Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14](=[CH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.CN(C)C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[CH2:15][C:14](=[CH2:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=C(C)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Yield: 89.3 %

Procedure:
Ethyl 4-hydroxybenzoate (50.0 g), methallyl chloride (32.6 g) and potassium carbonate (45.6 g) were refluxed with heating in acetone (150 ml) for 40 hours. The reaction mixture was filtrated and the filtrate was concentrated under a vacuum. The residue, after toluene (150 ml) was added thereto, was washed with 2% sodium hydroxide aqueous solution and water successively. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum, thereby yielding an oily compound. This compound was dissolved in N,N-dimethylaniline (80 ml) and refluxed with heating for about 10 hours. While being cooled with ice, the reaction mixture was acidified with concentrated hydrochloric acid and then extracted with toluene. The extract was extracted with 10% sodium hydroxide aqueous solution. The water layer was acidified with concentrated hydrochloric acid and then extracted with toluene. The extract was washed with water, dried over sodium sulfate anhydride and then concentrated under a vacuum, thereby yielding 59.2 g of ethyl 4-hydroxy-3-methallylbenzoate.
Reaction SMILES: BrC(Br)[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.O.C[C:18](C)=[O:19]>>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:3][CH:4]=2)[C:9]=1[CH:18]=[O:19]
Reactant: CC(C)=O
Reactant: COc1ccc2cc(C(Br)Br)ccc2c1
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 24 °C
Reaction time: 10 h

Procedure:
A solution of 2-dibromomethyl-6-methoxynaphthalene (3 g) in acetone (25 ml) was treated with water (7 ml) and the mixture stirred at 24° C. for 10 hours. The solvent was removed under vacuum and the residue dissolved in toluene (30 ml). The toluene solution was washed with saturated sodium bicarbonate solution (2×10 ml) and water (10 ml) and dried over MgSO4. The dried solution was filtered and the filtrate evaporated down to a yellowish-brown semi-solid. This was recrystallised twice from isopropanol (2×10 ml) to give 0.5 g of pure 2-methoxynaphthaldehyde as confirmed using HPLC (conditions; spheresorb C18 25 cm×4.5 mm i.d. (column), 65% acetonitrile/35% water (eluent), 1 ml/min (flowrate), 310 nm (wavelength). The samples were dissolved in acetonitrile and 20 μl injected onto the column. The retention time for 2-methoxynaphthaldehyde was about 6 minutes.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: OCCBr
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Solvent: ClCCl
Product: O=C(CCBr)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, Mass.) was washed with deionized water to remove color. A mixture of 225 gm D-glucose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50Wx4 was treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction was monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction was complete after about four hours, and it was allowed to cool to room temperature. The solution was filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate was stripped to an amber oil in a rotory evaporator to give a total of 400 g after stripping.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][C:36]2=[O:48])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[CH:32][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]5=[O:48])=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)C(=O)C1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1Cc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1

Procedure:
Compound 357 was prepared as a off-white solid (TFA salt) from compound 4 and compound 358 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.67 (1 H, s), 9.35 (1 H, s), 8.70 (1 H, d), 8.66 (1 H, d), 8.48 (1 H, d, J=1.7 Hz), 8.20 (1 H, dd, J=8.8, 2.2 Hz), 7.91 (1 H, d, J=8.8 Hz), 5.48 (1 H, quin, J=8.7 Hz), 4.76 (2 H, s), 3.96 (2 H, s), 3.71 (2 H, t, J=5.7 Hz), 3.53-3.62 (2H, m), 2.46-2.61 (2 H, m), 2.14-2.33 (4 H, m), 1.82-1.98 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 442.9.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([C:19]1[N:20]=[C:21]([CH3:31])[S:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:18].[Br:32]Br>C(OCC)C.ClCCl>[Br:32][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([C:19]1[N:20]=[C:21]([CH3:31])[S:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:18]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3o2)c(-c2ccc(F)cc2)s1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2Br)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To (RS)-2-(2-benzofuranylmethyl)-1-((5-(4-fluorophenyl)-2-methyl-thiazol-4-yl)-carbonyl)-piperidine, E1 (0.90 g, 2 mmol) in dry diethyl ether (10 ml) and dichloromethane (20 ml) cooled to −12° C. under argon, was added drop-wise a solution of bromine (0.36 g, 2 mmol) in dichloromethane (10 ml) over 0.5 h. The resulting solution was warmed to ambient temperature over 1.5 h, then stirred for a further 18 h. The reaction mixture was evaporated then re-evaporated from dichloromethane (3×). The resulting amorphous solid was chromatographed (silica gel with ethyl acetate-hexane mixtures) to afford the title compound as an amorphous solid (0.27 g, 25%).
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26](OC)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
To a solution of (2S, 4S)-1-N-dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (2.09 g, 4.06 mmol) in tetrahydrofuran (20 ml) at −78° C. was added dropwise diisobutylaluminum hydride (1.0M in hexane, 15.0 ml, 15.0 mmol). After stirring at this temperature for 5 min. and at 0° C. for 2.5 h, the reaction was quenched with water at 0° C. After stirring at r.t. for 10 min., the mixture was diluted with ethyl acetate (250 ml), washed with 2N sodium hydroxide (3×100 ml), 35% sodium and potassium tartrate (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 3:1 to 2:1) to afford the title compound (1.65 g, 79%) as a colorless oil. [a]D=−18.5° (c 0.92, CHCl3).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:14]=2)=[C:6]2[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]=12.I[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:14]=2)=[C:6]2[CH2:11][CH2:10][N:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8](=[O:12])[C:7]=12
Reactant: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)NCC2
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)N(c1ccccc1)CC2
Temperature: 150 °C

Procedure:
To a solution of 3-(methylsulfanyl)-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one (Example 3) (20 mg, 0.051 mmol) in DMF (120 μL) at rt was added iodobenzene (21 mg, 0.101 mmol), K2CO3 (7 mg, 0.051 mmol) and CuI (1.0 mg, 0.0051 mmol). The reaction mixture was heated at 150° C. for 72 h. The resulting mixture was concentrated and purified directly by silica gel chromatography (gradient elution, 0-50% EtOAc/hexanes) to afford the title compound. LRMS (ESI) m/z 471.9 [(M+H)+; calcd for C23H29N3O2S2Si: 472].
Reaction SMILES: CO[C:3](=O)[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:3][NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)NCCc1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Add dropwise via an addition funnel a solution of [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid methyl ester (13.0 g, 62.2 mmol) in tetrahydrofuran (100 mL) to a stirred solution at 0° C. of 1.0M lithium aluminum hydride in tetrahydrofuran (156 mL) and tetrahydrofuran (250 mL). Reflux for 18 hours, cool to 0° C., quench with saturated aqueous ammonium chloride then stir at room temperature for 3 hours. Filter off the aluminum salts, concentrate on a rotary evaporator, and dry under vacuum to yield 6.6 g of 4-(2-methylamino-ethyl)-phenol: 1H NMR (DMSO-d6, 300.00 MHz): 6.97 (d, 2H); 6.65 (d, 2H); 2.65-2.55 (m, 4H); 2.28 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]2)=[CH:4][CH:3]=1.[CH2:29](C([Sn])=C(CCCC)CCCC)[CH2:30]CC.CCOC(C)=O>C1(C)C=CC=CC=1>[CH:29]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]2)=[CH:4][CH:3]=1)=[CH2:30]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nccc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Aryl bromide from Step 1 was dissolved in toluene (about 0.15 mM solution) and treated with tributylvinyltin (1.5 eq) and [Ph3P]4Pd(0) (0.05 eq). The reaction mixture was stirred at 100° C. under N2 atmosphere for 2 h. After cooling to RT, the reaction mixture was poured into EtOAc and washed with brine. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, PE/EtOAc 8/2 v/v as eluent) to give the title compound as a viscous oil. MS (ES+) C22H26N2O5 requires 398. Found: 399 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]#[N:22])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2].[OH-].[Na+].OO.S([O-])([O-])=[O:37].[Na+].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:22])=[O:37])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C#N)c2c(c1)CCN2CCCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
(R)-5-[2-[[2-(2-Ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile (5.95 g) was dissolved in dimethylsulfoxide (16.4 ml), and 5N sodium hydroxide solution (0.25 ml) was added to the solution. To the mixture was added 30% hydrogen peroxide (1.55 ml) keeping inner temperature below 25° C., and the mixture was stirred overnight at an inner temperature of 25-30° C. A solution of sodium sulfite (2.39 g) in distilled water (82 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, distilled water and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was recrystallized from ethyl acetate to give (R)-5-[2-[[2-(2-ethoxyphenoxy)-ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (4.72 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.O>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a stirred suspension of zinc powder (0.71 g, 10.9 mmoL) in anhydrous THF (15 mL) was slowly added, via syringe, TiCl4 (0.58 mL, 1.0 g, 5.3 mmoL) at RT under a nitrogen atmosphere. The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2.5 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.408 g, 1.47 mmol) and cyclopentanone (0.38 mL, 0.36 g, 4.3 mmol) in THF (15 mL) and heating continued an additional 2 h. The reaction mixture was allowed to cool to room temperature and water (10 mL) slowly added. The reaction mixture was then filtered through a pad of Celite and the Celite pad washed with EtOAc. The filtrate was transferred to a separatory funnel and the organic layer was separated. The organic phase washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 0.391 g (81%) of compound 3 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.59 (m, 4 H), 2.27 (m, 4 H), 6.66 (d, J=8.5 Hz, 2 H), 6.89 (d, J=8.4 Hz, 2 H), 7.04 (d, J=8.4 Hz, 2 H), 7.45 (d, J=8.4 Hz, 2 H), 9.32 (s, 1 H). HRMS (EI) Calcd for C18H17BrO: 328.0463 (M+). Found: 328.0469.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:22])=[C:12]([C:17]([O:19]CC)=[O:18])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:23][CH3:24])=[C:5]([CH3:25])[O:4][N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:22])=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:23][CH3:24])=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(O)c(C(=O)O)cnc2cc1-c1c(C)noc1C
Reaction time: 0.17 h

Procedure:
Ethyl 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylate (for a preparation see Intermediate 58, 70.2 g, 205 mmol,) was suspended in a mixture of ethanol (200 ml) and sodium hydroxide (2M, 308 ml, 615 mmol) and the mixture was heated at reflux overnight. The reaction was concentrated to ca 200 ml in vacuo, diluted with water (500 ml) and the resulting solution washed with ethyl acetate (200 ml). The aqueous phase was acidified to pH4 with hydrochloric acid (1M), the resulting suspension stirred vigorously for 10 min. The solid was collected by filtration, washed with water (200 ml) and dried overnight at 40° C. in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid as a beige solid (54.7 g). Used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH2:24]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18]([NH:24][CH3:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CN
Product: CNC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
A 500-mL flask was charged with methyl 3-(3,5-ditert-butyl-4-hydroxy-phenyl)-3-oxo-propanoate (24.3 g, 79.3 mmol) and a 40% methylamine solution (55 g). The solution was stirred for 2 h. The conversion of the starting material (Rf 0.91) to the title compound (Rf 0.4) was monitored by TLC using 1:1 ethyl acetate-hexane as solvent and UV detection of the substances. The solution was diluted with 2-propanol (100 mL) and evaporated. The solid residue was taken up in boiling 2-propanol (ca. 100 mL) and evaporated again. The residue was again taken up in boiling toluene (ca. 75 mL) and the hot solution was concentrated to afford a crystalline suspension. This suspension was re-dissolved by heating and the hot solution was diluted with cyclohexane (80 mL) to cause immediate crystallization. The suspension was homogenized by reheating, allowed to cool to room temperature, then refrigerated overnight and filtered. The filter cake washed with cyclohexane and hexane, dried to constant weight at 65° C. and 20 torr to afford 22.77 g of the title compound. This material was recrystallized by dissolving in boiling toluene (ca. 120 mL) followed by the addition of cyclohexane (100 mL). The suspension was allowed to cool to room temperature, then refrigerated and filtered. The filter cake was washed with cyclohexane then hexane and dried to constant weight at 65° C. and 20 ton to afford 22.03 g of the title compound (91%). TLC (1:1 ethyl acetate-hexane) Rf 0.48; 1H-NMR (300 MHz, DMSO-d6) δ 1.37 (9H, s), 2.57 (3H, d, J=4.6 Hz), 3.73 (2H s), 7.73 (2H, s), 7.85 (1H, s), 8.08 (1H, br s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH2:27][OH:28])[CH:24]=[CH:25][CH:26]=1.[H-].[Na+]>CS(C)=O>[NH:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([O:28][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=3)=[CH:3][CH:4]=2)=[O:9])=[CH:11]1
Reactant: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Reactant: OCc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(c1ccc(OCc2cccc(C(F)(F)F)c2)nc1)c1c[nH]c2ncccc12
Temperature: 60 °C

Procedure:
To (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 in DMSO was added (3-trifluoromethyl-phenyl)-methanol 72. Sodium hydride was added and the reaction was heated to 60° C. for two hours. The reaction was quenched with water and extracted with ethyl acetate. The organic portion was dried with magnesium sulfate and concentrated to provide (1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone 73, which was used in the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:13]=O)[CH3:12]>>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:1]/[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#N)n1
Reactant: CN(C)C=O
Product: CN(C)/C=C/c1cccc(C#N)n1

Procedure:
20 g (169 mmol) of 6-methylpyridine-2-carbonitrile were reacted in a mixture of in each case 100 ml of DMF and DMF-dimethyl acetal in an autoclave at 175° C. overnight. After cooling, the mixture was concentrated by evaporation, the residue was dissolved in dichloromethane, the solution was filtered, the filtrate was concentrated and the residue was subjected to distillation under reduced pressure in a kugelrohr.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[F:16]>CS(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([C@@H:17]2[CH2:4][C@H:18]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=Cc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(Br)c1
Temperature: 50 °C

Procedure:
Under argon, 381 mg (9.52 mmol) of sodium hydride (60% in paraffin oil) were initially charged in 20 ml of DMSO, and 2.1 g (9.52 mmol) of trimethylsulphoxonium iodide were added in one portion at RT. After the evolution of gas had ceased, 2.0 g (7.3 mmol) of ethyl 3-(3-bromo-4-fluorophenyl)acrylate, dissolved in 10 ml of DMSO, were slowly added dropwise. The reaction mixture was heated at 50° C. overnight, then cooled to RT and, without further work-up, purified by flash chromatography on silica gel (mobile phase isohexane/ethyl acetate 100:1). This gave 907 mg (43% of theory) of the target product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([CH:30](C(OCC)=O)[C:31]([O:33]CC)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[C:7]([CH2:10][CH:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:31]([OH:33])=[O:32])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared following the procedure of Example 21 using 2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]-1H-imidazol-5-carboxaldehyde and diethyl benzylmalonate; mp 120°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>ClCCCl>[Cl:15][CH2:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:19]
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)CCCl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15° C. After stirring at room temperature for 2 hours, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as an oil. MS: 202.1 (M+H+)+.