Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O>[N:34]1([C:40]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Temperature: 50 °C
Yield: 99 %

Procedure:
To 6.50 g (23.5 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 39 g of toluene and 2.62 g (25.9 mmol) of triethylamine, and the resultant mixture was stirred at 30° C. To the mixture was added dropwise 7.73 g (51.7 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 30° C. for 2 hours, and then further heated to 50° C. to effect a reaction for 2 hours. After completion of the reaction, pure water was added to the reaction mixture, and an organic phase and an aqueous phase were separated, and then the resultant organic phase was quantitatively determined by an HPLC internal standard analysis method, which showed that 9.07 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1.FC(F)(F)C(O)=O.ClCCl.C(N(CC)CC)C.ClC1[N:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42]>ClCCl.O1CCCC1.CO>[Cl:49][C:46]1[CH:47]=[N:48][C:14]([N:12]2[CH2:11][CH:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:13]2)=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(F)cc2F)C1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-((2,4-difluorophenyl)amino)azetidine-1-carboxylate (D31) (90 mg, 0.316 mmol) in dichloromethane, a mixture of trifluoroacetic acid/dichloromethane (3 ml/1 ml) was added and the reaction mixture was stirred 1 h. The solvents were evaporated in vacuo and the residue was dissolved in tetrahydrofuran/methanol (3/1 ml) triethylamine (0.132 ml, 0.95 mmol) was added followed by the addition of methyl 2,5-dichloronicotinate (52.33 mg, 0.253 mmol) and the resulting mixture was stirred 12 h at 75° C. The residue abtained after solvent evaporation was purified by Biotage SNAP-Si column eluting with cyclohexane/ethyl acetate from 100/0 to 90/10. Collected fractions afforded the title compound (D85) (0022/086/5) (38 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.[F:29][C:30]1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:2]=[CH:3][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)=[CH:32][CH:31]=1
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Product: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(Cc3ccc(F)cc3)c2=O)CC1
Yield: 54.8 %

Procedure:
The general procedure of Example 1 (6) was repeated by use of 2-(4-fluorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a pale yellow powder (yield: 54.8%).
Reaction SMILES: C([N:9]1[CH2:18][C:17]2[CH:16]=[N:15][C:14]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:13]=3[C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.O[Li].O.C(O)(C)C>CO.O>[CH3:26][O:25][C:20]1[C:21]([O:23][CH3:24])=[CH:22][C:13]2[C:12]3[CH2:11][CH2:10][NH:9][CH2:18][C:17]=3[CH:16]=[N:15][C:14]=2[CH:19]=1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: COc1cc2ncc3c(c2cc1OC)CCNC3
Temperature: 64 °C
Yield: 58.3 %

Procedure:
A 2 L three-necked, round-bottomed flask, was equipped with a magnetic stirrer and stir bar, condenser, heating bath, thermocouple and nitrogen inlet. A stirred solution of 3-benzoyl-8,9-dimethoxy-1,2,3,4-tetrahydrobenzo[c]-2,7-naphthyridine (25.9 g, 74.4 mmol) and LiOH.H2O (34.4 g, 819 mmol) in methanol (800 mL) and water (55 mL) was heated at gentle reflux (internal temperature 62-66° C.) for 20 hours. Solvents were removed under reduced pressure and the residue was stirred in a mixture of methanol (180 mL) and dichloromethane (3 L) overnight. The batch was washed with saturated aqueous sodium chloride (0.5 L) diluted with water (0.4 L), and the separated organic layer was dried over anhydrous sodium sulfate (100 g). Removal of the drying agent by filtration and evaporation of solvent in vacuo gave a crude dark brown solid (12.1 g). The crude product was stirred in refluxing isopropanol (35 mL) for 1 hour, cooled to 22° C., and collected on a fritted glass funnel to afford the title compound as a grey solid (10.6 g, 58% yield).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([CH:52]1[CH2:56][CH2:55][C:54](=[CH:57][N:58]([CH3:65])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]1=[O:66])[CH2:48][CH2:49][CH2:50][CH3:51].Br[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.CCCC[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:68]1([C:52]2([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:56][CH2:55][C:54](=[CH:57][N:58]([CH3:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]2=[O:66])[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: Brc1ccccc1
Reactant: CCCCCC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd]
Agent: CCCC[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC1(c2ccccc2)CCC(=CN(C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 84 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol, 10 mol % Pd), (S)-BINAP (46 mg, 0.075 mmol, 15 mol %) and 2-pentyl-5-(N-methyl-anilinomethylene)-cyclopentanone (136 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. Bromobenzene (157 mg, 1.0 mmol) and sodium 1-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory: funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 146 mg (84%) of the title compound. The ee was determined to be 93% by chiral HPLC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10](=[O:14])([O:12][CH3:13])N.ClC1C=C(NC(NC2C=CC(Cl)=C(Cl)C=2)=O)C=CC=1Cl.CO>ClC1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:14])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COC(N)=O
Agent: O=C(Nc1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)c(Cl)c1
Solvent: Clc1ccccc1
Solvent: CO
Product: COC(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 6 h

Procedure:
648 g of 3,4-dichloroaniline, 360 g methyl carbamate, 280 g N,N'-bis-(3,4-dichlorophenyl)-urea, 385 g methanol and 1600 g chlorobenzene were reacted in the apparatus described in Example 1 for 6.0 hours at 200° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography (HPLC). A yield of 990 g (80% of the theoretical yield) of N-(3,4-dichlorophenyl)-carbamic acid-methyl ester was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[C:4]([C:3]1[C:6]([NH:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CNc1cccc(N)c1C#N
Solvent: C1COCCO1
Product: CNc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (example 156b) (0.14 g, 0.97 mmol) in 1,4-dioxane (3 mL) was added benzoyl isocyanate (0.17 g, 1.17 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The obtained precipitate was filtered and dried under vacuum to give N-(2-cyano-3-(methylamino)phenylcarbamoyl)benzamide (57 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 2.75 (d, J=4.4 Hz, 3H), 6.26 (d, J=4.8 Hz, NH), 6.43 (d, J=9.6 Hz, 1H), 7.40-7.43 (m, 2H), 7.51-7.55 (m, 2H), 7.63-7.65 (m, 1H), 8.01 (d, J=8.4 Hz, 2H), 11.23 (s, NH), 11.30 (s, NH). MS 295 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:41]([O:43][C:44](=[O:48])[CH:45](Br)[CH3:46])[CH3:42]>C1COCC1.ClCCl>[CH2:41]([O:43][C:44](=[O:48])[CH:45]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:46])[CH3:42]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(O)c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol), 2-oxindole (266 mg, 2 mmol) and piperidine (43 mg, 0.5 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60-70° C. under nitrogen. Then the reaction mixture was chilled and evaporated under vacuum to dryness. The residue was submitted to column chromatography over silica gel using dichloromethane/ethanol 4% as eluant to give pure 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole in 60% yield (365 mg). To a solution of 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole (300 mg, 0.99 mmol) in THF (5 ml) was added at room temperature a solution of 1M tetrabutylammonium fluoride (5 ml) and 2-bromopropionic acid ethylester (0.9 ml, 6.9 mmol). The reaction mixture was stirred at room temperature for another 1 h and then diluted with dichloromethane. The organic layer was washed with 5% NaHCO3 solution and water, dried over sodium sulfate and then evaporated under vacuum. The oily residue was chromatographed on silica gel using ethyl acetate as eluant to give pure title compound in 86% yield (330 mg).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:43]([OH:45])=[O:44])[CH2:41][OH:42]>C(N(CC)CC)C.C1COCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:43]([OH:45])=[O:44])[CH2:41][OH:42])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: N[C@@H](CO)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
The suspension of mixed anhydride is prepared by using 3.55 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 1.0 g of N-methylmorpholine, 1.4 g of isobutyl chlorocarbonate and 60 ml of THF in the same manner as Example 1. To the suspension 20 ml of the aqueous solution of 2.1 g of L-serine and 2.0 g of triethylamine is added. The mixture is stirred under ice-cooling for 30 minutes and at room temperature for an additional 1 hour. After removing THF in vacuo, it is acidified with N--HCl, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is crystallized from benzene to give 3.6 g (82%) of the titled compound.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)([O-])=O.[ClH:17]>[Pd].CO>[ClH:17].[NH2:3][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)COc1ccc(N)cc1

Procedure:
A stream of hydrogen was passed through a mixture comprising 19.6 g of 1-(4-nitrophenoxy)propan-2-one, 300 ml of methanol, 30 ml of concentrated aqueous hydrochloric acid and 4 g of 10% w/v palladium-on-charcoal at room temperature for 5 hours. At the end of this time, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, to give 20 g of the title compound. This compound was used directly and without further purification in the next step.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(-n2cccn2)c1
Temperature: 180 °C
Yield: 96 %

Procedure:
A mixture of 1-iodo-3-nitrobenzene (18.7 g, 75 mmol), pyrazol (7.66 g, 113 mmol), potassium carbonate (11.2 g, 81 mmol) and catalytic amounts of cuprous iodide and copper-bronze in dry N-methyl-2-pyrrolidone (50 ml) is heated to 180° C. for 4.5 hours. After cooling the mixture is filtered through celite. The filtrate is poured into ice water (700 ml) and the product is filtered off, washed with water and dried to yield 13.57 g. Yield: 96%. Mp 85-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH:38](Br)([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH:38]([CH3:40])[CH3:39])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CC(C)Br
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with isopropyl bromide
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.[CH3:23][CH:24]([CH3:28])[CH2:25][CH:26]=O.[BH4-].[Na+]>CO.O>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1
Reactant: NCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CCNCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Temperature: 50 °C

Procedure:
To a solution of 4-(8-aminomethylquinolin-4-yloxy)benzamide (23 mg, 0.08 mmol, Preparation 90) in MeOH (5 mL) was added 3-methylbutyraldehyde (8.5 μL, 0.08 mmol) and 4 Å molecular sieves (500 mg). The resulting mixture was heated to 50° C. for 16 h then cooled to rt and NaBH4 (6 mg, 0.16 mmol) was added. After 3 h a few drops of water were added, the mixture filtered and washed with MeOH. Solvent was removed in vacuo and the residue purified by column chromatography (0.25% NH4OH(aq), 5% MeOH in DCM) to give the title compound: RT=2.65 min; m/z (ES+)=364.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8]C)=[O:7].Br[CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]2([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.CO>[CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: COC(=O)C[C@H](C(=O)N(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@@H](CC(=O)O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 14 h

Procedure:
The phenol 22.2 (315 mg, 1.26 mmol) is dissolved in 5 mL of DMF and 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (available from Maybridge) (1.38 mmol) is added followed by cesium carbonate (600 mg, 1.88 mmol). The reaction is stirred for 14 hours and diluted with 250 mL of EtOAc. The organic layer is washed with 1N HCl (aq) (50 mL), saturated NaHCO3 (aq) (50 mL), and brine (2×50 mL). The organic layer is dried with MgSO4, filtered, and concentrated under reduced pressure. The residue is dissolved in 15 mL THF and 0.111 N NaOH (aq) (16 mL, 1.78 mmol) and MeOH (10 mL) is added. The solution is stirred for 8 hours and concentrated to remove the organic solvent. The slurry is diluted with water (50 mL) and DCM (300 mL). The mixture is adjusted with 2 N HCl (aq) to a pH of 2 and then extracted with DCM (3×75 mL). The combined organic layers are dried with Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography to yield compound 22.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.009 g of product in 39% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.C(C1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][C:17]=2[CH:16]=1)(=O)C.[C:29](=[O:32])([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].[H-].[Na+].Cl>ClCCl.O.C(O)C>[OH:32][C:29]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][C:17]=2[CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccccc1-2
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCc1ccccc1-2
Yield: 78.7 %

Procedure:
Then, 2.00 g (11.6 mM) of m-chloroperbenzoic acid was added to a solution of 2.54 g (11.4 mM) of 2-acetyl-9,10-dihydrophenanthrene in 75 ml of dichloromethane at room temperature under stirring to be dissolved therein. To the resultant solution, 1.11 g (11.1 mM) of potassium carbonate was added, followed by heat-refluxing for 2 hours and 10 minutes. After the reaction, the reaction mixture was cooled on an ice bath and poured into 10%-sodium hydrogencarbonate aqueous solution. The resultant organic layer was washed with 5%-sodium hydrogencarbonate aqueous solution, followed by evaporation under reduced pressure to obtain a residue. To the residue, 1.59 g (24.1 mM) of sodium hydride, 25 ml of ethanol and 10 ml of water were added at about 70° C. on a hot water bath, followed by heat-stirring for 0.5 hour. After the reaction, the solvent was distilled-off under reduced pressure from the reaction mixture to obtain a residue. To the residue, 200 ml of water was added and 2.50 ml (28.3 mM) of concentrated hydrochloric acid was further added thereto to precipitate a crystal. The crystal was recovered by filtration and dissolved in ethyl acetate, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) to obtain 1.24 g of 2-hydroxy-9,10-dihydrophenanthrene (Yield: 55.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[N:25]=[C:26]([NH:29][NH2:30])[S:27][CH:28]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]>C(O)(=O)C.C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[N:25]=[C:26]([NH:29][N:30]=[C:11]([CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[C:12]([OH:14])=[O:13])[S:27][CH:28]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1[N+](=O)[O-])=NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-(2-Nitro-phenyl)-2-oxo-propionic acid (1.0 mmol, 209 mg) in 5% acetic acid (2 mL) was added in to solution of 4-(3,4-dichloro-phenyl)-thiazol-2-yl-hydrazine (1.0 mmol, 259 mg) in ethanol (4 mL). The reaction mixture was stirred at 90° C. for 1 h and cooled to 0° C.; the orange solid was precipitated, filtered and washed by water. Recrystallization from MeOH—H2O afford the final product as a yellow power (600 mg, 66.7%). mp; Z/E isomer was further separated by HPLC-MS, using gradient eluting solvents: 0.05% HOAc in acetonitrile 50% : 0.05% HOAc in water 50% to 0.05% HOAc in acetonitrile 75%: 0.05% HOAc in water 25% in 20 min.