Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([OH:16])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[O:10])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:21])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[O:10])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: COc1ccc(C=O)c(O)c1-c1cc2ccccc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C=O)c(OC)c1-c1cc2ccccc2s1
Yield: 97.1 %

Procedure:
Ex-44B: 3-Benzo[b]thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde (Ex-44A, 57.4 mg, 0.202 mmol) was dissolved in acetone (5 mL) and potassium carbonate (31 mg, 0.22 mmol) was added. Methyl iodide (25 uL, 0.40 mmol) was added and the solution was heated to reflux for 3.5 h. After cooling, the crude reaction mix was concentrated on the rotavap. The resulting residue was taken up in 10 mL of a 1:9 mix of saturated, aqueous NH4Cl to water and extracted with EtOAc (2×15 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to provide 58.5 mg of 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde as an orange, oily residue which was used without further purification, 97% yield. 1H-NMR (CDCl3) δ 10.31 (s, 1H), 7.92 (d, J=9 Hz, 1H), 7.81–7.88 (m, 2H), 7.56 (d, 1H), 7.33–7.39 (m, 2H), 6.88 (d, J=9 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH2:18][Cl:19])(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:20]/[C:21](/[CH3:27])=[CH:22]\[C:23]([O:25][CH3:26])=[O:24]>C(O)(C)C>[CH3:26][O:25][C:23]([C:22]1[CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[C:11]([C:10]([O:16][CH2:17][CH2:18][Cl:19])=[O:15])=[C:12]([CH3:14])[NH:20][C:21]=1[CH3:27])=[O:24]
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(=O)CC(=O)OCCCl
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc(Br)n1
Reaction time: 9 h
Yield: 48.6 %

Procedure:
A solution of 6-bromo-2-pyridine aldehyde (1.542 g, 8.29 mmol), chloroethyl acetoacetate (1.388 g, 8.43 mmol) and methyl 3-aminocrotonate (948 mg, 8.29 mmol) in 12 ml of isopropanol was stirred under a nitrogen gas stream, at 40° C. for 9 hours and at room temperature for 13 hours. The reaction solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [silica gel; ethyl acetate-n-hexane (2:3)]. The crude product thus obtained was recrystallized from isopropyl ether-methanol to obtain 1.730 g (49% yield) of the above-captioned compound (m.p. 152° to 153°C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(NC(=O)CCCCBr)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a mixture 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.29 g, 5.20 mmol) and triethylamine (0.58 g, 5.72 mmol) in anhydrous dichloromethane (25.0 mL) was added dropwise 5-bromopentanoyl chloride (1.141 g, 5.72 mmol) in anhydrous dichloromethane (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (40 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo to afford the title compound as a yellow oil (1.91 g, 92%): 1H NMR (300 MHz, CDCl3) δ 8.81 (br s, 1H), 7.33-7.23 (m, 5H), 5.91 (s, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.51 (t, J=6.7 Hz, 2H), 2.46 (s, 3H), 2.35 (t, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.53 (m, 2H); MS (ES+) m/z 410.1 (M+1), 412.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48](N1C=CN=C1)=[O:49]>CN(C=O)C>[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:16][CH2:15]1)=[O:49]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCNCC2)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a warm (70° C.), stirred, solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine (0.211 g, 0.49 mmol) and DIPEA (0.51 mL, 2.92 mmol) in DMF (5 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 2 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 213 mg (76%) of COMPOUND 276 as a white solid. 1H NMR (CDCl3) δ 1.13-1.27 (m, 2H), 1.54-1.62 (m, 8H), 2.26 (s, 6H), 2.47-2.595 (m, 3H), 3.37 (s, 2H), 3.62 (s, 2H), 4.03-4.07 (m, 2H), 6.69 (s, 2H), 6.99-7.10 (m, 3H), 7.14-7.20 (m, 4H), 7.84 (d, 1H, J=7.2 Hz), 8.08 (s, 1H), 8.50 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 17.31, 17.84, 27.16, 30.28, 41.87, 43.64, 53.13, 54.60, 57.03, 120.55, 125.05, 125.26, 127.82, 130.57, 132.31, 133.09, 138.09, 142.53, 144.49, 145.58, 145.90, 148.90, 154.11, 154.58, 157.80; ES-MS m/z 538 (M+1). Anal. Calcd. For C32H39N7O.0.4H2O.0.3CH2Cl2: C, 68.02; H, 7.14; N, 17.19. Found: C, 67.67; H, 7.01; N, 17.32.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.ON1C2N=CC=CC=2N=N1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>ClCCl>[N:21]1([C:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-4-hydroxycyclohexanecarboxylic acid (720 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.33 g, 6 mmol) and 1-hydroxy-7-azabenzotriazole (816 mg, 6 mmol) in dichloromethane (6 ml) was treated with morpholine 1.3 ml, 15 mmol). After stirring at room temperature for 18 hours, the crude reaction was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo, and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D55); MS (ES+) m/e 214 [M+H]+.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].O>O1CCCC1>[N+:14]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:3][C:1]#[N:2])[CH:22]=[CH:23][CH:24]=1)([O-:16])=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
At 0° C., 75.5 g of diethyl cyanomethylphosphonate dissolved in tetrahydrofuran are poured into a suspension of sodium hydride in tetrahydrofuran. After 30 minutes' contact at ambient temperature, 56 g of 3-nitrobenzaldehyde dissolved in tetrahydrofuran are poured in. After 1 hour, hydrolysis is carried out with 300 ml of water and then the solvent is concentrated. Following extraction with dichloromethane, washing the organic phase with water, drying over magnesium sulphate and concentration, the precipitate is taken up in diethyl ether and filtered off.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=C[CH:9]=1.CC(=NO)C(=O)CC.[CH:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[CH2:8]([C:7]1[O:37][C:36]([C:35]2[CH:34]=[CH:33][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:39][CH:38]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:9]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 4-isopropylbenzaldehyde gave 5-ethyl-4-iodomethyl-2-(4-isopropylphenyl)oxazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1)#[N:2].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:29])=[C:4]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[CH:5]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1cc(Nc2cc(N[C@H](CC3CCCCC3)C(N)=O)ccc2C#N)sn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC3CCCCC3)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-cyclohexylpropanamide (241 mg, 0.629 mmol) in DMSO (2 mL), K2CO3 (300 mg, 2.17 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 90 C for 10 min, the mixture was purified by HPLC to give the titled compound (81 mg). MS 402.4 (M+H); UV 204.7, 298.3 nm
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11](N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C@H:24]1[CH2:29][C:28]2[C:30]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH:36]3C)=[CH:31][CH:32]=[C:33]([CH3:34])[C:27]=2[O:26][CH2:25]1>CN(C)C=O>[CH3:34][C:33]1[C:27]2[O:26][CH2:25][C@@H:24]([NH:23][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[CH2:29][C:28]=2[C:30]([N:35]2[CH2:40][CH2:39][N:38]([CH3:11])[CH2:37][CH2:36]2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(N2CCNCC2C)c2c1OC[C@@H](N)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N[C@@H]2COc3c(C)ccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
4—Methylbenzoic acid (22 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole (27 mg, 0.17 mmol) were dissolved in dry N,N-dimethylformamide (2 mL) and stirred at 75° C. for 1 h. The reaction mixture was cooled to room temperature and a solution of (S)-3-amino-8-methyl-5-(methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (40 mg, 0.15 mmol) dissolved in dry N,N-dimethylformamide (4 mL) was added. The reaction mixture was stirred at room temperature for 4 days and the solvent was evaporated in vacuo. The crude material was partitioned between methylene chloride (40 mL) and water (10 mL). The organic phase was washed with water (10 mL) and brine (5 mL) and dried (MgSO4). The solvent was evaporated in vacuo giving 48 mg of a crude product. Purification by preparative TLC on silica using chloroform/ethanol (saturated with ammonia) (15:1) as the eluent afforded 23 mg (40% yield) of the title compound as a white solid: mp 191-192° C.; EIMS (70eV) m/z (relative intensity) 379 (100, M+); [α]21D−7° (c 0.10, chloroform).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1.[CH3:20][NH:21][CH3:22].Cl>>[CH3:20][N:21]([CH3:22])[CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1
Reactant: CNC
Reactant: Cc1cccc(C=Cc2ccccc2OCCCl)n1
Agent: Cl
Product: Cc1cccc(C=Cc2ccccc2OCCN(C)C)n1

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-6-methyl-pyridine was prepared from 2-[o-(β-chloro-ethoxy)-styryl]-6-methyl-pyridine and dimethylamine, and the free base was converted into its monohydrochloride, yielding 45% of theory of the compound of the formula ##STR11## which had a melting point of 200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16](F)=[C:17]([C:19]#[N:20])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1.BrC1SC(C(N2CC(=O)NC2)=O)=NC=1C1C=CC(F)=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:11][C:12]=2[C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(-c2sc(C(=O)N3CNC(=O)C3)nc2-c2cccc(Cl)c2)ccc1F
Agent: O=C1CN(C(=O)c2nc(-c3ccc(F)c(Cl)c3)c(Br)s2)CN1
Product: N#Cc1cccc(-c2sc(C(=O)N3CNC(=O)C3)nc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 5 starting with the compound from Example 7A. 12.0 mg (22% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5]CC)=O.[CH3:13][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16]>>[CH3:16][O:15][P:14]([CH2:13][C:3](=[O:5])[C:2]([CH3:1])([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:19])[O:17][CH3:18]
Reactant: CCCCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC

Procedure:
Prepared from ethyl 2,2-dimethyl-caproate and dimethyl methylphosphonate according to the usual method.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Br[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15][CH2:16][CH3:17])[C:13]=1[OH:14])[CH:9]=[O:10]>C1COCC1.CN(C)C=O.C(OCC)(=O)C.[Cu]Cl>[CH2:16]([O:15][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([O:4][CH3:3])[C:13]=1[OH:14])[CH:9]=[O:10])[CH3:17]
Reactant: CO
Reactant: CCOc1cc(C=O)cc(Br)c1O
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a suspension of sodium hydride (843 mg) in THF (5 mL) was added methanol (675 mg) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. 3-Bromo-5-ethoxy-4-hydroxybenzaldehyde (1.29 g) in dimethylformamide (10 mL), and copper(I) chloride (31 mg) were added thereto, and the mixture was stirred at 120° C. for 4 hours under heating. The mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1, v/v) to give the title compound (630 mg).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].N=[O:13].Cl>>[N:1]1[C:2](=[O:11])[C:3](=[O:13])[CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: N=O
Agent: Cl
Product: O=C1C=c2ccccc2=NC1=O

Procedure:
Quinolinone compounds (e.g., Structure 16) may be converted into corresponding quinoline-diones (e.g., Structure 24), hydroxy quinolinones (e.g., Structure 25), and quinoline-thiones (e.g., Structures 26 and 27) by the processes shown in Scheme V. The process of Scheme V begins with the deprotection of the imino ether of Structure 16 by treatment with a mineral acid, for example, hydrochloric acid, to afford a quinoline-dione compound of Structure 24. Alternatively, this transformation can be carried out with a Lewis acid, for example, boron trichloride, to afford a quinoline-dione compound (e.g., Structure 24). See T. Sala, et al., supra. A quinoline-dione compound (e.g., Structure 24) can be converted to a hydroxy quinoline compound (e.g., Structure 25) by addition of an organometallic reagent, for example, methyl lithium, which affords a hydroxy quinoline compound (Structure 25).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1.C(OCC)(=O)C>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:36])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 12 %

Procedure:
To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (54 mg) in N,N-dimethylformamide (1.0 ml) was added a solution of phenylacetyl isocyanate in hexane (0.972 ml, Production Example 1), followed by stirring at room temperature for 25 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated to give a solid, which was suspended in ethyl acetate. The solid was filtered off, washed with ethyl acetate, and dried under aeration to provide the titled compound (9.5 mg, 12%) as colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:7]3[CH:8]=[C:9]([S:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:13])=[O:12])[S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccccc1
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(S(=O)(=O)Cc4ccccc4)cc23)CC1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.00 g (7% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=5.5 Hz 1H), 7.27-7.40 (m, 5H), 7.15-7.21 (m, 2H), 4.45 (s, 2H), 3.50-3.56 (m, 4H), 3.40-3.45 (m, 4H), 1.49 (s, 9H); MS (ESI+) for C23H27N3O4S2 m/z 474 (M+H)+. HPLC 77%, RT 3.93 min (ACE3 C8 50×4 mm, 5-50% acetonitrile in 3 min).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][C:18]([F:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[N:3]=[C:4]([CH3:7])[S:5][CH:6]=3)=[N:16][C:15]=2[CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: C#CCCc1nc2cc(F)cc(Cl)c2o1
Reactant: Cc1nc(I)cs1
Product: Cc1nc(C#CCCc2nc3cc(F)cc(Cl)c3o2)cs1
Yield: 55.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-iodo-2-methylthiazole (200 mg, 0.89 mmol) and 2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole (199 mg, 0.89 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 157 mg (0.49 mmol, 55%) of 7-chloro-5-fluoro-2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(Cl)c32)ccc1C(C)(C)C#N
Yield: 159.6 %

Procedure:
To a solution of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.44 mmol) prepared according to scheme 12, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (88.5 mg 0.44 mmol) prepared according to scheme 16 and DMAP (106 mg, 0.88 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (166 mg, 0.44 mmol) after 18 hours of stirring, the mixture is diluted with methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4 u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (290 mg, 53%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3H) 1.76 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.19-5.36 (m, 2H) 7.13-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.59 (dd, J=8.98, 4.30 Hz, 1H) 8.14 (s, 1H), MS [M+H], calcd: 413.2, found: 413.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)Cl.Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH3:19][O:18][N:17]([CH3:16])[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=1
Reactant: CNOC
Reactant: Cc1cncc(C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1cncc(C)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
A mixture of 5-methyl-nicotinic acid (1.8 g, 13.1 mmole) and SOCl2 (10 mL) was heated to 75° C. for three hours. The remaining SOCl2 was removed by vacuum distillation and the oily residue carefully redissolved in dichloromethane (16 mL). Then N,O-dimethylhydroxyl amine hydrochloride (1.4 g, 14.4 mmol) was added. The reaction mixture was purged with argon and triethylamine (5.11 mL, 36.7 mmol) was dropwise added at 0° C. It was stirred for 24 hours at room temperature. The mixture was diluted with dichloromethane, washed with NaOH 2N, brine, dried and concentrated to yield a brown oil which was purified by column chromatography (SiO2, n-Hex/EtOAc 1:1 to EtOAc) to afford the title compound (1.7 g, 71% yield) as a brownish oil.