Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.O>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:25])=[O:24]
Reactant: Nc1cc(O)ccc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
20.1 g of 3-amino-4-phenoxyphenol and 23.7 g of pyridine were dissolved in 200 ml of methylene chloride. To the resulting solution being ice-cooled was dropwise added a solution of 12.6 g of methanesulfonyl chloride in 60 ml of methylene chloride, at the same temperature in 30 minutes. The mixture was subjected to reaction at the same temperature for 2 hours. 200 ml of water was added thereto and then 4N hydrochloric acid was added to adjust the pH to 3. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. Thereafter, the organic layer was subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from benzene to obtain 23.7 g (yield: 84.9%) of 3-methylsulfonylamino-4-phenoxyphenol having a melting point of 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:7]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][C:31]1[N:32]=[CH:33][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:35][CH:36]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:48][C:45]2[CH:46]=[C:47]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][N:39]=[C:38]3[NH:37][C:34]2[CH:33]=[N:32][C:31]([CH3:30])=[CH:36][N:35]=2)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:7]=1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: CCOC(COc1cnc(F)c(Cl)c1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Oc2ccc3ncnc(Nc4cnc(C)cn4)c3c2)c(Cl)c1)OCC
Temperature: 25 °C
Yield: 53 %

Procedure:
3-Chloro-5-(2,2-diethoxyethoxy)-2-fluoropyridine (460 mg, 1.74 mmol) and potassium tert-butoxide (160 mg, 1.4 mmol) were added to an N,N-dimethylacetamide suspension (0.9 ml) of 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol (180 mg, 0.71 mmol), and reacted under a nitrogen atmosphere at 200° C. for 30 minutes, using microwaves. The reaction solution was cooled to room temperature, then diluted with chloroform. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain 6-{[3-chloro-5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazoline-4-amine (187 mg, yield: 53%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:27]([N:46]1[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2[CH:64]=[CH:63][C:60]([CH2:61]Br)=[CH:59][CH:58]=2)=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[N:8]([CH2:61][C:60]2[CH:59]=[CH:58][C:57]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[C:50]3[N:46]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:47]=[N:48][N:49]=3)=[CH:64][CH:63]=2)[C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 78.1 %

Procedure:
Following a procedure similar to that described in Example 82(a), but using 189 mg of propyl 4-(1-hydroxy-1-methylethyl)-2-propoxymethylimidazole-5-carboxylate [prepared as described in Preparation 45(iii)], 78 mg of potassium t-butoxide and 445 mg of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide as starting materials and then purifying the product by column chromatography through silica gel using a 1:1 mixture of hexane and ethyl acetate as the eluent, 395 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[H-].[Na+].[CH2:33](Br)[C:34]#[CH:35]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:35][C:34]#[CH:33])[C:9](=[O:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: C#CCBr
Reactant: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C#CCN(C(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccnc(CC)c1Cl
Temperature: 25 °C

Procedure:
1.0 g (2.3 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetamide was dissolved in 5 ml of N,N-dimethylacetamide, and the solution was stirred at room temperature. Then, 0.067 g (2.8 mmol) of sodium hydride was gradually added thereto, and the mixture was further stirred for one hour at room temperature. Then, 10.3 (2.5 mmol) of propargyl bromide was added thereto, and the mixture was stirred for one hour at room temperature. Then, 0.3 g (2.5 mmol) of propargyl bromide was further added thereto, and the mixture was stirred for one hour at a temperature of from 50° to 60° C. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then purified by high performance liquid chromatography to obtain 0.5 g of the desired product as a brown viscous substance (refractive index nD20 =1.35619).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:56])([CH3:55])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[N:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:55])([CH3:56])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([C:51]([F:53])([F:52])[F:54])[N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C(F)(F)F)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C(F)(F)F)nn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (344 mg), sodium hydrogen carbonate (554 mg) and dimethyl sulfoxide (2 mL) was stirred at 60° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (200 mg) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (65 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (61 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→25/75 (volume ratio)] to give the title compound as a colorless amorphous compound (149 mg, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][C:10]2([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Sn](Cl)(Cl)(Cl)Cl.C([O:26][CH2:27][CH3:28])(=O)C.[CH:29]1[CH:34]=CC=C[CH:30]=1>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([C:27](=[O:26])[CH2:28][CH2:30][CH2:29][CH3:34])[CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][C:10]2([CH3:16])[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccccc1
Reactant: CC(C)(C)c1cccc2c1SCCC2(C)C
Reactant: CCOC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To 500 mg (2.1 mmol) of 8-tert-butyl-4,4-dimethylthiochromane and 0.29 mL (2.34 mmol) of pentlanoyl chloride in 10 mL benzene at 0° C. is added 0.27 mL (2.34 mmol) of tin tetrachloride. The reaction is allowed to stir 1 hour at 0° C. and is then diluted with ether and washed with water and 10% sodium chloride. The product is purified by flash silica gel chromatography, eluting with 7:3 hexane:ethyl acetate to give 250 mg (37% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:21]=[O:22])[S:5][CH:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1csc(C=O)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-Ethylthiophene (2 g, 17.8 mmol) dissolved in diethyl ether (18 ml) was added with a solution of n-butyl lithium in hexane (1.5 M, 14 ml, 21.4 mmol) at room temperature and refluxed by heating at 60° C. for 15 minutes. The reaction solution was returned to room temperature and added dropwise with dimethylformamide (2 ml, 23.2 mmol) dissolved in diethyl ether. After the reaction solution was stirred for 2 hours at room temperature, the reaction was stopped with saturated aqueous ammonium chloride, and the reaction solution was extracted with chloroform. The collected organic layer was washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[OH-].[K+].[CH3:15]I>CC(C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To 5-nitroindoline (1.0 g, 6.1 mmol) in acetone (12 ml), powdered potassium hydroxide (1.7 g, 30.5 mmol, 5 eq) was added followed by the addition of methyl iodide (1.2 g, 9.1 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and water was added and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to yield 1-methyl-5-nitro-2,3-dihydro-1H-indole (1.0 g, 92%). The crude compound was used in the next stage without purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:28]C1C=CC=CC=1)[CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[N:19]=2)[C:14](=[O:22])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]1)C1C=CC=CC=1.C(N(CC1C=CC=CC=1)CCBr)C1C=CC=CC=1>>[CH3:28][N:8]([CH3:1])[CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[N:19]=2)[C:14](=[O:22])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]1
Reactant: CCOC(=O)c1cn(CCN(Cc2ccccc2)Cc2ccccc2)c2nc(C)ccc2c1=O
Agent: BrCCN(Cc1ccccc1)Cc1ccccc1
Product: CCOC(=O)c1cn(CCN(C)C)c2nc(C)ccc2c1=O

Procedure:
1-[2-(Dibenzylamino)ethyl]-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p. 170°-174° (72 %) (2-Dibenzylaminoethyl bromide).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][NH2:52])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:52][CH2:51][CH:48]3[CH2:49][CH2:50][O:45][CH2:46][CH2:47]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Reactant: NCC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Yield: 81.7 %

Procedure:
Combined 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid (30 mg, 0.096 mmol), EDCI (27.6 mg, 0.144 mmol), HOBT (19.47 mg, 0.144 mmol), and DMF (961 μl), then added (tetrahydro-2H-pyran-4-yl)methanamine (17.66 μl, 0.144 mmol) and Hunig's base (68.3 μl, 0.384 mmol) and stirred at room temperature overnight. The reaction mixture was purified via preparative HPLC to give the title compound (32.1 mg, 82%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.35 (qd, J=12.38, 4.55 Hz, 2 H) 1.71 (d, J=12.88 Hz, 2 H) 1.84-1.99 (m, 1 H) 3.42 (td, J=11.68, 1.64 Hz, 2 H) 3.95 (d, J=3.28 Hz, 1 H) 3.98 (s, 3 H) 4.19 (s, 3 H) 7.76 (d, J=6.57 Hz, 1 H) 7.84 (s, 1 H) 8.03 (d, J=6.57 Hz, 1 H) 8.28-8.47 (m, 2 H) 8.55 (br. s., 1 H) 8.85 (br. s., 1 H). MS m/z [M+H]+ 410.1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.[CH:22]1[CH:23]=[CH:24]C2N(O)N=[N:28][C:26]=2[CH:27]=1.C(N(C(C)C)CC)(C)C.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[C:46]1[N:50]=[C:49](N2CCCCC2)[O:48][N:47]=1>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:28]1[CH2:24][CH2:23][CH:22]([C:49]2[O:48][N:47]=[C:46]([C:42]3[S:41][CH:45]=[CH:44][CH:43]=3)[N:50]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCCC(F)(F)F
Reactant: c1csc(-c2noc(N3CCCCC3)n2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC(F)(F)F)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-[(3-(thien-2-yl)-1,2,4-oxadiazol-5-yl]-piperidine (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 83%; 1H NMR (CD2Cl2) δ 7.80 (dd, J=1.2 Hz, J=3.6 Hz, 1H), 7.56 (dd, J=1.2 Hz, J=5.0 Hz, 1H), 7.19 (dd, J=3.6 Hz, J=5.0 Hz, 1H), 4.48-4.55 (m, 1H), 3.87-3.95 (m, 1H), 3.19-3.33 (m, 2H), 2.89-3.00 (m, 1H), 2.44 (t, J=7.3 Hz, 2H), 2.15-2.31 (m, 4H), 1.86-1.96 (m, 4H). tR LCMS 6.1 min. Purity >99%; MS [M+H]+ m/z 374.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6](F)[CH:7]=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30](CCC[CH:34]2[NH2:37])=[CH:29][CH:28]=1.C(N(CCC)[C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([CH2:53]C)[CH:52]=1)C(O)=O)=O)CC>>[CH2:9]([C@H:10]([NH:14][C:15](=[O:24])[C:46]1[CH:50]=[C:51]([CH3:53])[CH:52]=[C:44]([CH3:42])[CH:45]=1)[C@H:11]([OH:12])[CH2:13][NH:37][CH2:34][C:35]1[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:36]=1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: COc1ccc2c(c1)C(N)CCC2
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C)cc(C)c2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl 1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and 3,5-dimethylbenzoic acid (IX), the title compound is obtained, MH+=433.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Na].O>C(O)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1CCc2ccccc2N1
Temperature: 25 °C

Procedure:
2-Methylquinoline (10 g, 0.070 mol) was refluxed in 250 ml ethanol. While refluxing, sodium (22.9 g, 1.0 mol) was added cautiously over a period of 1 hour. The mixture was refluxed for an additional 3.5 hours, cooled to room temperature, poured into 500 ml H2O, and extracted 3×500 ml toluene. The organic layers were combined, dried (K2CO3) and stripped to yield title produce as an oil, 9.2 g.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26])=O)(C)(C)C.Cl.C(Cl)[Cl:29].[NH4+].[OH-]>C(OCC)(=O)C.CO>[ClH:29].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of the compound of Example 38 (4.00 g, 0.0110 mole) in 10 mL of ethyl acetate at room temperature was added 5N HCl in ethyl acetate (50 mL, freshly prepared, 0.25 mole) in one portion. The solution was stirred for 3 hrs, solvent was evaporated, CH2Cl2 was added and the solvents were reevaporated. The residue was pumped at <1 mm Hg on a vacuum pump for 24 hours to afford 3.37 g (~Quantitative crude yield) of product as a colorless foam. TLC (silica gel; CH2Cl2, methanol, conc. NH4OH: 27:3:1): Rf=0.32.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([F:17])=[C:10]([C:8]2[CH2:7][N:6]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[O:39][CH3:40])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:9]=2)[CH:15]=1
Reactant: COC(=O)Cl
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCCC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)CN1C(=O)N(C)C
Reaction time: 8 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in CH2Cl2 was added 21 μL (0.15 mmol) of triethylamine and 5.8 μL (0.10 mmol) of methyl chloroformate. After stirring overnight the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 22-1 as a white solid. Data for 22-1: 1HNMR (500 MHz, d6-DMSO) δ 7.6 (m, 1H), 7.5-7.1 (m, 8H), 6.2 (s, 1H), 4.95 (m, 1H), 4.7 (m, 1H), 3.55 (s, 3H), 3.0 (m, 2H), 2.7 (s, 6H), 2.7-2.5 (m, 1H), 2.05 (m, 1H), 1.4 (m, 2H) ppm. HRMS (ES) calc'd M+H for C24H27ClFN3O3: 460.1798. Found: 460.1797.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Nc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 34.3 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 5-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 78 mg of the target compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1B(O)O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:3]=[CH:4][C:5]=2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[CH3:14])[N:10]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1ccncc1B(O)O
Product: Cc1csc(Nc2ncc(-c3cnccc3C)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=348.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 4-methylpyridine-3-boronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:14]([Cl:21])=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([OH:24])=[O:20])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of diallyl 2-chloro-6-(hydroxymethyl)benzyl phosphate (2.62 g, 7.88 mmol) obtained from Example 27-(3) in acetone (25 ml) was cooled to 0° C., and Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 12 ml, ca. 32 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then 2-propanol (1 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and then the filtrate was concentrated under reduced pressure to give an oily residue. The residue was thoroughly dried using a vaccum pump, and then subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:dichloromethane=1:10˜1:1) to afford the title compound (2.065 g, 76% yield) as a pale brown oil.