to 90:10) to provide 1.49 g of 1-[3-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a brown solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([NH:33][C:32]2[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:31]=2[CH3:30])=[O:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:4])[CH3:3])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Nc1c(C)cccc1C
Temperature: 10 °C
Reaction time: 12 h

Procedure:
The title compound of Example 11 (2.3 g, 0.0068 mole) was dissolved in benzene and the solution cooled to 10° C. in an ice bath. A solution of oxalyl chloride (1.14 g, 0.009 mole) in benzene (10 ml) was added dropwise over a period of 20 minutes. The ice bath was removed and the solution stirred at room temperature for 12 hours. The benzene was removed, fresh benzene (10 ml) added and the procedure repeated. The residue was taken up in benzene and a solution of 2,6-dimethylaniline (0.84 g, 0.007 mole) in benzene (25 ml) added over a period of 20 minutes, followed by the dropwise addition of a solution of triethylamine (1 ml). The solution was stirred for 4 hours and the benzene removed. The residue was taken up in ethyl ether (100 ml), stirred, and the white solid filtered. The filtrate was stripped and the product purified by chromatography on silica. The product was recrystallized from ethyl acetate/hexane, filtered and dried, m.p. ca. 137°-139.5° C.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=[CH:3]1.[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=4)[N:4]=[CH:3]3)=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: Nn1cnc2ccc(Cl)cc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccc(Cl)cc2c1=O

Procedure:
3-Amino-6-chloro-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.70 (m, 12H), 1.93-1.98 (m, 3H), 2.10 (s, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 11.18 (s, 1H) ppm; MS (DCI/NH3) m/z 372 (M+H)+; Elemental Analysis: Calculated for C20H22ClN3O2.0.2H2O: C, 63.98; H, 6.01; N, 11.19. Found: C, 3.87; H, 5.85; N, 11.14.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li][CH2:17]CCC.COS(OC)(=O)=O.Cl>CCOCC>[CH3:17][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: Cc1cc2ccccc2c2ccccc12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
9-Bromophenanthrene (27 g, 102 mmol) was dissolved in 400 mL of dry ether and cooled to −78° C. 170 mL of BuLi (1.6 M in hexane) was slowly added into this solution in 45 minutes. The reaction mixture was warmed to room temperature. The mixture was then stirred at room temperature for 2 h before it was cooled to −78° C. again and Me2SO4 (17.6 g, 133 mmol) in ether was slowly added. The mixture was stirred at room temperature for 10 h. The mixture was poured into 15% HCl aqueous solution and extracted with CH2Cl2 and dried over MgSO4. The solvent was evaporated to give a residue which was recrystallized from hexane to yield 14.2 g of product as a white solid.