Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][NH2:8].[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20]>CO>[OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][NH:8][CH2:16][CH:17]([OH:18])[CH2:19][OH:20]
Reactant: OCC1CO1
Reactant: NCCCN(CC(O)CO)CC(O)CO
Solvent: CO
Product: OCC(O)CNCCCN(CC(O)CO)CC(O)CO

Procedure:
N,N-di-(2,3-dihydroxypropyl)trimethylenediamine (11.1 g., 0.05 mole) is dissolved in 125 ml. of methanol and heated under reflux with agitation. Glycidol (3.7 g., 0.05 mole) is added dropwise over a period of 1.5 hour and the solution mixed an additional hour at 60° C.-80° C. The methyl alcohol and other volatiles are removed by stripping under reduced pressure to leave the product suitable for use in the next steps.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>>[Cl:1][C:2]1[C:3]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[F:27])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: Nc1ccccc1F
Product: Fc1ccccc1Nc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc12
Yield: 56 %

Procedure:
By a procedure similar to that of Example 219 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and 2-flouroaniline, the title compound was obtained in 56% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32](Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(N)ccc2c1=O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 6-amino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (synthesized according to the method similar to that in Example 111 (1)) (0.1 g, 0.24 mmol), acetyl chloride (38 mg, 0.48 mmol), sodium hydrogencarbonate (81 mg, 0.96 mmol), water (0.5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 6-acetylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (80 mg, 73%) as crystals.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[CH:11]=[CH:12][C:13]([N+:28]([O-])=O)=[C:14]([CH:27]=1)[NH:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25]#[N:26].O>CN(C)C=O>[NH2:28][C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:27][C:14]=1[NH:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25]#[N:26]
Reactant: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Nc2cc(F)ccc2N)sc2ccccc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 145.6 %

Procedure:
Sodium hydrosulfite (86%, 233 g) was suspended in dimethylformamide (240 ml) and the suspension was heated to 110° C. To this suspension was added dropwise at 110° C. a solution of 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (120 g), dimethylformamide (720 ml) and water (27.5 ml), which solution had been heated to 65-70° C. The reaction mixture was stirred at 110° C. for 1 hour and cooled to 20° C. Water (3.3 L) was added in 6 portions over 1 hour and the mixture was stirred at 20° C. for 1.5 hours. The precipitated crystals were filtered by suction and washed with water (2 L) to give 2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carbonitrile (158 g, (wet weight)) as ocher crystals.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C1(C)C=CC=CC=1.CS(C)=O>[Cl:18][C:19]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2cccc(Cl)c2Cl)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (100 mg, 0.43 mmol) in toluene (2 mL) and DMSO (1 drop) was added 2,3-dichloroaniline (0.07 mL, 0.43 mmol) and reaction was stirred at 110° C. overnight. The resulting solid was collected by filtration, washed with ethyl acetate to remove toluene and dried in vacuo. LC-MS (m/z) 349 (M+).
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8]([C:10]2[C:11]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)=[O:9])=O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH:1]1([C:4]2[O:9][C:8]([C:10]3[C:11]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=3)=[N:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(C(=O)NNC(=O)C2CC2)c(OCC[Si](C)(C)C)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(OCC[Si](C)(C)C)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
N′-cyclopropanecarbonyl-2-methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carbohydrazide (9.27 g) obtained in Step 4 was dissolved in acetonitrile (250 mL), and triphenylphosphine (7.90 g) and triethylamine (7.0 mL) were added thereto. The mixture was stirred at 40° C. for 1 hour. Then, carbon tetrachloride (4.7 g) was added, and the mixture was stirred at 40° C. for 3 hours. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography. The fraction of the desired product was collected, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue to precipitate crystals. The resulting crystals were collected by filtration and dried thoroughly under reduced pressure to give 5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-4-(2-trimethylsilylethoxy)-2-methylthiopyrimidine [Compound (AA) in which —X—Y—Z— is —O—C(c-C3H5)═N—] (5.18 g, yield 59%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:56])[CH2:10][C:11]1([CH2:45][C:46]([O:48]CC2C=CC=CC=2)=[O:47])[C:17](=[O:18])[N:16]([C:19]([CH:31]([CH3:33])[CH3:32])([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:20](=[O:22])[NH2:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:12]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([O:8][C:9]([CH2:10][C:11]1([CH2:45][C:46]([OH:48])=[O:47])[C:17](=[O:18])[N:16]([C:19]([CH:31]([CH3:33])[CH3:32])([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:20](=[O:22])[NH2:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:12]1=[O:44])=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)OCc3ccccc3)(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)O)(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)cc1
Reaction time: 2.5 h
Yield: 32.6 %

Procedure:
450 mg (0.6 mmols) of {3-(Benzyloxycarbonyl-methyl)-1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}acetic acid benzyl ester, prepared as in Intermediate 27, is dissolved in 100 mL of ethyl acetate and 45 mg of 10% Pd/C is added. The reaction mixture is then kept under a hydrogen atmosphere with stirring for 2.5 h. The solution is then filtered through celite and the solvent is removed in vacuo. The resulting white solid is purified by reverse phase MPLC in methanol/water 70/30 as eluent to afford 130 mg (32%) of the title compound as a white solid: 1H NMR (CDCl3, 300 MHz) δ7.38-6.54 (m, 18H), 5.29-4.88 (m, 4H), 4.23 (m, 1H), 3.83 (d, J=7.5, 3H), 3.23-2.69 (m, 4H), 1.08-1.02 (m, 6H); low resolution MS m/e 664.
Reaction SMILES: COC1C=CC([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17](OC)[C:11]=3[CH:10]=2)=CC=1.FC1C=C(C=C(F)C=1F)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[S:13]1[CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: COc1ccc(-c2cc3c(OC)cccc3s2)cc1
Agent: O=C(Cl)c1cc(F)c(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2sccc2c1
Reaction time: 18 h
Yield: 10.8 %

Procedure:
To a well stirred solution of 2-(4′-methoxyphenyl)-4-methoxybenzo[b]thiophene (0.201 g, 0.74 mmol) and 3,4,5-trifluorobenzoyl chloride (0.288 g, 1.48 mmol) in CH2Cl2 (7 mL) was added AlCl3 (0.304 g, 2.22 mmol) portion-wise over a 15 minute period. After 18 h, water was added, and the product was isolated initially with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed sequentially with NaHCO3 and brine and then dried over MgSO4. Purification by flash chromatography (silica gel, 80:20 hexane/EtOAc) afforded benzo[b]thiophene (0.032 g, 0.08 mmol, 10%) as a white solid. Recrystallization (Ethanol/hexane/CH2Cl2) yielded a highly pure crystalline sample. 1H-NMR(CDCl3, 360 MHz) δ7.74 (d, J=8.9 Hz, 2H, ArH), 7.70 (d, J=9.3 Hz, 1H, ArH), 7.68 (s, 1H, ArH), 7.43 (dd, J=7.5, 6.6 Hz, 2H, ArH), 7.00 (d, J=8.9 Hz, 2H, ArH), 6.83 (d, J=8.4 Hz, 1H, ArH), 4.09 (s, 3H, —OCH3), 3.87 (S, 3H, —OCH3). 13C-NMR (CDCl3, 90 MHz) 190.5, 160.1, 159.1, 152.3, 150.0, 146.6, 141.3, 134.4, 132.9, 132.1, 127.9, 126.9, 122.4, 114.5, 114.1, 114.1, 114.0, 113.9, 113.8, 56.0, 55.4. HRMS (EI) M+ calcd for C23H15F3O3S 428.0694 found 428.0620. Compound 12A shows an inhibition of tubulin polymerization >40 μM. Biological activity of compound 12A is shown in Table 18.
Reaction SMILES: C([O:8][C:9](=[O:62])[CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][N:32]([C@H:46]([C:48]2[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[C:50]([C:58]([F:61])([F:60])[F:59])[CH:49]=2)[CH3:47])[C:33]2[N:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:35][N:34]=2)[CH2:19][CH3:20])[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:61][C:58]([F:59])([F:60])[C:50]1[CH:49]=[C:48]([CH:46]([N:32]([CH2:31][C:22]2[CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=[CH:26][C:21]=2[N:18]([CH2:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:10][C:9]([OH:62])=[O:8])[CH2:12][CH2:13]2)[CH2:19][CH3:20])[C:33]2[N:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:43])=[O:44])=[CH:35][N:34]=2)[CH3:47])[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, a solution of (S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (7) (34.2 g, 37.88 mmol, >99% ee) obtained in Step 5 in ethanol (340 mL) was added with 10% Pd—C (wet, 3.4 for hydrogen substitution, and then the mixture was stirred at room temperature for 2 hours. The reaction suspension was filtered through Celite, and washed with ethanol (50 mL), and the washing solution was concentrated under reduced pressure to obtain substantially optically pure trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (III) (white amorphous, 31.78 g, yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:19])[CH:3]=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[C:31]([NH:1][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:19])[CH:3]=1)([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)Cl
Reactant: CC(CCCc1ccc(F)cc1)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Product: CCOC(=O)Nc1cc(C(C)CCCc2ccc(F)cc2)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
The title compound was prepared by reacting 10-amino-8-[5-(4-fluorophenyl)-2-pentyl]-5,5-dimethyl-5H-[1]benzopyrano[4,3-c]pyridine with ethyl chloroformate according to the method of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]#[N:13])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.[OH-:16].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]([NH2:13])=[O:16])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: [OH-]
Reactant: COc1ccc2ncc(Cl)c(C#N)c2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(C(N)=O)c2n1
Yield: 64 %

Procedure:
3-Chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile (5.0 g, 22.8 mmol, 1.0 eq) is suspended in a 10% sodium hydroxide aqueous solution (125 mL) and the resulting mixture is heated to reflux for 30 minutes. The reaction mixture is then extracted with ethyl acetate (3×100 mL) and the pH is adjusted to 3-4 by the addition of a 3N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:1 to 4:1, v/v) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carboxylic acid amide as an off-white solid (3.44 g, 64% yield).
Reaction SMILES: [C:1]([C:3]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8])#[N:2]>ClC1C=CC=CC=1Cl>[C:1]([C:3]1[C:4]2[O:5][C:6]([CH3:10])([CH3:9])[CH:7]=[CH:8][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])#[N:2]
Reactant: C#CC(C)(C)Oc1cccc(F)c1C#N
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=Cc2ccc(F)c(C#N)c2O1

Procedure:
One thousand mL of stirred, 1,2-dichlorobenzene was heated to 180 ° C., and a solution of 75.0 grams (0.37 mole) of 3-(2-cyano-3-fluorophenoxy)-3-methyl-1-butyne in 100 mL of 1,2-dichlorobenzene was added dropwise. Upon completion of the addition, the reaction mixture was stirred at 180° C. for one hour, after which the reaction mixture was cooled and subjected to column chromatography on silica gel. The 1,2-dichlorobenzene solvent was separated by elution with hexane. The product was removed from the column by elution with methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 37.0 of 8-cyano-2,2-dimethyl-7-fluoro-2H-1-benzopyran, mp 99°-101° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:3]/[CH:2]=[CH:1]/[C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC1(O[Si](C)(C)C)CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](C/C=C/C1(O[Si](C)(C)C)CCCCC1)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic maintained at 130°-135° C. for one hour.
Reaction SMILES: C1([S:7]P(C2C=CC=CC=2)(=S)O)C=CC=CC=1.[CH2:17]([O:19][C:20](=[O:26])[C:21]([C:24]#[N:25])([CH3:23])[CH3:22])[CH3:18]>C(O)(C)C>[NH2:25][C:24](=[S:7])[C:21]([CH3:23])([CH3:22])[C:20]([O:19][CH2:17][CH3:18])=[O:26]
Reactant: OP(=S)(Sc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)(C)C#N
Solvent: CC(C)O
Product: CCOC(=O)C(C)(C)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
A mixture of diphenyldithiophosphonic acid (ALFAAESAR, 1.42 g, 5.67 mmol) and 2-cyano-2-methylpropionic acid ethyl ester (ABCR, 0.412 mL, 2.83 mmol) in isopropanol (30 mL) was heated under reflux for 4 h. Reaction mixture was cooled to room temperature and a precipitate was formed. Reaction flask was placed in the freezer for 1 h. Reaction mixture was filtered and filtrate was concentrated. Residue was taken up in DCM (100 mL) and washed with water (20 mL), 1N NaOH (20 mL), saturated NaHCO3 (20 mL) and dried over sodium sulfate and concentrated. The resulting oil was loaded on a 25 g silica cartridge and eluted with linear gradient 0-50% hexane-ethyl acetate to yield the title compound (110 mg, 0.628 mmol, 22.2% yield). Another impure batch was loaded on a 10 g silica cartridge and eluted with linear gradient 0-50% hexane-ethyl acetate to recover the title compound (120 mg, 0.685 mmol, 24.17% yield). Total yield: (230 mg, 1.313 mmol, 46.32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.70 (br s, 1H), 8.86 (br s, 1H), 4.05 (q, 2H), 1.39 (s, 6H), 1.15 (t, 3H). [ES+MS] m/z 176 (MH+).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([C:26]4[N:27]=[CH:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:20]=3)=[N:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(Cl)(=O)OC(Cl)C>ClC(Cl)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([C:21]2[CH:20]=[C:19]([NH:18][C:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[CH:11]=[CH:12][N:13]=3)[CH:24]=[CH:23][C:22]=2[CH3:25])[N:27]=1
Reactant: Cc1ccc(Nc2nccc3c2CCN(Cc2ccccc2)C3)cc1-c1cc2ccccc2cn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2nccc3c2CCNC3)cc1-c1cc2ccccc2cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 6-benzyl-N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (320 mg, 0.7 mmol) in dichloroethane is added DIEA (225 mg, 1.75 mmol) and 1-chloroethyl carbonochloridate (200 mg, 1.4 mmol). The reaction mixture is stirred at 90° C. for 12 hours. After cooling, the solvent is removed by rotary evaporation. The residue is redissolved in 20 ml of methanol and stirred at room temperature for 15 hours. After removing solvent, the crude product is purified by silica gel flash chromatography, eluted with 5% methanol in ethyl acetate to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine as a light yellow solid. MS m/z 367.2 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24](Br)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:26])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[Cl:28][C:29]1[C:37]2[S:36][C:35]([SH:38])=[N:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]([CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([S:38][C:35]3[S:36][C:37]4[C:29]([Cl:28])=[CH:30][CH:31]=[CH:32][C:33]=4[N:34]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:26])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Reactant: Sc1nc2cccc(Cl)c2s1
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1

Procedure:
The title product was prepared according to the procedure described for example 81 using (1S)-2-{4-[2-(6-amino-8-bromo-9H-purin-9-yl)ethyl]piperidin-1-yl}-1-methyl-2-oxoethyl acetate and 7-chloro-2-mercaptobenzothiazole. LC-MS [M+H]+ 562.1, along with hydrolyzed product, the mixture was used for the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH:5]=[C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([O:11][C:12](=O)[CH:7]12)=[O:10].C(N(CC)CC)C>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][CH2:6][C:7]1[CH:12]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1ccccc1C=C1C=CC=C2C(=O)OC(=O)C12
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccccc1CCc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
10 g (0.0397 mol) of 2-methoxybenzylidene phthalic anhydride (compound 1) is placed in a 500 ml autoclave. 230 ml of ethanol, 4.02 g (1 eq.) of triethylamine and 20 g of Raney nickel freshly prepared from 40 g of 50% Raney nickel alloy by a conventional method are added. The reaction mixture is stirred under an H2 pressure of 4 kg/cm2 at room temperature for 2 days. After the catalyst is filtered off and washed with ethanol, the filtrate is evaporated. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give 6.548 g (yield 64%) of colorless acicular crystals having a melting point of 118° to 119° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18].Cl.C(NCCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])=[O:10])=[CH:11][CH:12]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ccc(Br)cc1
Agent: CCN=C=NCCCNCC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(NC(=O)COc2ccc(Br)cc2)c1
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a mixture of (4-bromo-phenoxyacetic acid (392.5 mg, 1.8 mmol), 3-amino-benzamide (408.2 mg, 3.0 mmol), N-(3-ethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (517.6 mg, 2.7 mmol) and 1-hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo-phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield).