Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(COc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-(4-(phenoxymethyl)phenyl)propanoate (S26, 185 mg, 0.65 mmol) in a THF/MeOH (1/1, 10 mL) was treated with aqueous 4 N NaOH (1 mL) and was stirred overnight at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to afford S27 (115 mg, 0.45 mmol, 69%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 7.39 (d, 2H, J=7.7 Hz), 7.30 (t, 2H, J=7.4 Hz), 7.25 (d, 2H, J=7.7 Hz), 7.00-6.96 (m, 3H), 5.05 (s, 2H), 2.99 (t, 2H, J=7.7 Hz), 2.71 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 178.8, 158.7, 139.9, 135.1, 129.5, 128.5, 127.8, 120.9, 114.7, 69.7, 35.4, 30.2.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[OH-].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]([OH:32])[CH2:30]Cl)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH:29]([OH:32])[CH2:30][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: OC(CCl)CN1CCN(c2ccc(Cl)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCCc2c(OCC(O)CN3CCN(c4ccc(Cl)cc4)CC3)cccc21
Yield: 79 %

Procedure:
A solution of 4.05 g (0.025 mol) 5-hydroxy-1-oxotetraline in 50 ml isopropanol was mixed with 25 ml 1N isopropanolic potassium hydroxide solution and heated under reflux for ten minutes. Thereafter, the crude 1-(4-chlorophenyl)-4-(3-chloro-2-hydroxypropyl)-piperazine prepared above was added thereto after the whole of the reaction mixture had been dissolved by the addition of 20 ml hot isopropanol and the reaction mixture then stirred under reflux for six hours. During this time, a weak current of nitrogen was passed through the apparatus. After cooling and filtering off with suction the precipitated potassium chloride, the filtrate was acidified by stirring with approximately 7N methanolic hydrochloric acid. Upon cooling, colorless crystals separated out which were filtered off and recrystallized from approximately 85% aqueous ethanol. There were obtained 8.92 g (79% of theory) 5-{3-[4-(4-chlorophenyl)-1-piperazinyl]-2-hydroxypropoxy}-3,4-dihydro-2H-naphthalene-1-one; m.p. 204°-205°C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[C:12]([C:14]([O:16]C)=O)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]#[N:20]>>[CH:1]1([O:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH2:18][C:19]#[N:20])[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(OC2CCCCC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OC2CCCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cyclohexyloxy)picolinate following the method described in Example 6 gave 3-(6-(cyclohexyloxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.2 g, quant.).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[S-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>C(O)C>[Cl:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:12])[CH:2]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10]2
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccc(Cl)cc2CC1Sc1ccccc1

Procedure:
2.5 g of 2-bromo-5-chloroindan-1-one and 2.8 g of sodium thiophenoxide was suspended in 30 ml of ethanol and heated under reflux for 3 h. The cooled reaction mixture was concentrated and purified chromatographically on silica gel using toluene/ethyl acetate 10/1. This gave 5-chloro-2-phenylsulfanylindan-1-one of melting point 89° C.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1COCC1>[C:14]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(=O)c(O)co1
Agent: CN(C)C
Solvent: C1CCOC1
Product: CC(=O)Oc1coc(C)cc1=O
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (833 μl; 6.33 mmol; 1.33 equiv.) was added drop-wise and the contents stirred (˜5 min). Acetic anhydride (641 μl; 5.00 mmol) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 650 mg product (3.87 mmol; 81% yield). This compound was found to have an EC50 of 106 μM. 1H NMR (DMSO-d6) δ 8.39 (s, 1H; 2-H); 6.36 (s, 1H; 5-H); 2.30 (s, 3H); 2.24 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)=O.[Br:15][C:16]1[CH:17]=[N:18][NH:19][CH:20]=1.[H-].[Na+]>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][N:19]([CH2:6][CH:7]2[CH2:9][CH:8]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:20]=1
Reactant: CCOC(=O)C1CC1COS(C)(=O)=O
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1Cn1cc(Br)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A reaction mixture of ethyl 2-{[(methylsulfonyl)oxy]methyl}cyclopropanecarboxylate (880 mg; 4.0 mmol), 4-bromopyrazole (4-2, 588 mg, 4.0 mmol) and NaH 60% in mineral oil (240 mg, 6.0 mmol) with 3.0 mL of DMF was formed. The resulting mixture was stirred at 90° C. under N2 for four hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2×50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then concentrated by vacuum to afford 812 mg of (4-3) as a yellow oil (74%). 1H NMR (400 MHz, chloroform-D) δ ppm 0.85 (dd, J=7.96, 3.16 Hz, 1H) 0.88-0.98 (m, 1H) 1.18-1.29 (m, 3H) 1.56-1.71 (m, 1H) 1.79-1.94 (m, 1H) 3.96-4.08 (m, 2H) 4.07-4.17 (m, 2H) 7.45 (d, J=3.79 Hz, 2H). LCMS calcd for C10H13BrN2O2 (M+H) 274, found 274. HPLC purity 95%.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.[O:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18]1.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][N:31]([C:2]4[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[F:16])[N:3]=4)[CH2:30]3)=[CH:27][CH:28]=2)[CH2:18]1
Reactant: c1cc([C@H]2CNCCO2)ccc1N[C@@H]1CCOC1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(N[C@@H]4CCOC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.08 g, 0.35 mmol), (2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)morpholine obtained in Reference Example 7 (0.11 g, 0.44 mmol) and triethylamine (0.22 g, 2.2 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 2-((2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)-morpholin-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.07 g, 47%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]2([CH2:23][CH:22]([NH2:24])[CH2:21]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:24][CH:22]2[CH2:21][C:19]3([CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:20]3)[CH2:23]2)[C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(N)C2)C1
Reactant: Nc1ncnc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(CC(Nc3ncnc(N)c3Cl)C2)C1
Temperature: 155 °C
Reaction time: 4 h

Procedure:
In a round bottom flask containing 5,6-dichloro-pyrimidin-4-ylamine (300.00 mg; 1.83 mmol; 1.00 eq.) and 6-amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (466.02 mg; 2.20 mmol; 1.20 eq.) in NMP (1.00 ml) was added DIPEA (0.91 ml; 5.49 mmol; 3.00 eq.). The reaction mixture was stirred at 155° C. for 4 h before it was concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:18])[CH3:17].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CC(=O)Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and acetyl chloride in the presence of diisopropylethylamine to give a tan solid (52% yield). 1H-NMR (CDCl3): δ 8.86 (s, 1H), 7.59 (m, 1H), 7.22 (m, 1H), 7.16 (d, 1H), 5.80 (m, 1H), 5.10 (m, 1H), 2.67 (m, 2H), 2.22 (m, 1H), 2.04 (s, 3H), 1.91 (m, 2H), 1.81 (m, 1H); MS m/z 306 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C=O)C>CCOCC>[CH3:13][Si:12]([CH3:14])([C:15]([CH3:18])([CH3:17])[CH3:16])[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To 4-amino-3-nitrophenol (20 g, 128.9 mmol) was added tert-butyldimethylsilyl chloride (21.5 g, 142.9 mmol), imidazole (13.3 g, 194.8 mmol), and DMF (100 mL). The mixture was stirred at room temperature for 3 h and then diluted with Et2O and washed with H2O. The organics were concentrated under reduced pressure and the resulting solid recrystallized from Et2O—H2O; yielding 26.5 g (76%) product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=2)[NH:33][CH:32]=1>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:40][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH3:30]
Reactant: Cc1c[nH]c2ccc(O)cc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (207 mg, 1.5 mmol), 3-methyl-5-hydroxyindole (88 mg, 0.6 mmol), (Can. J. Chem. 1964, 42, 514), and DMA (2.0 ml) was purged with nitrogen for 5 minutes at 25° C. This mixture was then stirred at 100° C. for 3 hours then allowed to cool to ambient temperature, was filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanolic ammonia (7M) (90/10) to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (155 mg, 69%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][C@@H:48]([CH2:50][CH2:51][CH2:52][CH3:53])[CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][C@@H:48]([CH3:49])[CH2:50][CH2:51][CH2:52][CH3:53])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[C@@H](C)N
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCC[C@H](C)NC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-2-aminohexane (Alfa) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: C[Al](C)C.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH2:15].C[O:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[C:25]([C:29]3[C:34]([Cl:35])=[CH:33][C:32]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][C:30]=3[Cl:42])[NH:26]2)=[CH:22][CH:21]=1)=O.C[Al](C)C.N1C2C(=CC=CC=2)C=CC=1N>C1(C)C=CC=CC=1>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[C:25]([C:29]3[C:30]([Cl:42])=[CH:31][C:32]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:33][C:34]=3[Cl:35])[NH:26]2)=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cc(N4CCOCC4)cc3Cl)[nH]c2c1
Reactant: Nc1ccc2ccccc2n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2cc(-c3c(Cl)cc(N4CCOCC4)cc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A 2 M solution of AlMe3 in toluene (0.74 mL, 1.48 mmol) was added to a flask charged with dry toluene (6 mL) at 0° C. under N2. In one proportion quinolin-2-ylamine (0.213 g, 1.48 mmol) was added and the mixture was allow to stir for 50 min. The reaction was allowed to warm to ambient temperature over 15 min then a suspension of 2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-1H-indole-6-carboxylic acid methyl ester (0.500 g, 1.23 mmol) in toluene was slowly added to the mixture at 0° C. Upon completing the addition the mixture was heated at 100° C. After 20 h an additional portion of AlMe3/quinolin-2-ylamine solution (0.438 mmol) was added and heating was continued for an additional 3 h. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was partitioned between EtOAc (70 mL) and 1 N HCl (30 mL) and allowed to stir for 1 h. The resulting precipitate was filtered and dried under reduced pressure to afford 2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 11.26 (s, broad, 1H), 8.50 (d, J=8.97 Hz, 1H), 8.34 (d, J=8.97 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J=8.21 Hz, 1H), 7.97 (d, J=8.46 Hz, 1H), 7.76-7.82 (m, 2H), 7.68 (d, J=8.34 Hz, 1H), 7.57 (t, J=7.45 Hz, 1H), 7.17 (s, 2H), 6.54 (d, J=1.77 Hz, 1H), 3.71-3.77 (m, 4H), 3.24-3.32 (m, 4H). MS (m/z) 517.1 (M+1).
Reaction SMILES: C([O:3][CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[CH3:12][C:13]([CH2:15][C:16]([CH3:18])=O)=[O:14].[H-].[Na+]>C1COCC1>[OH:3][C:4]1[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[CH:18]=[CH:16][C:15]=1[C:13](=[O:14])[CH3:12]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)cc1O
Yield: 28.5 %

Procedure:
4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (5 g, 29.7 mmol) followed by 2,4-pentadione (3.05 ml, 29.7 mmol) were added to a cooled 0° C. suspension of NaH (2.38 g, 59.4 mmol) in THF (120 mL). The reaction mixture was refluxed for 4 hrs and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave the title compound as a yellow oil (1.73 g, 29%). 1H NMR (400 MHz, CDCl3): δ 2.69 (s, 3H), 7.15 (d, J=9.9 Hz, 1 H), 7.25 (s, 1 H), 7.86 (d, J=8.3 Hz, 1 H), 12.29 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN3CCOCC3)cc2)c1

Procedure:
Starting from compound D2 and morpholine the title compound can be obtained analogously as described for compound C5.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][C:7]1[CH:8]=[C:9]2[C:14](=O)[O:13][C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1>O>[CH3:6][C:7]1[CH:8]=[C:9]2[C:14](=[O:13])[N:2]([OH:3])[C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride in an amount of 21.4 g was dissolved in 80 ml of distilled water. To this solution, 12.3 g of NaOH dissolved in 50 ml of distilled water was added over a period of 30 minutes as the solution was cooled in an ice bath. Thereto, 50.0 g of 4-methylphthalic anhydride was further added, and stirred for 1 hour at room temperature, followed by 4-hour reflux. The reaction solution was cooled in an ice bath, and the powdery matter thus precipitated was filtered off and washed with water. The resultant crude crystals were recrystallized from an acetone/water mixture to give 27.0 g of 4-methyl-N-hydroxyphthalimide.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH:14]2CCCC2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(OC2CCCC2)c(O)c1Br
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred suspension of potassium fluoride (125 mg, 2.104 mmol) in dry DMSO (2.5 ml) was added a solution of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde (500 mg, 1.754 mmol) in DMSO (2.5 ml). A solution of 4-fluoronitrobenzene (500 mg, 2.631 mmol) in DMSO (2.5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 6 h. The reaction mixture was cooled to room temperature and the contents were poured into water (100 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (500 mg) mp: 115–117° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[K+]>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: N#CCc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(c1ccc(F)cc1)c1cccnc1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
In a 1 liter 3 neck round bottomed flask was charged 20.0 g. of 4-fluorobenzyl cyanide (1.0 eq., 0.15 moles), in 300 ml. dimethylsulfoxide (DMSO) (dried over molecular sieves), and 46.8 g. of 3-bromopyridine (2.0 eq., 0.30 moles) while stirring under N2. The reaction mixture was heated to 60° C. at which time 12.4 g of KOH (1.5 eq., 0.22 moles) as powdered pellets was added neat. The reaction exotherms to 80° C. and was monitored by GLC. After 30 min., an additional 2.4 g. of potassium hydroxide (KOH) was added (0.3 eq., 0.043 moles) and 1 hr. later GLC showed 6% unreacted nitrile. The reaction was quenched by the addition of 500 ml. of water and then extracted with 1 liter of ether. The organic phase was washed 3 times 250 ml. H2O, dried over MgSO4 and concentrated to give 50 g. of oil. The crude product was distilled under vacuum to give 15.7 g. of oil (49.4% yield) bp 160°-170° C. @1-2 min. Hg.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].CCOCC>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)O)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of sodium borohydride was added in one portion to a stirred mixture of 15.0 g of 6A, 200 ml of ether and 40 ml of ethanol. The mixture was stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure. 1.6 liters of water was added to the residue and the mixture was extracted with chloroform. The extract was dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The solution was filtered through charcoal. 400 ml of hexane was added. The solid which formed was collected, recrystallized from a 3/50 v/v mixture of chloroform and hexane and dried in a vacuum oven to give ethyl 5-(4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylate (6B), mp: 108°-109° C.