Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6](C2CCCCO2)[N:5]=[CH:4][C:3]=1[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])C#N>Cl.C(O)(=O)C.O>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[CH2:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:26])([F:27])[F:25]
Reactant: N#CC(c1ccccc1C(F)(F)F)c1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]ncc(Cc2ccccc2C(F)(F)F)c1Cl
Temperature: 120 °C
Yield: 60.2 %

Procedure:
A mixture of [5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yl]-(2-trifluoromethyl-phenyl)-acetonitrile (550 mg, 1.38 mmol) in concentrated hydrochloric acid (8.4 mL), glacial acetic acid (2.1 mL) and water (2.1 mL) (4:1:1, 0.11 M) was heated to 120° C. overnight. After this time, the reaction was cooled to 25° C. and then poured onto ice, followed by rinsing with minimal water. The resulting aqueous mixture was brought to pH=4-5 by treatment with a 4N aqueous sodium hydroxide solution. The resulting tan solids were collected by filtration. The solids were subsequently washed with water (2×10 mL) and dried in vacuo to afford 4-chloro-5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (0.24 g, 62%) as a tan solid; ES+-HRMS m/e calcd for C12H8N2OF3Cl [M+H+] 289.0350, found 289.0350.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(OC(C)C)(C)C.[F:12][C:13]([F:40])([S:36](F)(=[O:38])=[O:37])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].Cl>O>[CH2:1]([NH:4][S:36]([C:13]([F:12])([F:40])[C:14]([F:34])([F:35])[C:15]([F:32])([F:33])[C:16]([F:30])([F:31])[C:17]([F:28])([F:29])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])(=[O:38])=[O:37])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O
Product: C=CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Allyl amine (45.0 milliliters, 3.0 molar equivalent) and isopropyl ether (200.0 milliliters) were charged into a 3-neck 500-milliliter round bottom flask equipped with a Claisen joint adapter, dropping funnel and overhead mechanical stirrer at room temperature under a nitrogen blanket. The Claisen joint adapter was attached to a Thermowatch® thermometer adapter and water cooled condenser (to the nitrogen inlet). The mixture was warmed to 25° C. with stirring. Perfluoro-1-octanesulfonyl fluoride (100.0 grams, 1.0 molar equivalent, Aldrich Chemical Co.) was added by the dropping funnel over 1.5 hours. The reaction mixture was maintained at about 25° C. by immersing the reaction flask in a room temperature water bath. After the addition was completed, the reaction mixture was heated for 2 hours at 30° C., followed by 2 hours at 40° C. Upon cooling to 30° C. using a water bath, 120 milliliters of a 9% aqueous hydrochloric acid solution was added over 15 minutes while maintaining the temperature at 25° C. After separation of the layers in a separatory funnel, the organic layer was washed with an aqueous 4.5% hydrochloric acid 4.0% ferrous sulfate solution. The organic phase was isolated and evaporated in vacuo, further dried under vacuum (0.1 millimeters Hg) in a water bath at 70° C. for 0.5 hours to give a red pasty solid. The crude reaction product was subjected to high vacuum distillation to give a slightly yellow solid (boiling point 98° C.) (0.1 millimeters Hg)(85.62 grams, 80% purified yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.ICCCC(O[C:19]([CH3:22])([CH3:21])[CH3:20])=O>C=C(C)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCCI
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: C=C(C)C
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1

Procedure:
4-(Bromomethyl)benzoic acid (6 g, 26 mmol) and isobutene (30 ml) were reacted by the same procedure as described in Example 3 for the preparation of tert-butyl 4-iodobutanoate and afforded the title material (2.4 g) as a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:40]=[N:41][C:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:43]([CH3:45])[CH:44]=1)=[O:37].O>ClCCl>[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([CH:46]2[CH2:51][CH2:50][N:49]([CH:3]3[CH2:2][O:1][CH2:4]3)[CH2:48][CH2:47]2)=[N:41][CH:40]=1)=[O:37]
Reactant: O=C1COC1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C2COC2)CC1
Reaction time: 5 h
Yield: 35.5 %

Procedure:
3-Oxetanone (121 mg) and sodium triacetoxyborohydride (143 mg) were added at room temperature to a solution of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (250 mg) described in Reference Example 171 in dichloromethane (24 ml), and stirred at the same temperature for five hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and concentrated. 1N Aqueous solution of sodium hydroxide (20 ml) was added to the resulting residue, solid was collected by filtration purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.C(O)(=O)C.[Br:17]Br.C([O-])(O)=O.[Na+]>O>[Br:17][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: BrBr
Reactant: c1ccc(Nc2nccs2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc(Nc2ccccn2)s1
Reaction time: 0.25 h

Procedure:
To a flask containing pyridin-2-yl-thiazol-2-yl-amine (5-2, 3.92 g, 0.0221 mol) was added acetic acid. Bromine (1.14 mL, 0.0221 mol) was then added dropwise to the stirred solution at ambient temperature. The reaction was stirred for 15 min, resulting in an orange-white precipitate. At 15 min, 100 mL H2O were added and solid NaHCO3 introduced, causing a large amount of foaming. The product was obtained as a tan colored precipitate, which was washed with 1.5 L H2O and dried under high vacuum overnight. 1H NMR (DMSO-d6): δ11.53 (bs, 1H), 8.31 (d, 1H, J=3.3 Hz), 7.73 (t, 1H, J=7.6 Hz), 7.45 (s, 1H), 7.05 (d, 1H, J=8.4 Hz), 6.96 (t, 1H, J=5.5 Hz). Mp: 210-212° C. (dec). [M+H]+=255.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:10]#[N:11])[C:3]=1[CH3:21].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])([CH3:22])[C:10]#[N:11])[C:3]=1[CH3:21]
Reactant: Cc1cc(C)c(C(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C)(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
A solution of (6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-acetonitrile (0.250 g, 0.834 mmol) in 4 ml of dry THF was cooled to −78° C. and treated with lithium bistrimethylsilylamide (1.0 M in THF, 0.92 ml) and stirred at that temperature for 45 minutes. Methyl iodide (0.426 g, 3.00 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow oil. The oil residue was purified through silica gel chromatotron using ethyl acetate/hexane (4:6) as eluent to give 161 mg (62%) of yellow solid, mp 181–183° C. 1H NMR (CDCl3) δ 6.980 (s, 2H), 3.45 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.25 (s, 3H) ppm.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.O>C1(C)C=CC=CC=1>[C:1](=[N:14][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cccc(N=C(c2ccccc2)c2ccccc2)c1

Procedure:
3-(Benzhydrylidene-amino)-phenol was prepared as follows: A stirred solution of benzophenone imine (15.0 g, 82.8 mmol) and 3-aminophenol (9.03 g, 82.8 mmol) in 25 mL toluene was heated at reflux with removal of H2O with a Dean-Stark trap for 3.5 h. The crystals that formed from the cooled reaction mixture were collected by vacuum filtration, washed with hexanes and air dried. In this manner, 3-(benzhydrylidene-amino)-phenol was obtained as a light yellow solid (17.3 g, 76%): 1H NMR (CDCl3) δ 7.64 (d, 2H, J=7.1 Hz), 7.38 (d, 1H, J=7.1 Hz), 7.34–7.15 (m, 7H), 7.04 (d, 2H, J=7.2 Hz), 6.88 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J=7.8 Hz). Anal. Calc. for C19H15NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51; H, 5.65; N, 5.03.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH3:13])(=O)C.[OH-].[Na+]>C(O)C.O>[CH3:14][CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5][OH:4]
Reactant: CCC/C=C\CC(C)CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC/C=C\CC(C)CCO
Yield: 91.8 %

Procedure:
In the next step, 55.0 g (278 mmol) of this (5Z)-3-methylnon-5-enyl acetate was dissolved in 600 mL of a 1:1 mixture of ethanol and water. With vigorous stirring, 55.5 g (1.39 mol) of sodium hydroxide was added, and the reaction mixture was subsequently heated to reflux for 3 h. After the reaction mixture had cooled to room temp., the ethanol was removed in a rotary evaporator under reduced pressure, and the resulting residue diluted with 300 mL of water. The crude product was extracted twice with 500 mL of ether each, and the combined organic extracts were washed twice with 300 mL of brine. After drying with sodium sulphate and removal of the solvent under reduced pressure, the resulting residue (51.2 g) was purified by flash chromatography (1.00 kg of silica gel, pentane/ether, 9:1, Rf=0.11) to provide 39.9 g (92%) of (5Z)-3-methylnon-5-en-1-ol as a colourless liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)(=[O:4])=[O:3].O.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C>[Br:14][C:10]1[CH:9]=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: BrBr
Reactant: COc1cccc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(S(C)(=O)=O)c1
Reaction time: 15 h
Yield: 45 %

Procedure:
1-Methanesulfonyl-3-methoxy benzene was dissolved in 90 mL glacial acetic acid. 100 mL water was added. A solution of bromine (4.79 g, 30 mmol) in 10 mL acetic acid was added dropwise at 10° C. The stirring was continued at rt for 15 h. The pH of the mixture was adjusted to pH 8 with aqueous NaOH solution, and extracted with EtOAc (3×200 mL) and dried over Na2SO4. The crude compound was purified by column chromatography (SilicaGel 230-400 mesh; 20% EtOAc in hexanes as an eluent) to give 1-bromo-2-methanesulfonyl-4-methoxy benzene (2.4 g, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[CH3:18][O:19][C:20](=O)C.COCCl>CN(C)C=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(C)=O
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Agent: COCCl
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 12 h

Procedure:
A mixture of 23 g. of methyl 6-hydroxy-2naphthyl-α-methylacetate, methylacetate, 25 g. of chlorodimethyl ether, and 500 ml. of dimethylformamide is allowed to stand at room temperature for 12 hours. The reaction mixture is evaporated under reduced pressure to give methyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
Compound 1 (150 mg, 0.32 mmol) was dissolved in DCM and TFA (0.25 mL, 3.20 mmol) was added. The resulting mixture was stirred overnight. The mixture was concentrated, diluted with DCM and washed with saturated NaHCO3 solution. The filtrate was dried anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with 0-30% 1M methanolic ammonia/dichloro-methane to give desired product, Compound 2 as a white solid (0.10 g, 85%). MS: m/z 370.2 [M+H]+. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.76 (s, 3H), 3.16 (m, 2H), 4.11 (m, 2H), 4.37 (m, 3H), 7.53 (m, 3H), 7.71 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:15]2[C:16](=[O:17])[C:8]3([CH2:7][C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:9]3)[NH:13][C:14]2=[O:18])=[CH:23][CH:22]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)NC3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.4 g, 5.66 mmol, described in Intermediate 6), 4-methoxybenzyl alcohol (0.94 g, 6.80 mmol), diethyl azodicarboxylate (1.48 g, 8.49 mmol), and triphenylphosphine (2.23 g, 8.49 mmol) in THF (15 mL) was stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound as a yellow solid. MS: m/z=368 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:30][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:28])=[CH:23][CH:22]=1
Reactant: NCCCSc1ccncc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 76.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.65 ml (4.96 mmol) of 4-toluoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 910 mg of the desired compound (76.6%, colorless powder), mp: 110.0°-111.0° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:26]([C:29]1[CH:42]=[CH:41][C:32]([O:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([O:40][C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]4[CH:41]=[CH:42][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=4)=[CH:39][CH:38]=3)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 93.2 %

Procedure:
2-(4-(3-Chloro-5-trifluoromethyl-2-pyridyloxy)phenoxypropionic acid chloride hydrochloride (0.7 g) and 4-(4-nitrophenoxy)phenol (0.5 g) were dissolved in dry tetrahydrofuran (10 ml), and stirred with an addition of triethylamine (0.5 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure and the residue was dissolved in methylene chloride (20 ml), followed by washing with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and the residue obtained was purified by medium pressure column chromatography by using silica gel, to obtain 4-(4-nitrophenoxy)phenyl 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate (0.9 g) (oily product).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:35]1(/[CH:41]=[CH:42]/[C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([C:43](=[O:44])/[CH:42]=[CH:41]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CCNCC2)s1)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(S(=O)(=O)N2CCN(C(=O)/C=C/c3ccccc3)CC2)s1)c1ccc(Cl)cc1
Yield: 21 %

Procedure:
To a stirred solution of 1 (36 mg, 0.09 mmol) and iPr2NEt (32 μl, 0.189 mmol) in CHCl3 (2 mL) was added [(2E)-3-phenylprop-2-enoyl]chloride (15 mg, 0.09 mmol). After 4 h the reaction mixture was washed with HCl (1 N) and sat. NaCl solution, and dried over MgSO4. The solvent was evaporated and the residue was filtered through silica gel using AcOEt/MeOH 1% as eluent to afford 159 as white solid (10 mg, 20%). M/Z APCI: 531.2 (M+1), 529.1 (M−1). Anal. HPLC: rt.=6.18 min (method a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Yield: 72.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (58 mg) was dissolved in toluene (5 ml) with heat, 2,4-dichlorophenyl isocyanate (93 mg) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 69 mg of the title compound (yield: 73%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH:17]=[CH:16]2.[BH4-].[Na+]>CO.O>[CH3:23][N:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]1=[O:24]
Reactant: Cn1c(=O)ccc2cc(OCCN)ccc21
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCNCc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
3-Pyridine carbaldehyde(0.99 ml) and 6-(2-Aminoethoxy)-1-methyl-1H-quinolin-2-one(2.18 g) were added to methanol (50 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride(0.757 g) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound(3.063 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:37]1([CH2:43][CH2:44]N)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[N:37]1([CH2:43][CH2:44][NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: NCCN1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCN3CCCCC3)cc21
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 2-piperidin-1-yl-ethylamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-6 as an oil in 100% yield.