Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[C:39]2[C:34](=[N:35][CH:36]=[N:37][C:38]=2[Cl:40])[N:33]([CH3:41])[N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:30][C:31]2[C:39]3[C:34](=[N:35][CH:36]=[N:37][C:38]=3[Cl:40])[N:33]([CH3:41])[N:32]=2)[CH:9]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccc(NCCO)c(Cl)c2)cc1O
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2ccc(NCCO)c(Cl)c2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-(2-hydroxyethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide (34.2 mg, 0.11 mmol) and potassium carbonate (17.3 mg, 0.123 mmol) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (25.4 mg, 0.097 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step (described in Example 9) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-chloro-N-[3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-4-methyl-phenyl]-4-(2-hydroxy-ethylamino)-benzamide as a white solid. (Yield 22 mg).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:27]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)(=O)=O>CN(C=O)C>[CH2:3]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:27]4[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:1][O:2]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(CN2CC3(COC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
2A (0.77 g, 3.75 mmol) was dissolved in dry DMF (20 mL) and Cs2CO3 (2.44 g, 7.50 mmol) was added. The reaction mixture was stirred at room temperature for 10 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.88 g, 7.50 mmol) was added. The reaction mixture was thereafter stirred at 90° C. for 24 h. The mixture was filtered and the solvent was evaporated. The residue was dissolved in DMSO (6 mL) and purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer). The pure fractions were combined and concentrated. Dichloromethane was added and the solution was dried (phase separator) and concentrated. There was obtained 1.00 g (74%) of 3A as an oil which solidified on standing at room temperature. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 3.34 (s, 4H), 3.46 (s, 2H), 3.99 (dd, 2H), 4.28 (dd, 2H), 4.73 (s, 4H), 4.84 (m, 1H), 6.68 (d, 2H), 7.15 (d, 2H), MS (APCI+) m/z 361 [M+H]−.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(=[O:4])=[O:3].C1C(=O)N([Br:21])C(=O)C1>C(#N)C>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)CCc1cnc(N)cn1
Solvent: CC#N
Product: CS(=O)(=O)CCc1cnc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To 5-(2-(methylsulfonyl)ethyl)pyrazin-2-amine (213 mg, 1.06 mmol) in acetonitrile (6 mL) was added NBS (179 mg, 1.007 mmol) and was stirred at room temperature for 1 h. The solvent was concentrated off to residue. To the crude was added ethyl acetate, washed with saturated sodium carbonate, water (2×), dried sodium sulfate, filtered and concentrated to constant mass to give 210 mg of the desired product as free base used as is, (71% yield). LCMS (m/z): 280.0/282.0 (MH+), 0.38 min.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Cl[CH:5]([C:11]([CH3:13])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH3:13][C:11]1[N:3]=[CH:1][S:2][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NC=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CCOC(=O)c1scnc1C
Temperature: 110 °C

Procedure:
Thioformamide (7.5 g, 122.72 mmol), ethyl 2-chloroacetoacetate (16.4 g, 99.52 mmol) and magnesium carbonate (20 g, 237.22 mmoL) were taken dioxane (100 mL) and heated at 110° C. for 4 hrs. The reaction mixture was cooled to room temperature and filtered to remove magnesium carbonate. The solvent was evaporated to dryness and the residue was taken in ether (200 mL) and washed successively with 0.5 M NaOH solution (200 mL×2) and saturated brine solution (100 mL) and dried over Na2SO4. It was filtered and evaporated to give 4-methyl-5-(ethoxycarbonyl)thiazole as an oil which was purified by silica gel column chromatography using hexanes:EtOAc (8:2, v/v) as a eluent; yield: 3.28 g (17%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]([C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:37]1[CH:36]=[CH:35][C:34]([N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:42][CH:41]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(c2ccc(Br)cc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccc(OC)cc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 62.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (83.3 mg) was reacted with N-(4-methoxybenzyl)-N-(4-bromophenyl)pyrimidin-2-amine (102.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-methoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (102.4 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1→1/3) and thin layer chromatography (silica gel, mobile phasae: cyclohexane/ethyl acetate=1/5) were used for purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.Br[CH:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:23]=[C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: Cc1ccc(B(O)O)cc1Oc1ccc(C(F)(F)F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 50 °C
Yield: 29.3 %

Procedure:
To a solution of 4-methyl-3-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid (1.13 g, 0.0038 mol) and tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (871 mg, 0.006 mol) in THF (10.5 mL) was added K3PO4 (2.43 g, 0.011 mol). The flask was put under vacuum and flushed with N2 three times. Water (0.19 mL) was added and the system was flushed with N2 again. PdCl2(dppf) (310 mg, 0.0004 mol) was added and the system was flushed with N2 two to three times again. The reaction mixture was refluxed at 50° C. for 1 h. The reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane) to give the pure title compound (0.50 g). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.90 (dd, J=2.25 Hz, J=8.75 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.03-6.98 (m, 2H), 6.89 (s, 1H), 6.31 (s, 1H), 3.49 (t, J=5.0 Hz, 2H), 3.40 (t, J=5.5 Hz, 2H), 2.47 (t, J=5 Hz, 2H), 2.30 (s, 3H), 2.13 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2I)[CH2:3][CH2:2]1.C([Li])(C)(C)C.CN([CH:25]=[O:26])C.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH:25]=[O:26])[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: -78 °C
Yield: 94.1 %

Procedure:
1-(Cyclopropoxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 12; 5.84 g, 17 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to −78° C. Tert-butyl lithium solution (20 mL, 1.7M in pentanes, 34 mmol) was then added dropwise. The solution was stirred at −78° C. for 10 minutes, before N,N′-dimethylformamide (5.3 mL, 68 mmol) was added, and the resulting solution allowed to stir to room temperature. Saturated aqueous ammonium chloride solution (50 mL) was then added and the mixture extracted with diethyl ether (2×100 mL). The extracts were dried (MgSO4) and concentrated to yield an oil. Purification of this by silica chromatography gave the title compound as a clear oil (3.94 g, 16 mmol).
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)Cc1ccccc1)C(=O)NCc1ccc(O)cc1
Yield: 61 %

Procedure:
Prepared analogously to Example 5f) from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl)-ornithinamide, phenylacetic acid and TBTU in a yield of 61% of theory. It was further processed without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33]1([C@@H:39]2[CH2:41][C@H:40]2[C:42](Cl)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([C@H:40]4[CH2:41][C@@H:39]4[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:43])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@H]1C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.162 g, 0.371 mmol) in pyridine (2 mL) at 0° C. was treated with trans-2-phenyl-1-cyclopropylcarbonyl chloride (0.134 g, 0.742 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0° C., the ice bath was removed and the reaction mixture stirred at room temperature for 5 h. Additional trans-2-phenyl-1-cyclopropylcarbonyl chloride (0.034 g, 0.186 mmol) was added and the reaction mixture stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was then added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel using 15% methanol in dichloromethane then 20% methanol in dichloromethane as eluent. The column afforded 0.150 g (70%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide (0.147, 0.253 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.088 g, 0.759 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.204 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.64 (s, 1H), 8.23-8.21 (m, 2H), 7.33-7.29 (m, 2H), 7.24-7.17 (m, 4H), 6.16 (s, 6H), 4.69-4.66 (m, 1H), 3.90 (s, 3H), 2.90-2.60 (m, 7H), 2.37-2.35 (m, 2H), 2.10-1.99 (m, 8H), 1.70-1.50 (m, 3H), 1.32 (m, 1H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.346 min (97%).
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[OH-].[Na+]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][C:3]([OH:12])=[O:2]
Reactant: COC(=O)CSc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1ccccn1
Yield: 95 %

Procedure:
A solution of the ester from above (751 mg, 4.10 mmol) in MeOH (50 ml) and 1N NaOH (10 ml) was stirred at room temperature for 45 minutes to give (pyridin-2-ylsulfanyl)-acetic acid (655 mg, 95%) after acidic work-up.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N+:11]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1>C(O)(=O)C.[Fe]>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH:5]=2)[NH2:11])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(C2CC2)ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(C2CC2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 4-cyclopropyl-1-fluoro-2-nitrobenzene (0.700 g, 4.26 mmol) in acetic acid (6.0 mL) was added iron powder (1.0 g). The reaction mass was stirred at RT for 2 h. The reaction mass was quenched in water and basified with NaHCO3, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.50-0.52 (m, 2H), 0.83-0.85 (m, 2H), 1.71-1.74 (m, 1H), 4.97 (s, 2H), 6.21 (m, 1H), 6.44 (d, J=9.0 Hz, 1H), 6.77-6.84 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:29](=[O:43])[CH2:30][C:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([O:20][C:17]1[N:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:39])[F:41])[CH:33]=4)[CH2:30][C:29](=[O:43])[NH:28][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(C(F)(F)F)c2)=Nc2ccc(-c3ccc(OCc4ccccc4)nc3)cc2N1
Yield: 30.5 %

Procedure:
Prepared from {4-(6-benzyloxy-pyridin-3-yl)-2-[3-oxo-3-(3-trifluoromethyl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K 23) (198 mg, 0.33 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (49 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]([C:18](OCC)=[O:19])=[CH:16][N:15]=2)[S:11][CH:12]=1>CCOCC.C1COCC1>[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]([CH2:18][OH:19])=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[S:11][CH:12]=1
Reactant: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(Nc2cc(Oc3ccccc3)c(CO)cn2)n1
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of 1M lithium aluminum hydride (70 mL, 70 mmol) in ether at 0° C. was added a solution of ethyl 6-(4-methylthiazol-2-ylamino)-4-phenoxynicotinate (14 mmol) in THF (50 mL). The reaction mixture was stirred for 1.5 hours, then slowly quenched with sodium sulfate decahydrate and stirred for 1 hour. The reaction mixture was filtered, the solids were washed with THF and the organic layer was concentrated. Water and ethyl acetate were added to the residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated to 50 mL of ethyl acetate, and filtered. The residue was purified using silica gel column chromatography with 30% ethyl acetate in hexanes as eluent to afford the desired product (3.0 g, 66% yield) as light yellow solid. 1H NMR (DMSO) δ 10.83 (s, 1H), 8.20 (s, 1H), 7.50 (m, 2H), 7.30 (m, 1H), 7.17 (m, 2H), 6.49 (d, 1H), 6.35 (s, 1H), 5.07 (t, 1H), 4.55 (d, 2H), 2.17 (d, 3H); Mass spectrum (esi) m/z=314 (100)(M+H).
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4][C@@H:3]([C:6]([O:8]C)=[O:7])[NH:2]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:14]1([CH2:13][O:12][C:10]([N:1]2[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of 3-methyl 1-(phenylmethyl) (3S)-1,3-pyrazolidinedicarboxylate (2.77 g, 10.5 mmol) in THF (20 mL) at 0° C. was added a portion of LiOH monohydrate. The mixture was warmed up to rt and stirred for 2 hours. TLC showed that the starting material was consumed completely. THF was distilled off, and the mixture was cooled to 0° C. Citric acid (4.8 g, 25.2 mmol) in water (20 mL) was then added dropwise. The aqueous mixture was extracted with DCM (8×20 mL), the combined organic phases were dried (Na2SO4), filtered and concentrated to provide (3S)-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid as yellowish solid (1.8 g, 83%). 1H NMR (300 MHz, DMSO-D6) δ 7.43-7.29 (m, 5H), 5.07 (s, 2H), 3.76-3.71 (m, 1H), 3.52-3.37 (m, 2H), 2.25-2.06 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:32])[CH:9]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:9][C:10]=4[F:32])=[O:15])[CH2:21][CH2:20]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2F)CC1
Yield: 73 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 1, the title compound (308 mg) was obtained.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]([CH3:38])([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[NH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][N:33]=3)=[CH:25][N:24]=2)=[CH:18][N:17]=1)[C:10]([O:12][CH3:13])=[O:11].[CH3:39][Si:40]([CH3:47])([CH3:46])[CH2:41][CH2:42][O:43][CH2:44]Cl>O>[CH3:8][C:9]([CH3:38])([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[N:33]([CH2:44][O:43][CH2:42][CH2:41][Si:40]([CH3:47])([CH3:46])[CH3:39])[CH:32]=[C:31]([C:34]([F:35])([F:37])[F:36])[N:30]=3)=[CH:25][N:24]=2)=[CH:18][N:17]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(-c3ncc(C(F)(F)F)[nH]3)cn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60%, 35 mg) was added to an N,N-dimethylformamide (3 mL) solution containing methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate (320 mg) at 0° C., and the resulting mixture was stirred at the same temperature for 1 hour. To the mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (195 μL), a temperature of the mixture was raised to room temperature and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and then with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain a mixture (324 mg) of methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate and methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-pyrazin-2-yl}pyridin-2-yl)oxy]propanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:33][CH:34]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
A solution of 1-(4-nitrobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (22.4 mg, 0.047 mmol) in EtOH (3 mL) was hydrogenated at 1 atm for 1 h in the presence of 5% palladium on charcoal (10 mg) at 25° C. The catalyst was removed by filtration and washed with EtOH (5 mL). The combined filtrate was evaporated to afford 1-(4-aminobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 516) as a pale yellow solid (20.1 mg, 96%). The purity was determined by RPLC/MS (99%); ESI/MS m/e 449.1 (M++H, C23H27F3N4O2).