Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=1
Reactant: ClCc1csc(Cl)n1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(CN2CCCC2)cs1
Yield: 62.6 %

Procedure:
2-Chloro-4-chloromethyl-thiazole (610 mg, 3.6 mmol), pyrrolidine (0.4 mL, 4.8 mmol), and potassium carbonate (1.05 g, 7.6 mmol) were stirred in DMF (6 mL) for 5 hours. After completion, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was thrice extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% [8:1 EtOH:NH4OH(aq)]/DCM). This resulted in 457 mg (63% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=5[CH3:27])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1cccc(C)c1B(O)O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5c(C)cccc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-dimethyl-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.96 min; Mass spectrum (ESI+): m/z=485 [M+Na]+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1CCN2C(=NCCC2)CC1>CC1C=CC=CC=1C.CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:4]1[C:3]2[NH:8][C:9]3[C:14]([C:2]=2[CH:7]=[CH:6][CH:5]=1)=[CH:13][C:12]([C@@H:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[CH:11][CH:10]=3
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncccc3Cl)cc2)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc3[nH]c4ncccc4c3c2)C1
Temperature: 155 °C
Yield: 51.9 %

Procedure:
(S)-tert-Butyl 2-(4-(3-chloropyridin-2-ylamino)phenyl)morpholine-4-carboxylate (47 mg, 0.12 mmol), palladium(II)-acetate (2.7 mg, 0.012 mmol), tricyclohexylphosphine tetrafluoroborate (9 mg, 0.024 mmol) and DBU (37 mg, 0.24 mmol) were dissolved in a mixture of o-xylene (0.7 ml) and dimethylacetamide (0.7 ml). The mixture was degassed with argon for 5 min and heated at 155° C. for 16 h in a closed vial. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. Flash chromatography (2 g silica gel, 10 to 30% ethyl acetate in heptane) yielded a white solid (22 mg, 52%), MS (ISP): 354.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.284 mol), 4-fluoro phenylboronic acid (120 g, 0.853 mol), Cu(AcO)2 (113 g, 0.568 mol) and pyridine (88 g, 1.137 mol) in DCM (500 mL) was stirred at RT for 4 h open to air. The solids were removed via filtration, washed with water and the filtrate extracted with DCM (2×). The combined organics were dried over Na2SO4 and concentrated to afford ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. The product was carried forward without further purification. (77 g, 95% yield).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].C(O)C.Cl>O>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)NC(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Ethyl 3-diisopropylaminopropionate may be obtained in the following manner: ethyl 3-bromopropionate (18.1 g) is introduced dropwise in the course of 30 minutes into a solution of diisopropylamine (28.5 cc) and ethanol (40 cc) maintained at a temperature of 25° C. The suspension obtained is heated to reflux for 4 hours. After being cooled, the reaction mixture is taken up with water (100 cc) and 4N aqueous hydrochloric acid solution (70 cc). After the mixture is washed with ethyl ether (100 cc), it is alkalinized to a pH in the region of 9 with 4N aqueous sodium hydroxide solution. The oil formed is extracted with methylene chloride (3×150 cc). After being washed with water (2×100 cc) and dried, the methylene chloride solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Ethyl 3-diisopropylaminopropionate (11.6 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
Reaction SMILES: C(OC([NH:8][N:9]1[C:14](=[O:15])[CH2:13][N:12]([S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=3)[CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH:10]1[CH2:30][C:31]([O:33][CH3:34])=[O:32])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][N:9]1[C:14](=[O:15])[CH2:13][N:12]([S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=3)[CH:20]=2)(=[O:17])=[O:18])[CH2:11][CH:10]1[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
Methyl 1-(tert-butoxycarbonylamino)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-2-piperazineacetate (500 mg) was combined with a 4N solution of hydrochloric acid in ethyl acetate (10 ml) and stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was combined with an aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, dried and concentrated to obtain the title compound (373 mg) as a colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:12]=[C:13]([NH2:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:11]=1)=[O:5])C.[OH-].[K+].[ClH:24].CCOCC>C(O)C>[ClH:24].[NH2:21][C:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:9]2[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]2[N:12]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccccn3)c(N)nn2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Nc1nn2cc(C(=O)O)cnc2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A solution of 2-amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (1.58 g, 5.58 mmol) and potassium hydroxide (0.95 g, 16.7 mmol) in ethanol (30 mL) was refluxed for 3 h, then cooled down to room temperature. The precipitate was filtered off, washed with ether, suspended in ether, treated with 2M HCl/Et2O (15 mL, 30 mmol), stirred 0.5 h, and filtered, washing with ether to provide an HCl salt of the title compound as a brown solid (0.88 g, 54% yield). MS (ES+) 256. δH (500 Mhz, DMSO-d6) 7.25 (1H, m), 7.94 (1H, t), 8.56 (1H, d), 8.60 (1H, d), 8.83 (1H, d), 9.16 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]([C:9]#[N:10])[CH2:8][C:5]=2[CH:4]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][CH:12]=1)[CH:7]([C:9]#[N:10])[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[CH2:20][CH2:8]2
Reactant: COc1ccc2c(c1)CC2C#N
Reactant: C=Cc1ccc(OC)cc1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2C#N)cc1

Procedure:
A mixture of 4-methoxybenzocyclobutane-1-carbonitrile (16 g) and 4-methoxystyrene (23.5 g) was stirred and heated at 175° for 45 minutes. The mixture was cooled, and purified by flash column chromatography on silica (K60), eluting with a mixture of ethyl acetate and petroleum ether (b.p. 40°-60°), 1:9 by volume, to give 1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)naphthalene-1-carbonitrile, m.p. 127°.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>>[C:7]([C:5]1[CH:4]=[N:3][N:2]([O:1][C:12](=[O:13])[N:11]([CH3:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1cnn(O)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC(=O)c1cnn(OC(=O)N(C)c2ccccc2)c1

Procedure:
The title compound was prepared from 1-hydroxy-4-acetylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (89%, oil).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2].[I:15]N1C(=O)CCC1=O.C(O)(=O)C>CO>[I:15][C:12]1[S:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1ccccc1-c1cccs1
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1ccc(I)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-nitro-phenyl)-thiophene (23 g, 0.11 mol) and N-iodosuccinimide (37 g, 0.165 mol) were dissolved in 110 ml of methanol. To this solution, acetic acid (10 g, 0.165 mol) was added. After stirring the reaction mixture for 4 hours at room temperature, the solvent was evaporated. The remainder was taken up in a mixture of ice and water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and evaporated, delivering 2-iodo-5-(2-nitro-phenyl)-thiophene (28 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:15][C:16](=[O:41])[CH:17]([N:21]([C:23](=[O:40])[C@H:24]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:25]C(OC(C)(C)C)=O)[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:15][C:16](=[O:41])[CH:17]([N:21]([CH3:22])[C:23](=[O:40])[C@H:24]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH2:25])[CH:18]([CH3:20])[CH3:19])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-2-[N-(N-Boc-phenylalanyl)-N-methylamino]-3-methylbutanamide (333 mg) was dissolved in methylene chloride (4 ml) and, after adding TFA (2 ml), the solution was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride and washed with saturated aqueous NaHCO3. The resulting organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 75:1:0.1) to yield N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methyl-2-(N-methyl-N-phenylalanylamino)butanamide in the amount of 164 mg (60%).
Reaction SMILES: I([O-])(=O)(=O)=O.[CH2:6]([O:13][C:14]1[C:15]([CH2:24][CH:25]=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:6]([O:13][C:14]1[C:15]([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=CCc1ccc2cccnc2c1OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: OC(Cc1ccc2cccnc2c1OCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirring solution of 3-[8-(benzyloxy)quinolin-7-yl]propane-1,2-diol (8.08 mmol) in tetrahydrofuran (60 mL) and water (20 mL) in a round bottom flask was added sodium (meta)periodate (8.08 mmol, 1.0 eq.) all at once and the resulting solution was stirred for 30 min. The tetrahydrofuran was then removed by rotary evaporation at room temperature (elevated temperatures will result in decomposition of the product) and the resulting heterogeneous mixture was diluted with water (40 mL) and washed with diethyl ether (2×50 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated (at room temperature) to give the product as a pale yellow oil that was analytically pure and used directly in the ensuing step. (Caution: Compound decomposes rapidly at temperatures greater than 25° C., in the presence of silica gel, and potentially if brought to dryness in presence of periodate salts present in crude reaction mixture.) To a stirring solution of the (8-benzyloxy-quinolin-7-yl)-acetaldehyde (8.08 mmol, 1.0 eq.) from the initial step in tetrahydrofuran (10 mL) at −78° C. was dropwise added a 1M solution of phenylmagnesium bromide in THF (8.08 mmol, 1.0 eq.). On completion of addition, the reaction mixture was allowed to stir at −78° C. for 1 h and was then warmed to room temperature and stirred 30 min. The reaction was then quenched by addition of saturated aqueous sodium bicarbonate solution (5 mL) and allowed to stir for 5 min. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to give a thick yellow syrup that was purified by column chromatography using 20% ethyl acetate/hexanes to give the final product as a pale yellow solid (2.72, 34% for 2 steps). MS (ESI) m/z 356.3; HRMS: calcd for C24H21NO2+H+, 356.16451; found (ESI-FTMS, [M+H]1+), 356.16552.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27](C)([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.CCN(CC)CC.ClC(OC(C)C)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (53 mg, 0.118 mmol) in CH2Cl2 (1.0 mL) was added TFA (0.5 mL) dropwise. The reaction mixture was stirred for 1 h and evaporated under reduced pressure. The residue was then dissolved in CH2Cl2 (1.5 mL) followed by addition of Et3N (82 μL, 0.59 mmol) and isopropyl chloroformate (0.295 mL, 0.295 mmol, Aldrich). The resulting mixture was stirred at room temperature for 30 min, quenched with H2O (0.2 mL) and then evaporated to dryness. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water containing 0.05% trifluoroacetic acid) to give Example 3 (44.5 mg, white solid, 87%) upon lyophilization. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.80 Hz, 2 H), 7.61 (d, J=8.25 Hz, 2 H), 7.30 (d, J=7.70 Hz, 1 H), 6.28 (d, J=2.20 Hz, 1H), 6.19 (dd, J=7.70, 2.20 Hz, 1 H), 4.86-5.00 (m, 1 H), 4.51-4.63 (m, 1 H), 3.77 (app brs, 2 H), 3.33-3.44 (m, 2 H), 3.11 (s, 3 H), 1.96-2.11 (m, 2 H), 1.73-1.86 (m, J=7.15 Hz, 2 H), 1.26 (d, J=6.05 Hz, 6 H). MS (ESI) 435 (M+H).
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:22])[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Pd]>[NH:1]([C:8]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:22])[C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c([nH]c3ccc(Nc4ccccc4)cc13)CCCC2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1c2ccccc2[nH]c2ccc(Nc3ccccc3)cc12
Yield: 88.9 %

Procedure:
A mixture of 70 g of 5,6,7,8-tetrahydro-2-anilinoacridone and 700 ml of Dowtherm® A was brought to reflux in a 2-liter resin kettle, in a nitrogen atmosphere. A stainless steel mesh basket containing 14.5 g of 0.5% palladium on 1/8 inch alumina pellets was lowered into the reaction mixture. The mixture was refluxed for 18 hours. The basket was removed from the reaction mixture, which was then allowed to cool. The precipitated product was collected on a filter and washed with four 350 ml aliquots of methanol. Vacuum oven drying at 100° C. overnight gave 61.4 g (89%) of the product that was analyzed by microanalysis.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][N:11]=2)[CH2:3]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=2)[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:2]1[CH2:5][CH:4]([C:6]3[C:7]([N:12]4[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]4)=[N:8][CH:9]=[CH:10][N:11]=3)[CH2:3]1)[CH:30]=[CH:29]2
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: OCC1CCN(c2nccnc2C2CNC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(N3CC(c4nccnc4N4CCC(CO)CC4)C3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of [1-(3-azetidin-3-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (284 mg, 1.0 mmol) and 2-chloro-6-methyl-quinoline (purchased from ALDRICH) (177 mg, 1.0 mmol) in DMF (15 mL) was added Cs2CO3 (650 mg, 2.0 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc:Petrol ether=5:1) on silica gel to give (1-{3-[1-(6-methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-methanol (102 mg, 0.26 mmol 26%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([NH2:24])=[C:19]([CH3:25])[CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:26]([O-:28])=[O:27])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=O)[O:35]C(C)(C)C)([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[C:19]([CH3:25])[C:20]([NH:24][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[C:21]([CH3:23])[CH:22]=2)[CH:13]=[CH:12][C:11]=1[N+:26]([O-:28])=[O:27])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Yield: 60.9 %

Procedure:
A mixture of 2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-amino-3,5-dimethylphenoxy)nitrobenzene (2.27 g), di-t-butylcarbonate (1.28 g),triethylamine (0.59 g) and anhydrous tetrahydrofuran (20 ml) was heated at reflux for 6 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=10:1 as the eluant to afford the title compound (1.74 g, mp 154-156° C. ).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:38]
Reactant: O=C(O)CCCCCBr
Reactant: Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.6 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 6-bromohexanoic acid (2.93 g, 15 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 2.1 g (yield: 69%) of 6-bromo-N-(2,4-difluorophenyl)hexanamide as colorless needle-like crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>>[CH3:18][NH:19][C:20](=[O:21])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CN=C=O
Product: CNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (55.8 mg, 0.248 mmol) using the same procedure employed for Example 2 (2), but with methylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (43.8 mg, 63%) having the following characteristics.