Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(-c2cnc(N)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
A solution of 3.30 g of 2-amino-5-(4-dimethylaminophenyl)-3-nitro-pyridine (compound G2) and 330 mg of Pd/C (10%) in 260 ml of methanol is treated with hydrogen under vigorous stirring at room temperature for 17 h. The suspension is filtered with suction through a celite pad. The colorless filtrate is evaporated to dryness to afford 2.85 g of the pure title compound of m.p. 155° C. MS: 229.3 (MH+). TLC: Rf=0.38 (dichloromethane/methanol 10:1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[Cl:19])=[C:6]2[N:5]=[C:4]2[CH2:21][CH2:22][CH2:23][C:3]=12.C(N(CC)CC)C.[NH2:31][CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34].O>CN(C)C(=O)C.C(O)(C)C>[CH3:34][CH2:33][CH:32]([NH:31][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[Cl:19])=[C:6]2[N:5]=[C:4]2[CH2:21][CH2:22][CH2:23][C:3]=12)[CH2:35][CH3:36]
Reactant: CCC(N)CC
Reactant: COc1ccc(-c2c(C)nn3c(Cl)c4c(nc23)CCC4)c(Cl)c1
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(CC)Nc1c2c(nc3c(-c4ccc(OC)cc4Cl)c(C)nn13)CCC2
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
Under argon gas atmosphere, a mixture of a solution of the compound prepared in Example 5 (177.6 g) in N,N-dimethylacetamide (355 mL) and a solution of triethylamine (103.2 g) and 3-aminopentane (88.9 g) in isopropyl alcohol (178 mL) was stirred for 4 hours at 95 to 105° C. of internal temperature. Water was poured into the reaction solution that was cooled to 70 to 80° C. of internal temperature. The diluted solution was cooled to 50 to 60° C. of internal temperature, and then after the crystal was precipitated, the solution was stirred for 30 minutes. Furthermore, water was poured into the solution, and the diluted solution was stirred for 1 hour at 20 to 30° C. of internal temperature. The precipitated crystal was collected by filtration, and the obtained crystal was dried under reduced pressure for 14 hours or more at about 50° C. to give the crude crystal of the title compound (174 g, (97.4 area %), quantitative value: 85% (two process)).
Reaction SMILES: F[C:2]([N:7](C)C)(F)[CH:3]([F:5])[F:4].B(F)(F)F.[N:14]1[CH:19]=C[CH:17]=[CH:16][CH:15]=1.C(OCC)=CC.[OH-].[Na+].CNN>C(OCC)C.O1CCOCC1.O>[F:5][CH:3]([F:4])[C:2]1[C:16]([CH3:17])=[CH:15][N:14]([CH3:19])[N:7]=1
Reactant: CN(C)C(F)(F)C(F)F
Reactant: c1ccncc1
Agent: CC=COCC
Agent: CNN
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn(C)nc1C(F)F
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (3.2 g, 22 mmol) in diethyl ether (10 ml) and dioxane (10 ml) was added dropwise, under a nitrogen atmosphere, at a temperature of from 0 to 5° C., a solution of BF3-etherate (49% BF3, 5.6 ml, 44 mmol). After the addition had ended, the reaction mixture was stirred for 5 min. Subsequently, pyridine (1.7 g, 22 mmol) and a solution of ethyl prop-1-enyl ether (1.7 g, 20 mmol) in dioxane (2 ml) were added dropwise successively to the reaction mixture at a temperature of from 0 to 5° C. After stirring at room temperature for 6 hours, the reaction mixture was added at a temperature of from 0 to 5° C. to a mixture of sodium hydroxide (4.4 g, 110 mmol) and methylhydrazine (1.4 g, 30 mmol) in water (75 ml) and then stirred at room temperature for 3 h. Subsequently, water (50 ml) was added and the mixture was extracted with methyl tert-butyl ether. The resulting organic phases were dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. 3-Difluoromethyl-1,4-dimethylpyrazole was obtained in a yield of 25%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH3:25])[C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH3:25])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-nitro-2-pyridinyl)amino]piperidine (EXAMPLE 204, Part A, 1.0 g, 3.05 mmol) is dissolved in ethanol (170 ml) and 0.25 g of platinum oxide is added. The reaction is placed on a Parr hydrogenator at 10 psi for 1 hr and then it is filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CD3OD) 7.52, 7.17, 6.97, 6.79, 3.37, 3.02, 2.94, 2.75, 1.90, 1.60, 1.52 and 0.74δ.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH:4]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl [3-(hydroxymethyl)phenyl]carbamate (0.6 g, 2.7 mmol) [J. Med. Chem. 1989, 32, 807-826] in dichloromethane (8.4 mL) at −10° C. was treated with N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) followed by methanesulfonyl chloride (0.31 mL, 4.0 mmol and stirred at −10° C. for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow oil that was used without further purification. LCMS for C13H19NO5SNa (M+Na)+: m/z=323.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)[CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2ccc(OC)c(C)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A solution of 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine (0.83 g; 3.07 mmol) and 4-trifluoromethoxy benzyl bromide (1.18 g; 4.61 mmol) in dry DMF (6 ml) was treated under nitrogen with NaH (95% dispersion in oil; 0.12 g; 4.61 mmol) and the mixture heated at 60C for 1 hr. Cooled to rt and quenched with a saturated solution of ammonium chloride. Diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel using dichloromethane-hexane mixture (4:1) afforded 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine (1.26 g; 82% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.NC1C=CC=CN=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C#CCO)cn1
Agent: [Pd+2]
Agent: Nc1ccccn1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(CCCO)cn1
Reaction time: 24 h

Procedure:
3-(6-Amino-pyridin-3-yl)-prop-2-yn-1-ol (7-2), 2.73 g (18.4 mmol) and Pd(OH)2 (0.27 g) were stirred in 30 mL EtOH (aminopyridine does not completely dissolve). Reaction was put under one atmosphere of H2 for 24 h. The reaction was filtered through a plug of celite, washed with EtOH, and concnetrated to afford the titled compound as an orange oil. 1H NMR (CDCl3) δ 7.90 (d, 1H, J=2.3 Hz), 7.31 (dd, 1H, J=2.4, 8.6 Hz), 6.43 (d, 1H, J=8.7 Hz), 4.38 (bs, 2H), 3.63 (t, 2H, J=7.5 Hz), 2.58 (t, 2H, J=7.2 Hz), 1.97 (bs, 1H), 1.82 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]([OH:17])=[CH:5][CH:4]=1.[C:18](Cl)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:18]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:11]([CH3:13])([CH3:14])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]=1[OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(O)c2c1C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(Cc2ccccc2)c(O)c2c1C(C)(C)CCC2(C)C

Procedure:
To a solution cooled to +5° C. of 23.44 g (0.1 mole) of 4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol, obtained in Example I, in 400 cm3 of anhydrous 1,2-dichloroethane and 11.7 cm3 (14.06 g=0.1 mole) of benzoyl chloride, there are added, by portions, 16 g (0.12 mole) of anhydrous aluminum chloride over a period of about 30 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27]C(=O)CC(=O)C(NC(OC(C)(C)C)=O)C1CCOC1)C>>[CH2:18]([O:17][C:15](=[O:16])[C:14]1[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:13]=1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]1[CH2:11][CH2:25][O:27][CH2:12]1)[CH3:19]
Reactant: CCOC(=O)CC(=O)C(NC(=O)OC(C)(C)C)C1CCOC1
Reactant: CCOC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Product: CCOC(=O)c1cc(Cl)cnc1C(NC(=O)OC(C)(C)C)C1CCOC1

Procedure:
Procedure same as that for ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate, using ethyl4-((tert-butoxycarbonyl)amino)-3-oxo-4-(tetrahydrofuran-3-yl)butanoate as a starting material. 1H NMR (CD3OD, 400 MHz): δ 8.73 (s, 1H), 8.24 (s, 1H), 5.66 (d, J=8.0 Hz, 1H), 4.61 (s, 1H), 4.45 (q, J=6.8 Hz, 2H), 3.92-3.86 (m, 1H), 3.82-3.56 (m, 3H), 2.82-2.86 (m, 1H), 1.95 (q, J=7.2 Hz, 1H), 1.74 (q, J=6.8 Hz, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.8 Hz, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:6](=[O:24])[N:7]2[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:6](=[O:24])[N:7]2[C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: COC(=O)c1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)N(Cc1ccc(OC)cc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(Br)cc(CO)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of methyl 5-bromo-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (INTERMEDIATE 27)(2 g, 3.63 mmol) in anhydrous THF at 0° C. was added lithium aluminum hydride (1.0M in THF, 4.7 mL, 4.73 mmol) slowly. The reaction was stirred at 0° C. for 40 min, quenched with water slowly and diluted with methylene chloride. The mixture was filtered through celite and rinsed with methylene chloride. Removal of the solvent and subsequent purification by flash chromatography using 20% of acetone in hexane as eluent provided the 5-bromo-1-(2,6-dichlorophenyl)-7-(hydroxymethyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 3.83 (s, 3H), 4.49 (s, 2H), 4.50 (s, 2H), 4.69 (s, 2H), 5.98 (s, 1H), 6.92 (d, 2H, J=8.5 Hz), 7.23 (s, 1H), 7.36 (m, 3H), 7.52 (d, 2H, J=8.0 Hz). MS (API-ES+): 523 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)[C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: N#CC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
A suspension of the α-amino nitrile (3 g, 6.8 mmol) from Step 1 in ether is cooled to −78° C. and is treated with lithium aluminum hydride (1.0 M solution in ether, 27.2 mmol) via slow addition. The cooling bath is removed and the reaction is allowed to warm to room temperature. Upon completion, 500 μL of water is added at 0° C. and the mixture stirred for 15 min. The mixture is filtered through a bed of Celite and the filtrate concentrated and purified by silica gel chromatography (eluting with 7N NH3 in IPA/methanol/dichloromethane 0.1:1:9) to give 1.5 g of 4-(4-chlorophenoxy)-N-(2-amino-1-(3-(benzyloxy)phenyl)ethyl)benzenamine as an oily brownish foam (50%).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:14])[CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH2:1]([O:8][CH:9]([CH3:14])[CH2:10][CH2:11][C:12]([OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(CCCO)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Product: CC(CCC(=O)O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 4-(benzyloxy)pentan-1-ol (350 mg, 1.80 mmol) in acetone (20 mL) was added Jones reagent (1.9M, 1.9 mL, 3.6 mmol) under ice-cooling, and the mixture was stirred for 30 min. Sodium sulfite was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residual aqueous solution was washed with ethyl acetate, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→40/60) to give the title compound (236 mg, yield 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20][C:21](O)=[O:22])[O:17][N:16]=1.CCOC(C)=O>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:21](=[O:22])[CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COC(=O)c1cc(C#N)ccc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)ccc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-amino-5-cyano-benzoic acid methyl ester (1.50 g, 8.51 mmol) and (3-methyl-isoxazol-5-yl)-acetic acid (1.32 g, 9.36 mmol) in 40 ml of POCl3 was heated at 80° C. for 2 hr and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×40 ml), sat. NaHCO3 (40 ml), brine (40 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave 2.31 g (91%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 11.49 (s, 1H), 8.85 (d, 1H, J=8.8 Hz), 8.35 (d, 1H, J=2.0 Hz), 7.79 (dd, 1H, J=8.8, 2.0 Hz), 6.20 (s, 1H), 3.97 (s, 3H), 3.95 (s, 2H), 2.33 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C15H13N3O4, 300.1 (M+H), found 299.9.
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.F[C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>CS(C)=O.C(OCC)(=O)C>[F:31][C:29]1[CH:30]=[CH:23][C:24]([C:25]#[N:26])=[C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)[CH:28]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(F)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
KOtBu (0.968 g, 8.63 mmol) was dissolved into DMSO (3 ml) in a 100 ml round bottom flask. (4-aminophenyl)(morpholino)methanone (1.631 g, 7.91 mmol) in 7 ml of DMSO was added. The mixture was stirred for 15 mins at r.t. 2,4-difluorobenzonitrile (1 g, 7.19 mmol) in 3 ml DMSO was added slowly into the mixture for about 5 mins. The resulting mixture was stirred for 1.5 hrs at r.t. The mixture was diluted with ethyl acetate and extracted with aqueous NH4Cl solution. The organic layer was then washed with water (4×), brine, dried with MgSO4 and concentrated. 2.54 g crude 4-fluoro-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (80% by LC/MS) was obtained. MS (ESI) m/z 326.11 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH:16]1([NH:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27](=[O:39])[C:28]([OH:38])=[CH:29][N:30]3[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:25][C:24]=2[F:40])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl-].[NH4+]>CN(C=O)C>[CH:16]1([NH:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27](=[O:39])[C:28]([O:38][C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)=[CH:29][N:30]3[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:25][C:24]=2[F:40])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=c1c(O)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
690 mg of potassium carbonate and 363 mg of 4-fluorobenzonitrile were added to a 10 ml DMF solution of 344 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-hydroxyquinolin-4(1H)-one, followed by overnight stirring at 80° C. After completion of the reaction and subsequent cooling to room temperature, aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 100 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}benzonitrile.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:39][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3cccc4ccccc34)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-methyl-2-(4-{2-[5-methyl-2-(4-naphthalen-1-ylphenyl)oxazol-4-yl]ethoxy}-phenoxy) propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield of a white solid. Rf=0.25 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.96 (d, 2H), 7.78-7.70 (m, 3H), 7.41-7.29 (m, 6H), 6.78-6.60 (m, 4H), 4.04 (t, 2H), 2.84 (t, 2H), 2.22 (s, 3H), 1.37 (s, 6H); MS (EI) 508.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH2:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].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>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:13])[CH3:12]
Reactant: OB(O)c1cccnc1
Reactant: CCN1C(=O)Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)Cc2cc(-c3cccnc3)ccc21
Temperature: 100 °C

Procedure:
To 5-bromo-1-ethyl-1,3-dihydro-indol-2-one (CAS#41192-37-4, 100 mg, 0.42 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 50.2 mg, 0.41 mmol), 1,2-dimethoxyethane (2.5 mL), and 2 M aqueous sodium carbonate (0.410 mL, 0.82 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.026 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and brine and the layers were separated. The aqueous layer was extracted two times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 100%) to afford 1-ethyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 239.1190 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.2 Hz, 3H), 3.61 (s, 2H), 3.83 (q, J=7.3 Hz, 2H), 6.96 (d, J=8.1 Hz, 1H), 7.38 (dd, J=7.3, 4.8 Hz, 1H), 7.46-7.57 (m, 2H), 7.78-7.95 (m, 1H), 8.58 (dd, J=4.7, 1.4 Hz, 1H), 8.83 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[S:40][C:39]([C:41](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:41][C:39]1[S:40][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(C(=O)Cl)s1
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)s1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 5-ethylthiophen-2-carbonyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a pink powder. APCI-Mass m/Z 455/457 (M+NH4). 1H-NMR (DMSO-d6) δ 1.17 (t, J=7.4 Hz, 3H), 2.71 (q, J=7.4 Hz, 2H), 3.15-3.43 (m, 4H), 3.67 (m, 2H), 4.36 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.20 (d, J=5.9 Hz, 1H), 5.40 (d, J=9.1 Hz, 1H), 6.62 (m, 2H), 7.04 (m, 1H), 7.11 (t, J=7.9 Hz, 1H), 7.38 (s, 1H), 7.54 (d, J=8.2 Hz, 1H).