Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([C:15]4[C:19]([NH2:20])=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1N=CN([C:28]([N:30]2C=NC=C2)=[O:29])C=1.[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]N>C1COCC1>[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38][N:20]([C:19]1[C:15]([C:13]2[NH:12][C:11]3[CH:21]=[CH:22][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][C:10]=3[N:14]=2)=[N:16][NH:17][CH:18]=1)[C:28]([NH2:30])=[O:29]
Reactant: NCc1c(F)cccc1F
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)N(Cc1c(F)cccc1F)c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Yield: 19.4 %

Procedure:
A mixture of 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (Example 1E.), (100 mg, 0.33 mmol), and CDI (217 mg, 1.34 mmol) in THF (2 ml) was subjected to microwave irradiation (150° C., 150 W) for 15 minutes. 2,6-Difluoro-benzylamine (384 mg, 2.68 mmol) was then added and the reaction mixture irradiated again under identical conditions for a further 15 minutes. After cooling, the heterogeneous mixture was filtered, the filtrate was concentrated and the residue purified by column chromatography (SiO2 eluting with gradient-DCM:MeOH:AcOH:H2O (240:20:3:2) (DMAW240 to (120:18:3:2) (DMAW120) to give 1-(2,6-difluoro-benzyl)-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-urea (30 mg 19%). (LC/MS Acidic: Rt 1.84 [M+H]+ 468).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[Na].[CH2:13]([C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]=2[OH:29])=[CH:19][CH:18]=1)[C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>C(O)C>[OH2:11].[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]([OH:11])[CH2:9][NH:10][CH:14]([CH3:16])[CH2:13][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]=2[OH:29])=[CH:19][CH:18]=1.[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]([OH:11])[CH2:9][NH:10][CH:14]([CH3:16])[CH2:13][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]=2[OH:29])=[CH:19][CH:18]=1
Reactant: CC(=O)Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1)NCC(O)c1cccc(Cl)c1
Product: O
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
A solution of 2-(3-chlorophenyl)-2-hydroxyethylamine (0.6 g) and the sodium salt of 4-[4-acetonylphenoxy]-3-hydroxy-1H-pyrrole-2,5-dione(1.0 g) in ethanol, was treated with sodium cyanoborohydride (0.25 g) and stirred at ambient temperature for 18 h. The solvent was evaporated in vacuo, the residue shaken with ethyl acetate and water and filtered. The insoluble material was washed with acetone and crystallised from methanol: water (95:5) to give 4-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxy]-3-hydroxy-1H-pyrrole-2,5-dione, hemihydrate, (0.55 g), as a (27:73)mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[Si:27]([O:34][CH2:35][C@H:36]([O:38][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[C:46]([CH:49]=O)[CH:45]=[CH:44]2)[CH3:37])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Si:27]([O:34][CH2:35][C@H:36]([O:38][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[C:46]([C:49]1[N:6]3[CH:5]=[C:4]([C@@H:3]([N:12]4[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]4)[C:2]([F:25])([F:1])[F:26])[CH:9]=[CH:8][C:7]3=[N:10][N:11]=1)[CH:45]=[CH:44]2)[CH3:37])([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(C=O)nc12
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 9B, Steps A-E; 0.32 g, 0.84 mmol) and (R)-8-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)quinoline-2-carbaldehyde (0.29 g, 0.84 mmol) in ethanol (4.2 mL, 0.84 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (4.2 mL) and iodosobenzene diacetate (0.30 g, 0.92 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.29 g, 49%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][NH:13][C:14](=[O:34])[CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:31][CH2:32][CH3:33].[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:36][C:22]1[C:21]2[N:20]=[C:19]([CH2:31][CH2:32][CH3:33])[N:18]([CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH3:12])=[O:34])[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)NC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)NC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (3.3 g, 15 mmol) was added to a solution of N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (1.83 g, 5.90 mmol) in chloroform (75 mL), and the reaction was stirred for 1.5 hours at ambient temperature. Concentrated ammonium hydroxide (75 mL of 29%) and p-toluenesulfonyl chloride (1.7 g, 8.9 mmol) were then sequentially added with stirring, and the reaction was stirred for 45 minutes. The aqueous layer was separated and extracted with chloroform (1×50 mL). The combined organic fractions were washed with 5% aqueous sodium hydroxide solution (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from a mixture of toluene (20 mL) and methanol (4 mL) and then recrystallized three times from 5:1 methanol:water (18 mL) and dried overnight in a vacuum oven at 80° C. During the recrystallization, the product was mixed with material from another run to provide 0.720 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylbutanamide as a tan solid, hp 177-179° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]=1[CH:4]=[N:5][OH:6].[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.C(OC(=O)C)C.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]=1[C:4]([Cl:16])=[N:5][OH:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)COc1cccc(F)c1C=NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)COc1cccc(F)c1C(Cl)=NO
Temperature: 50 °C
Yield: 90.1 %

Procedure:
To a solution of 2-fluoro-6-isobutoxybenzaldehyde oxime (0.99 g, 6.1 mmol, EXAMPLE 16, Step 3) in N,N-dimethylformamide (20 mL) was added N-chlorosuccinimide (0.63 g, 4.7 mmol) at 0° C. The mixture was heated at 50° C. for 1 h and cooled to room temperature. The mixture was diluted with ethylacetate (30 mL) and hexane (30 mL). The organic layer was washed with water (30 mL×2), dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 9:1 to 4:1) to give 1.04 g (90%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1)[C:9](=O)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[NH:14][C:13]=1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[NH:14][C:13]=1[C:24]1[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2C(=O)C(=O)N(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1

Procedure:
To a stirred solution of N-benzyl-2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]-N-[4-(4-methanesulfonylaminophenyl)butyl]-2-oxo-acetamide (73 mg in 4 mL dry tetrahydrofuran) was added 1 mL of a 1M solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[C:37]2[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:35][CH:36]=2)[N:31]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:30]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[N:8]([CH2:28][C:29]2[C:37]3[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)=[CH:35][CH:36]=3)[N:31]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[N:30]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(Cl)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridine-2(1H)-one (0.400 g, 1.23 mmol) and potassium carbonate (0.171 g, 1.23 mmol) suspended in dimethylformamide (5 mL) was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-6-amine (0.522 g, 1.23 mmol) as a solution in dimethylformamide (2 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 7.90 (d, J=7.3 Hz, 1H), 7.75-7.67 (m, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.07-7.03 (m, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 6.59 (d, J=7.3 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.31 (s, 2H), 5.29 (s, 2H), 4.48 (d, J=4.3 Hz, 2H), 3.71 (s, 3H), 3.69 (s, 3H). HRMS (M+1)=710.1557.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:11][C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]3[C:9]([NH:11][C:12]4[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=4)([N:10]=2)[N:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: CC1CCNCC1
Reactant: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NC23N=CN=C2C=NC(N2CCC(C)CC2)=N3)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2) and rinsed with Et2O (×2) to afford IV-33 as a white solid (225 mg, 90%): mp >300° C.; 1H NMR (DMSO) δ0.91 (3H, d), 1.10 (2H, m), 1.65 (3H, m), 2.24 (3H, s), 2.84 (2H, m), 4.60 (2H, m), 6.40 (1H, s), 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 (2H, m); IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:13]=2)[CH:8]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:4]([F:26])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-82, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.12 (s, 9H), 4.31 (d, J=6.8 Hz, 2H), 7.63-7.71 (m, 2H), 8.05-8.07 (m, 1H), 8.16 (m, 1H), 8.55 (d, J=13.2 Hz, 1H), 9.29 (s, 1H), 12.85 (s, 1H); MS (m/z): 472.41 (M÷H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)ccc4ccccc34)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2ccccc2c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 75 h
Yield: 85.2 %

Procedure:
To a solution of methyl 3-(4-{[3-(2-methyl-1-naphthyl)benzyl]oxy}phenyl)propanoate (0.648 g, 1.58 mmol) in a mixture of methanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 75 hrs. Water was added to the reaction mixture, acidified with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.534 g, yield 85%) as colorless needle crystals.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:26]([C:28]1[CH:38]=[C:37]([O:39][CH3:40])[C:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=2[CH:29]=1)=[O:27])[CH2:15][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=O)(C)(C)C.ClCCl.[C:44]1(=O)[CH2:47]C[CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>FC(F)(F)C(O)=O.ClCCl.C(=O)(O)[O-].[Na+]>[CH:6]1([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][N:14]([CH2:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[C:26]([C:28]2[CH:38]=[C:37]([O:39][CH3:40])[C:31]3[O:32][C:33]([CH3:35])([CH3:36])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH2:47][CH2:44][CH2:45]1
Reactant: O=C1CCC1
Reactant: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2

Procedure:
73 mg of (S)-2-{[(7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl)-quinoxalin-2-ylmethyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 3 mL 10% trifluoroacetic acid/dichloromethane and neutralized with aqueous sodium bicarbonate after 2 hours. The crude material was submitted to reductive amination reaction in dichloromethane using 53 mg (0.67 mmol) of cyclobutanone and 0.14 g (0.67 mmol) sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 42 mg pale yellow solid as the free base. LC-MSD, m/z for C29H34N4O4 [M+H]+: 503.6. 1H NMR (400 MHz, CDCl31HCl): δ 1.7 (s, 6 H), 1.7-3.0 (m, 11 H), 3.6-4.2 (m, 8 H), 5.3-5.4 (m, 1 H), 5.8-5.9 (m, 1 H), 6.6 (s, 1 H), 6.8 (s, 1 H), 8.0 (bs, 2 H), 8.3 (bs, 1 H), 8.5-8.6 (m, 1 H), 9.1 (bs, 1 H), 12.0 (bs, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])=[O:16]>C(OCC)(=O)C>[ClH:13].[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH2:14][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C(CCl)c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a mixture of 1,2,4-triazole (30.4 g, 0.44M) and triethylamine (15.1 g, 0.15M) in refluxing ethyl acetate (186 ml) was added a solution of 2-chloro-2',4'-difluoroacetophenone (38.1 g, 0.2M) in ethyl acetate (80 ml). The mixture was refluxed for six hours then cooled to room temperature and the insolubles were removed by filtration. The filtrate was washed with water (2×200 ml) and then the solvent was removed by distillation at reduced pressure. The crude product was dissolved in ethyl acetate (150 ml) then 25% w/v HCl gas in isopropanol was added. The mixture was granulated at 0° C. for one hour and then the solid was collected by filtration and dried to give the title compound (21.6 g, 40%), melting point 167°-170° C. IR (KBr) and nmr (DMSO) were consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:40])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (61.8 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.7 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (32.6 mg, 36%) as white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:13][C@@H:14]([NH:30][CH3:31])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([Cl:36])=[O:35]>ClCCl.O>[CH:7]1([CH2:13][C@@H:14]([N:30]([CH3:31])[C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:20][CH2:21]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1.[ClH:36]
Reactant: CN[C@H](CC1CCCCC1)CN1CCC(c2ccccc2OC)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C(C)(C)C)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.08 g of potassium carbonate (0.58 mmol) in 1 ml. of water was added a solution of 0.20 g of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0° C. and 0.075 g of trimethylacetyl chloride (0.62 mmol) was added. The reaction was allowed to stir overnight at 0° C., and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride.0.25 hydrate salt of the title compound with isopropanolic HCl to yield 0.157 g (58%) of white solid; mp=233–236° C.; MS (+) ESI m/z=429 (M+H)+.