Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17].C(N(CC)CC)C>C(OCC)C>[OH:17][C:11]1[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=1[NH:9][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(Br)ccc1O
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A solution of tert-butylacetyl chloride (2.7 g, 0.020 mol) in diethyl ether (20 ml) was added dropwise to a solution of 2-amino-4bromophenol (3.8 g, 0.020 mol) and triethylamine (2.1 g, 0.020 mol) in diethyl ether (160 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was evaporated in vacuo. Purification by flash column chromatography on silica gel, eluting initially with ethyl acetate:dichloromethane 1.5:98.5 and then with ethyl acetate:dichloromethane 2.5:97.5, gave N-(2-hydroxy-5-bromophenyl)-3,3-dimethylbutyramide (1.8 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19].N1C=CC=CC=1.[C:32](Cl)(=[O:54])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(Cl)(Cl)Cl>[C:32]([CH:21]([CH:22]([CH2:23][OH:24])[OH:25])[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:54])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(OC(=O)CCCCCCCCCCCCCCCCC)C(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 g (279.3 mmol) of 1-monostearin is dissolved in 750 ml of warm chloroform (Note: the chloroform is washed three times with distilled water, dried over MgSO4, and filtered before use). 24.8 ml (307.2 mmol) of pyridine is then added to the solution. (Note: the pyridine is dried over 3A molecular sieves, manufactured by Linde, before use). 110 g (307.2 mmol) of behenoyl chloride is dissolved in 250 ml of washed chloroform and added dropwise to the well stirred solution. The reaction is gently warmed with a heating mantel and is stirred overnight (16 hrs.) Upon completion of the reaction, the solvent is removed under reduced pressure. The remaining solid/oil is transferred to a 2 liter beaker and 1 liter of acetone/ethanol 50:50 is added. The mixture is heated to boiling and the remaining solids filtered. The filtrate is then placed in a 50° C. incubator overnight and filtered. The filtrate is cooled to room temperature and any solid diacylglyceride is removed by suction filtration.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccc2ccccc2n1
Product: O=C1CCc2cc(OCCCCSc3ccc4ccccc4n3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 2-mercapto-quinoline.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.[CH3:16][C:17]1(C)[O:22]C(=O)[CH2:20][C:19](=O)[O:18]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13](=[O:15])[CH2:16][C:17]([O:18][CH2:19][CH3:20])=[O:22]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (3.01 g, 14.67 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.23 g, 15.47 mmol) and 4-dimethylaminopyridine (2.73 g, 22.35 mmol) in dichloromethane (150 mL) was added a solution of DCC (3.36 g, 16.28 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at RT for 16 h. The insoluble materials were filtered off, and the filtrate was washed with 5% NaHSO4 aqueous solution. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was treated with EtOH (200 mL) and the resulting mixture was stirred at 70° C. for 4 h and then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with EtOAc. The organic layers were washed with water and brine, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a colorless solid (3.43 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=6.8 Hz, 3H,), 3.58 (s, 2H), 4.24 (q, J=6.8 Hz, 2H), 4.67 (s, 2H), 7.73-7.78 (m, 2H), 7.86-7.91 (m, 2H).
Reaction SMILES: C([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)C(C)C.[CH3:28][CH:29]([CH3:33])[CH2:30]C#C>>[C:29]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:33])([CH3:30])[CH3:28]
Reactant: COCCCC[C@@](O)(c1cccc2cc(CC(C)C)oc12)[C@@H]1CCCNC1
Reactant: C#CCC(C)C
Product: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCNC1

Procedure:
(S)-1-(2-isobutylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol using 4-methylpentyne in place of 3,3-dimethylbut-1-yne in Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccc(Cl)cc3nc2OC)CC1
Yield: 92 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 92%). 1H NMR (300 MHz, CDCl3): δ 3.17 (s, 4H), 3.82 (s, 4H), 3.89 (s, 3H), 4.15 (s, 3H), 6.89-6.97 (m, 3H), 7.06 (m, 1H), 7.45 (m, 1H), 7.75 (s, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[CH:7][CH:6]=1.Br[CH2:25][C:26]#[N:27]>CN(C)C=O>[O:21]=[C:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:22])[F:23])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]1[CH2:25][C:26]#[N:27]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 0.5 h

Procedure:
To a mixture of 95% dry sodium hydride (48 mg, 2.00 mmol) in anhydrous N,N-dimethylformamide (10 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg, 1.00 mmol). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of 2-bromoacetonitrile (480 mg, 4.00 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (as checked by LCMS), then quenched by addition of methanol (10 mL). The mixture was concentrated under reduced pressure, and the residue was subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (compound No. 90) (307 mg, 0.93 mmol, 93%). LCMS mz 331.0 (M+H), 353.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; CDCl3) δ 7.69 (m, 4H); 7.57 (dd, J=8.4 and 2.1 Hz, 1H); 7.47 (d, J=3.0 Hz, 1H); 7.16 (d, J=8.2 Hz, 1H); 6.90 (s, 2H); 3.05 (m, 2H); 2.79 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[F:70][C:71]([F:89])([F:88])[C:72]([NH:74][CH2:75][CH:76]1[CH2:81][NH:80][CH2:79][CH2:78][N:77]1[CH2:82][CH2:83][O:84][CH2:85][CH2:86][OH:87])=[O:73]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:9]1[C:8]2[C:2]([N:80]3[CH2:79][CH2:78][N:77]([CH2:82][CH2:83][O:84][CH2:85][CH2:86][OH:87])[CH:76]([CH2:75][NH:74][C:72](=[O:73])[C:71]([F:89])([F:88])[F:70])[CH2:81]3)=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC1CNCCN1CCOCCO)C(F)(F)F
Reactant: ClC1=Nc2ccccc2Sc2ccccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCC1CN(C2=Nc3ccccc3Sc3ccccc32)CCN1CCOCCO)C(F)(F)F

Procedure:
To a solution of 11-chlorodibenzo[b,f][1,4]thiazepine, prepared as described in the previous step, (2 g, crude) in dioxane (20 mL) was added Pd2(dba)3 (327 mg, 0.357 mmol), BINAP (225 mg, 0.357 mmol), triethylamine (6 mL, 42.9 mmol) and 2,2,2-trifluoro-N-((1-(2-(2-hydroxyethoxy)ethyl)piperazin-2-yl)methyl)acetamide, prepared as described as Step F, (2.4 g, crude). The resulting mixture was heated to reflux overnight under nitrogen atmosphere, filtered through CELITE™, and concentrated. The residue was purified by silica gel chromatography to provide the title compound. ESI-MS (M+1): 509 calc. for C24H27F3N4O3S 508.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26](O)=O)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:13]([O:12][C:10]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]1[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[N:9]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(I)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Temperature: 0 °C
Yield: 47 %

Procedure:
To a mixture of 4-iodo-benzene-1,2-diamine (1.5 g, 6.4 mmol) and (S)-N-Cbz-2-piperidine-carboxylic acid (available commercially at Aldrich) (1.7 g, 6.4 mmol) in DMF (20 mL) at 0° C. is added DIPEA (3.3 mL, 19.2 mmol) followed by HATU (3.0 g, 7.69 mmol). The reaction mixture is stirred at 0° C., brought to room temperature and stirred overnight. The reaction mixture is than concentrated in vacuum and the residue is dissolved in AcOH (15 mL) and stirred at 60° C. for 4 hours. The mixture is concentrated in vacuum and the residue is dissolved in EtOAc and washed with water, 1N HCl and brine, dried over sodium sulfate and concentrated in vacuum. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) to give the title compound (1.4 g, 47%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.CN(C)C=O.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:28][C:27]([NH:31][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([CH3:30])[CH3:29]
Reactant: CC(C)(C)N
Reactant: ClCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Temperature: 120 °C

Procedure:
A mixture of 1.65 g of the product of Step A, 20 ml of dimethylformamide, 15 ml of tert.-butylamine and 770 mg of potassium carbonate was heated for 4 hours at 120° C. and was then diluted with 100 ml of water. The mixture was extracted with ethyl acetate and the extracts were washed with water, dried, concentrated under reduced pressure at 50° C. The residue was chromatographed on silica (eluent: ethyl acetate-triethylamine 9-1) to obtain 1.7 g of N-(1,1-dimethylethyl)-2-[2-[2-(1H-indol-4-yl)-ethenyl]-phenoxy]-ethanamine (trans E).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:4]2[CH:3]=[CH:2][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(Nc2cc(Cl)n(-c3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reaction time: 3 h

Procedure:
A solution of 5-chloro-N-(4-methoxyphenyl)-1-phenyl -1H-pyrazol-3-amine (0.2 g) in ethanol (10 ml) and triethylamine (0.2 g) was reduced at atmospheric pressure of hydrogen over 10% palladium/charcoal (0.2 g), with stirring, over 3 hours. The solution was filtered and evaporated to leave the title compound as a colourless solid, mp 96°-98°, the NMR and mass spectra of which were identical to those for the title compound of Example 2.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OCC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCC(CO)CC2)nc1

Procedure:
4-Hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-piperidinemethanol. MS calcd. for C28H27ClN4O3 [(M+H)+] 503.2, obsd. 503.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:13]1C=CN=C1)=O>C(Cl)Cl>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: Cc1ncccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ncccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a stirred mixture of 2-methylnicotinic acid (15.0 g, 0.111 mol) and 1,1'-carbonyldiimidazole (36.0 g, 0.222 mol) was added 300 mL of methylene chloride dropwise. The reaction mixture was stirred at room temperature overnight. Ammonia gas was distilled into the reaction mixture for 30 minutes using a dry ice condenser and the mixture was stirred at room temperature for an additional hour. Solvent was removed under vacuum and the residue was dissolved with 500 mL of acetonitrile. The solution was concentrated to half volume at low temperature and the product precipitated out as white solid. The crude mixture was recrystallized from ethanol/ether to give 11.5 g of 2-methylnicotinamide as a colorless crystal (76%): mp 160°-163° C. Anal. Calc'd. For C7H8N2O: C, 61.75, H, 5.92, N, 20.57. Found: C, 61.44, H, 6.14, N, 20.66.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]1[CH:29]([CH2:30][C:31](O)=[O:32])[CH2:28][CH2:27][O:26][CH2:25]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][NH:23][C:31](=[O:32])[CH2:30][CH:29]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CN)cs2)c1-c1ccc(F)cc1
Reactant: O=C(O)CC1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CNC(=O)CC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using the compound obtained in step 2 and tetrahydropyranyl-4-acetic acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:27])([CH3:26])[C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16](Br)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([CH3:27])([CH3:26])[C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Temperature: 110 °C
Yield: 78.7 %

Procedure:
7-(3-Methoxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (300 mg, 0.700 mmol), tetrakis(triphenylphosphine)palladium (81 mg, 0.070 mmol), 3-pyridineboronic acid (172 mg, 1.401 mmol) and THF (7005 μL, 0.700 mmol) were combined in a sealable tube. Potassium carbonate (1.5 M) (1401 μL, 2.101 mmol) was added to the tube, which was then flushed with argon, sealed and heated at 110° C. for 1.5 hours. The reaction was diluted with water (50 mL) and poured into a separatory funnel containing ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide 7-(3-methoxy-3-methyl-1-butyn-1-yl)-3-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (235 mg, 0.551 mmol, 79% yield) as a light yellow solid. MS m/z=427.2 [M+H]+. Calc'd for C25H23N4O3: 427.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=[O:6].Br[CH2:32][O:33][CH3:34]>CN(C)C=O>[CH3:3][O:4][C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:10]=2[N:9]([CH2:32][O:33][CH3:34])[C:8]1=[O:30])=[O:6]
Reactant: COC(=O)C1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)C(C(=O)OC)C(c2ccccc2OC)Cc2cc(C(F)(F)F)ccc21
Yield: 76.4 %

Procedure:
To a suspension of sodium hydride (360 mg; 7.5 mmole; 50% oil dispersion/prewashed with dry ether several times) in dry dimethylformamide (30 ml), cooled at 0°-5° C. was added a solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (1.9 g; 5 mmole) in dry dimethylformamide (15 ml) dropwise and with stirring. The mixture was stirred for an additional 20 minutes at 0°-5° C., whereupon bromomethylmethyl ether (800 μl; 10 mmole) was added dropwise, and stirring was continued at this temperature for an additional hour. Excess sodium hydride was destroyed by the addition of water, and the mixture was diluted with ether and washed with water. The aqueous layer was extracted with ether (three times) and the combined extracts were dried (magnesium sulfate) and concentrated. The crude oily residue was flash chromatographed (silica gel/5-25% ethyl acetate:hexane) to obtain 1.67 g of the title compound as an oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH2:15][C:14](=O)[CH:13]=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)(Cl)Cl>[Cl:3][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=1
Reactant: CC(C)(C)C1=NC=CC(=O)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(Cl)ccn1
Reaction time: 48 h

Procedure:
Phosphorous oxychloride (21.8 ml) and 2-tert.butylpyridin-4-one (2.36 g) is heated at reflux in chloroform (15 ml) for 24 hours and then stood at room temperature for 48 hours before pouring onto ice (100 g). Extraction with CH2Cl2 (3 times 250 ml) is followed by drying of the combined organic layers over magnesium sulphate. Evaporation of the organic layers gives the title compound.
Reaction SMILES: [OH-].[K+].C(O)(C)C.[CH3:7][C:8]([CH2:15][CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:9][C:10]([O:12]CC)=[O:11].Cl>CCCCCC>[CH3:7][C:8]([CH:15]=[CH:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C=C(C)CC(C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Temperature: 0 °C

Procedure:
To 4.1 g. of potassium hydroxide in 50 ml. of isopropyl alcohol was added 12 g. of the above-obtained ethyl 3,7,11,15,19-pentamethyl-5-p-tolylsulfonyl-2,6,10,14,18-eicosapentaenoate, and the mixture was stirred at 50° C. for 3 hours. The reaction liquid was poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 100 ml. of diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated to remove the solvent. There was obtained 8.5 g. of an oil. The so obtained oil was dissolved in 40 ml. of n-hexane and chilled to -20° C. to crystallize. There was obtained 2.3 g. of the desired product as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25]CC1C=CC=CC=1)=[O:24])#[N:2].[OH-:33].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:23]([OH:25])=[O:24])(=[O:33])[NH2:2]
Reactant: N#Cc1cc(C(=O)OCc2ccccc2)c2c(c1)C(C(=O)OCc1ccccc1)CCN2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Yield: 60.4 %

Procedure:
A mixture of dibenzyl 6-cyano-1,2,3,4-tetrahydroquinoline-4.8 dicarboxylate (5 g), sodium hydroxide (4 g) in ethanol (50 ml) and water (500 ml) was refluxed for 18 hours. After cooling, water (100 ml) was added thereto. The mixture was adjusted to pH 2 by the addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.87 g, 60.5%) which was recrystallized from DMF-ethanol to white crystals, mp 265° C.-266 ° C.