Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)CCC>[C:1]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCC=O
Solvent: CCCCO
Product: CCCCOC(=O)CCC

Procedure:
Further n-butyraldehyde is supplied to nozzle 123 in second vaporiser 122 by way of line 124. Reference numeral 125 indicates a distribution tray. A hot vaporous mixture comprising unreacted hydrogen from first catalytic stage 116, product n-butanol, inerts, and a minor amount of by-products, e.g. n-butyl n-butyrate, also formed in first catalytic stage 116, exits vaporiser 122 overhead in line 126 at a temperature of 105° C. After passage through a heater 127, supplied with a suitable heating medium, e.g. steam, in line 128, the mixture passes on in line 129 at a temperature of 125° C. to second catalytic stage 130. The aldehyde is quantitatively hydrogenated, n-butanol being the major product, under adiabatic conditions. The temperature of the vaporous reaction mixture exiting second catalytic stage 130 in line 131 is 195° C. After heat recovery in heat exchanger 132 by indirect heat exchange with a cooling medium, e.g. boiler feed water, supplied in line 133, the reaction mixture, now at 150° C. passes on in line 109 to heat exchanger 108.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)S([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([O:16][C@H:23]([CH3:18])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)c(OCc2ccccc2)c1
Reactant: C[C@@H](CCCCc1ccccc1)S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCCc1ccccc1)Oc1ccc(Br)c(OCc2ccccc2)c1
Yield: 72 %

Procedure:
A mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophenol, 20.0 g. (82.6 mmole) of (S)-1-methyl-4-phenylbutylmethane sulfonate and 25.2 g. (200 mmole) of potassium carbonate in 100 ml. dimethylformamide was heated at 85° C. for 13.5 hours. The reaction was cooled and added to 500 ml. water-500 ml. ether. The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 750 g. of silica gel eluted with 10% etherhexane to yield 23.9 g. (72%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2ccc(Br)cc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 54.8 %

Procedure:
The product from Step B (97 g, 397 mmol) was added to polyphosphoric acid (580 g) and the resulting mixture was stirred at 90° C. for 10 minutes. After cooling to 0° C., 6 M NaOH (2 l) was added and the mixture was extracted with methyl tert-butyl ether. The organic extracts were dried over magnesium sulfate to give 7-bromo-3,4-dihydronaphthalen-1-one (49 g, 55%) after chromatography (6:1 to 4:1 heptane/ethyl acetate) and recrystallization from cyclohexane: 1H NMR (300 MHz, DMSO-d6) δ 7.91 (d, J=2.1 Hz, 1H), 7.71 (dd, J=8.1, 2.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 2.90 (t, J=6.0 Hz, 2H), 2.61 (t, J=6.3 Hz, 2H), 1.99-2.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[CH3:10][N:11]([CH3:22])[C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C1(C)C(C)=CC=CC=1.[Cu].O>[CH3:22][N:11]([CH3:10])[C:12](=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CN(C)C(=O)Cc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(C)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
In 80 ml of xylene (having a boiling point of 138° to 141° C.), 8.5 g (0.0525 mole) of 2,6-dichloroaniline was refluxed together with 5.2 g (0.0215 mole) of N,N-dimethyl-o-bromophenylacetamide, 5.0 g (0.0357 mole) of potassium carbonate, 1.0 g of copper powder, 1.0 g of cuprous iodide and 2.0 g of sodium iodide for 48 hours under agitation, while water formed by the reaction was being separated. After completion of the reaction, the reaction mixture was treated with active carbon while it was still warm, and the filtrate was concentrated. The obtained residue was mixed with methyl alcohol and the crystal precipitated on cooling was recovered by filtration, washed with methyl alcohol and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])(C(F)(F)F)[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10](=[O:27])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(=O)Cn1ccc(=O)c2ccccc21
Temperature: 120 °C
Yield: 56.7 %

Procedure:
To a solution of 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (2.25 g, 5.14 mmol) in DMF (40 mL) was added potassium carbonate (2.13 g, 15.4 mmol) followed by heating to 120° C. in a sealed reaction vessel for 14 hours. The solution was diluted with 300 mL of diethyl ether, washed with one 200 mL portion of saturated aqueous sodium bicarbonate, three 100 mL portions of water, one 100 mL portion of brine, dried over anhydrous sodium sulfite (Na2SO3), and concentrated in vacuo. The crude material was purified by flash column chromatography (5% MeOH/CH2Cl2) to give 1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]-1H-quinolin-4-one as a brown foam (1.07 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[Cl-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][Zn+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cccc(C[Zn+])c1
Reactant: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1nc(Cc2cccc(Cl)c2)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (1.46 g, 3.33 mmol), 3-chlorobenzylzinc chloride (0.5 M in tetrahydrofuran, 6.8 ml, 3.40 mmol), tetrakis(triphenylphoshino)palladium(0) (384 mg, 0.33 mmol), and tetrahydrofuran (10 ml) were combined and stirred for 18 hours at 50° C. The reaction was quenched with saturated, aqueous ammonium chloride, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 10% ethyl acetate in hexanes) to give 436 mg (30%) of 2,2-dimethyl-propionic acid 5-bromo-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.88 (s, 1H), 7.24-7.18 (m, 4H), 6.41 (s, 2H), 4.25 (s, 2H), 1.18 (s, 9H); MS: m/z 436.1, 438.1 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:23][O:24][C:25]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])([CH2:8][O:9][C:10]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH2:6][OH:7])=[N+:2]=[N-:3].CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(O)C>[N:1]([CH2:4][C:5]([CH2:8][O:9][C:10]([C:11]([F:14])([F:13])[F:12])([C:15]([F:18])([F:17])[F:16])[C:19]([F:21])([F:22])[F:20])([CH2:23][O:24][C:25]([C:30]([F:31])([F:32])[F:33])([C:26]([F:27])([F:28])[F:29])[C:34]([F:35])([F:36])[F:37])[C:6]([OH:40])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(CO)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: [N-]=[N+]=NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of alcohol 11 (19.0 g, 31.8 mmol) at 0° C. was added dropwise a solution of Jones reagent (2.7 N, 31 mL). After addition, the reaction mixture was stirred at room temperature for 1 hour and 2-propanol (10 mL) was slowly added. The solvent was removed under vacuo and the residue was dissolved in ether. Washing the ether solution with water, separation the layers and the aqueous lay was extracted with ether. The combined organic lay was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give the acid 12 as a solid (18.5 g, 95%). mp. 97-98° C.; 1H NMR (400 MHz, CD3OD) δ 3.62 (s, 2H), 4.25 (d, J=8.8 Hz, 2H), 4.33 (d, J=8.4 Hz, 2H); 19F NMR (376 MHz, CD3OD) δ −71.16 (s); 13C NMR (100.7 MHz, CD3OD) δ 50.9, 53.6, 67.5, 81.2 (m), 121.6 (q, J=292.6 Hz), 171.9; MS (CI) m/z 612 (M++1, 100), 584 (80); HRMS (CI) Calcd for C13H8F18N3O4: 612.0227, Found: 612.0204.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](O)[CH3:38]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][CH3:38])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: CCO
Product: CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting ethanol in place of 2-ethyl-1-hexanol (yield: 25 mg, 12%). mp 121-123° C. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (t, J=7 Hz, 3H), 3.30 (s, 3H), 4.51 (q, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 407 (M+H)+; (APCI−) m/z 441 (M+Cl)−. Anal. calc. for C19H16F2N2O4S.0.25H2O: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H, 4.21; N, 6.61.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([C:21]1[N:22]([Si](C(C)C)(C(C)C)C(C)C)[C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([N:30]1[C@@H:39]3[C@H:34]([CH2:35][CH2:36][CH2:37][CH2:38]3)[NH:33][C:32]([CH3:41])([CH3:40])[CH2:31]1)=[CH:25][CH:24]=2)#[N:20]>O1CCCC1>[C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([N:30]1[C@@H:39]3[C@H:34]([CH2:35][CH2:36][CH2:37][CH2:38]3)[NH:33][C:32]([CH3:41])([CH3:40])[CH2:31]1)=[CH:25][CH:24]=2)#[N:20]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c(C#N)cc2cc(N3CC(C)(C)N[C@H]4CCCC[C@@H]43)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CN(c2ccc3[nH]c(C#N)cc3c2)[C@H]2CCCC[C@@H]2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Tetrabutylammonium fluoride (1 M THF solution, 0.73 mL, 0.73 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution of (4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (170 mg, 0.366 mmol) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane= 1/10→ 1/1). The solvent was removed under reduced pressure. The obtained residue was recrystallized from ethyl acetate/n -hexane to obtain (4aS,8aS)-1-(2-cyano-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (30 mg, yield: 27%) in a white powder form.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:14])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1C(=O)CCC1=O
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)CCC1(C)C(=O)CCC1=O
Reaction time: 72 h

Procedure:
A mixture of 0.3 g. of 2-methylcyclopentane-1,3-dione, 0.33 ml. of methylacrylate and 0.1 g. of potassium t-butoxide in 200 ml. of t-butanol is allowed to stand at about 20°C for 72 hours. The reaction mixture is washed with water, dilute sodium hydroxide and then water to neutral, dried and evaporated to give 2-methyl-2-(β-carbomethoxyethyl)cyclopentane-1,3-dione which is purified by distillation. ##SPC6##
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: NC1CCCC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C(NC1CCCC1)c1cccc(Cl)c1
Yield: 92 %

Procedure:
Employing 0.16 g (1.9 mmol) of cyclopentylamine and 0.51 g, (2.9 mmol) of 3-chloro-benzoyl chloride in the procedure described above and elution with CHCl3/MeOH/Et3N (9.8:0.1:0.1) gave white crystals in 92% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[I:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([CH2:8][O:26][C:23]2[CH:24]=[CH:25][C:20]([I:19])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Yield: 90.4 %

Procedure:
Freshly ground potassium carbonate (8.3 g, 60 mmol) was added to a solution of methyl 3-bromomethyl-benzoate (12.83 g, 56 mmol; available from Lancaster Synthesis Ltd., Lancashire, UK) and 4-iodophenol (13.2 g, 60 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) in acetone (600 mL). The reaction mixture was heated at reflux overnight and then it was filtered and water was added. The resulting white solid was filtered off and dried in a vacuum oven overnight to give 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (18.63 g, 90%) as a white solid
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.NC1N=CC([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([C:39](=O)CO)[CH2:35][CH2:34]3)[CH:32]=2)=CC=1O[C@@H](C1C(Cl)=CC=C(F)C=1Cl)C>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH:32]=2)[N:3]=1)[CH3:11]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)CO)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 62 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-(4-bromo-pyrazol-1-yl)-1-methy-piperidine (prepared according to general procedure 11). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.46 (q, 1H), 6.15 (s, 2H), 4.02 (m, 1H), 2.84 (m, 2H), 2.19 (s, 3H), 2.00 (m, 4H), 1.85 (m, 3H), 1.75 (d, 3H); LCMS: 465 [M+1]; c-Met Ki: 0.03 μM.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14]S(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14][N:19]=[N+:20]=[N-:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC1CN(Cc2ccccc2)CC1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1O
Yield: 85.7 %

Procedure:
1-Benzyl-4-hydroxy-3-methanesulfonylmethylpyrrolidine (80.8 g) is added to methanol-water (3:2) (1 liter), and thereto is added dropwise sodium azide (24.5 g), and the mixture is refluxed for 24 hours. After the reaction, the mixture is concentrated and extracted with dichloromethane. The dichloromethane solution is washed with water and saturated saline, dried and concentrated to give 1-benzyl-4-hydroxy-3-azidomethylpyrrolidine (59.7 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[C:10]([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2]
Reactant: CCc1ccc(O)c(CC)c1C=O
Reactant: OB(O)c1ccccc1
Product: CCc1ccc(Oc2ccccc2)c(CC)c1C=O

Procedure:
2,6-Diethyl-3-phenoxy-benzaldehyde was prepared from 2,6-diethyl-3-hydroxy-benzaldehyde and phenylboronic acid in analogy to Example 219a): yellow oil; 1H-NMR (CDCl3): 1.20 (3H, t, CH3), 1.25 (3H, t, CH3), 2.93 (2H, q, CH2), 2.98 (2H, q, CH2), 6.91 (2H, d, 2×ArH), 7.00-7.10 (3H, m, 3×ArH), 7.28-7.38 (2H, m, 2×ArH), 10.6 (1H, s, CHO).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Oc2ccccc2)cc1
Yield: 92.6 %

Procedure:
To a solution of (4-(phenyloxy)phenyl)methanol (8 g, 40.0 mmol) in chloroform (20 ml) was added thionyl chloride (36 ml, 500 mmol) and the mixture was heated under reflux overnight. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1-(chloromethyl)-4-(phenyloxy)benzene (8.1 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[O:40]1[CH2:41][CH2:42][N:37]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:2]3[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:35][CH:34]=2)[CH2:38][CH2:39]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: O=C(NCCN1CCCC1)c1cc(Cl)nc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2ccccc12
Temperature: 130 °C
Yield: 74.2 %

Procedure:
In a sealed 5 ml microwave tubed, a suspension of 2-chloro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 11) (200 mg, 0.66 mmol), 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (preparation 2) (399 mg, 1.31 mmol), potassium phosphate (419 mg, 1.97 mmol) and tetrakis(triphenylphosphine)palladium (0) (22 mg, 0.02 mmol) in DMF/Water 3/1 (4 ml) was heated at 130° C. under microwave irradiation for 30 minutes. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (50 ml) and washed with NaHCO3 saturated aqueous solution (25 ml). The organic layer was separated and dried over MgSO4 before concentration to dryness. The reaction crude was purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired compound as a white solid (220 mg, 0.49 mmol, Yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:13])[CH3:12]>>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(Cl)cc1

Procedure:
Ethyl 4-chlorobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, p-chlorobenzonitrile (25.6 g, 0.186 mol) was reacted with hydrogen chloride in ethanol (250 mL) to give 36.8 g (90%) of the target compound as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCNC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (78) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.97 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[N:14]4)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:28](Br)[CH:29]=[CH2:30]>COCCOC.C1(C)C=CC=CC=1>[CH2:30]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[N:14]4)[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
4-p-hydroxyphenyl-7-phenyl-1,10-phenanthroline (0. 348 g) is reacted with Na metal (0.023 g) in ethylene glycol dimethyl ether (100 mL). To this mixture is added a solution of allylbromide (0.125 g) in ethylene glycol dimethyl ether (10 mL). The resulting mixture is stirred at 35° C. for 24 hours, or until the reaction is judged complete by TLC. The reaction mixture is diluted with toluene, washed with 10% NaOH, washed with water and dried over MgSO4. Roto-evaporation of the solvent gives a residue that is purified by column chromatography on silica gel.