Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[NH:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[H-].[Na+].[Br:25][CH2:26][CH2:27]Br>CN(C=O)C.O>[Br:25][CH2:26][CH2:27][N:18]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[C:15]=2[CH:16]=[C:17]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: BrCCBr
Reactant: CCOc1cccc(-c2nccc3[nH]c(C(=O)OC)cc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCBr)c1
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of methyl 4-(3-ethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (230 mg, 0.776 mmole) in DMF (7 mL) was added NaH (60% dispersion in mineral oil, 40 mg, 1.000 mmole) at RT. After gas evolution had ceased 1,2-dibromoethane (1 mL, 11.60 mmole) was added rapidly. After stirring overnight the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine then dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (135 mg, 43%) as a clear gum. 1H NMR (400 MHz, CDCl3): δ8.51 (d, J=6.0 Hz, 1 H); 7.60 (d, J=1.0 Hz, 1 H); 7.49-7.45 (m, 2 H); 7.40 (m, J=7.9 Hz, 1 H); 7.31 (dd, J=6.0, 1.0 Hz, 1 H); 6.99 (ddd, J=8.2, 2.6, 1.1 Hz, 1 H); 4.92 (t, J=6.83 Hz, 2 H); 4.12 (q, J=7.0 Hz, 2 H); 3.91 (s, 3 H); 3.71 (t, J=7.12 Hz, 2 H); 1.43 (t, J=7.12 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O>[OH:1][C:2]([C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)c3ccc(C(=O)O)cn3)s2)c1
Temperature: 100 °C
Yield: 93802.8 %

Procedure:
The product of Step 2 (366 mg, 0.710 mmol) was taken up in MeOH (8.0 ml) in a microwave vial, and sodium hydroxide (1.0 M in H2O, 1.42 ml, 1.42 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4), filtered and evaporated to a yellow solid that was triturated with CH2Cl2/hexanes, filtered, and dried to provide the title compound (334 mg, 0,666 mmol, 94% yield) as a pale yellow powder. MS ESI: [M+H]+ m/z 502.1. 1H NMR (500 MHz, DMSO-d6) δ 13.53-13.21 (s, 1H), δ 10.24 (s, 1H), 8.99 (d, J=2.0, 1H), 8.82 (d, J=4.9, 1H), 8.29 (dd, J=2.2, 8.3, 1H), 7.98-7.90 (m, 2H), 7.85 (d, J=8.3, 1H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.29 (s, 3H), 1.98 (s, 3H). rhSYK activity=+++
Reaction SMILES: CS(C)=O.F[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O>[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH2:17][CH2:16]1
Reactant: OC1CCNCC1
Reactant: N#Cc1cccc(F)c1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCC(O)CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A dimethylsulfoxide (30 mL) solution of 3-fluorobenzonitrile (9.73 g, 80.0 mmol) and 4-hydroxypiperidine (8.15 g, 81 mmol) was heated to 100° C. and stirred for 5 hours. The solution was cooled to room temperature and added dropwise to water (500 mL). The mixture was extracted with ethyl acetate (2×300 mL) and washed with water (2×200 mL), brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the crude product. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:32][C:33]([C:35]1[S:39][C:38]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:37]=2[C:36]=1[CH3:45])=[O:34]>C(#N)C>[Cl:44][C:42]1[CH:41]=[CH:40][C:38]2[S:39][C:35]([C:33](=[O:34])[CH2:32][N:1]3[CH2:8][CH2:7][CH2:6][C@H:2]3[C:3]([N:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[C:36]([CH3:45])[C:37]=2[CH:43]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: Cc1c(C(=O)CCl)sc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1sc2ccc(Cl)cc2c1C
Yield: 50 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol), with sodium carbonate (100 mg, 0.94 mmol), and 2-chloroacetyl-5-chloro-3-methylbenzo[B]thiophene (Ryan Scientific; Columbia, S.C.: 244 mg, 0.941 mmol, 1.5 eq) in acetonitrile (10 mL), provided 170 mg (50%) of L-isoleucine, N-[1-(2-(5-chloro-3-methyl-benzo[B]thiophene-2-yl)-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil that formed a waxy solid on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.Cl.C([C:28](C)=[O:29])C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:28]([C:16]1[CH:15]=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:29]
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)CC(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccn1)c1cc(Cl)ccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
183.8 g (1.25 mol) of 1,4-dichlorobenzene was weighed and then dissolved in a 1 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube by heating at 60° C. under a nitrogen atmosphere using an oil bath. Thereafter, 160.1 g (1.20 mol) of aluminum chloride was added, and 89.0 g (0.5 mol) of nicotinic acid chloride hydrochloride was added in small amounts under stirring over one hour. After completing the addition, internal temperature was raised to 90° C. to 100° C. and allowed to react. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was allowed to cool to 70° C., and then 150 mL of MIBK (methyl isobutyl ketone) was added to dilute. After allowing the solution to cool to room temperature, the reaction liquid was gradually added to 1 L of 2 N HCl, the product was extracted into an acidic water, and then the liquid of organic layer was separated to remove excessive 1,4-dichlorobenzene. A sodium hydroxide solution of 4 mol/L was gradually added till the pH of the aqueous layer became 3 to 4, and the product was extracted with MIBK. The organic layer was washed using water and a sodium chloride solution, the organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator. The approximate yield amount was 130 g. The course product was purified by means of column chromatography using a solvent of hexane/ethyl acetate as a developing solvent, whereby the intended product was obtained as a viscous liquid in an amount of 110 g and at a yield of 87%. A 1H-NMR spectrum of the resulting compound is shown in FIG. 1.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCCCCC.C(OCC)(=O)C>CC(C)=O>[N+:1]([C:4]1[N:5]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
To a mixture of 2-nitroimidazole (8 g, 70 mmol) and dry K2CO3 (9.7 g, 70 mmol) in acetone (100 mL) was added ethyl bromoacetate (11.6 g, 70 mmol). The suspension was stirred under N2 atmosphere for 48 h. TLC (silica gel, 40% hexane-ethyl acetate) showed a single UV-visible spot with Rf =0.55. The suspension was filtered and solid was washed with acetone (3×50 mL). The filtrate and the washings were combined and evaporated on a rotary evaporator to afford a thick yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:45]([O:47][CH2:48][C:49]([Cl:52])([Cl:51])[Cl:50])=[O:46]>C(Cl)Cl>[CH2:2]([O:4][C:5]([C:7]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[C:45]([O:47][CH2:48][C:49]([Cl:52])([Cl:51])[Cl:50])=[O:46])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH3:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a 0° C. solution of 3.0 g (5.83 mmol) (R,R)-5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt and 60 mL CH2Cl2 was added 2.54 mL (1.88 g, 14.57 mmol) of i-Pr2NEt followed by 0.84 mL (1.30 g, 6.12 mmol) of 2,2,2-trichloroethyl chloroformate. After stirring at room temperature for 6 h, the reaction mixture was quenched with 10 mL sat. aq. NaHCO3, and extracted with 3×100 mL Et2O. The combined organics were washed with 1×100 1N HCl, 1×100 mL brine, dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (4/1 to 2/1), gives 3.46 g (5.30 mmol, a 91% yield) of the title compound (Rf =0.32; 2/1 hexanes/EtOAc) as an oily, off-white solid; 1H NMR 300 MHz, CDCl3): δ 1.20-1.39 (complex m, 9H), 2.60-2.80 (m, 1H), 2.80-2.91 (m, 1H), 3.01-3.19 (m, 1H), 3.23-3.31 (m, 1H), 3.40-3.53 (m, 1H), 4.10-4.23 (m, 1H), 4.30-4.42 (complex m, 4H), 4.70-4.89 (m, 3H), 6.65-6.88 (complex m, 4H), 7.15-7.39 (complex m, 3H); MS (ES) m/z (relative intensity): 654 (M+ +H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[N:16]1.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:23][CH:22]=2)=[N:16]1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Reactant: C#CC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC(C)(C)C)cc3)[nH]c2=O)c1
Yield: 27.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (Intermediate-98, 0.060 g, 0.120 mmol), 3,3-dimethylbut-1-yne (0.014 g, 0.181 mmol), TBAF (0.094 g, 0.362 mmol), bis(triphenylphosphine)palladium (II)chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.015 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.03 (s, 6H), 1.30 (s, 9H), 2.50 (m, 1H), 4.27 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 3H), 7.61 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.38 (m, 1H); MS (m/z): 449.9 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2sccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2sccc21
Yield: 25 %

Procedure:
In close analogy to the procedure described above, 4-Methyl-6,7-dihydro-thieno[3,2-c]pyridine is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14].C(Cl)Cl.[OH2:18]>CN(C)C(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]([C:7](=[O:14])[CH2:6][CH2:5][OH:18])[C:7]2=[O:14]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(CCO)n1cnc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 199 mg) in 20 ml of N,N-dimethylacetamide was added 6-bromo-3H-quinazolin-4-one(0.9335 mg, 4.148 mmol). The mixture was stirred at room temperature for 40 mins resulting clear red solution. Acroyl chloride (471.8 ul, 5.8072 mmol) was added. The solution was heated at 70° C. for 8 hrs, cooled to room temperature, and poured into 30 ml of ice water. Methylene chloride added and product was in the water phase. The water solvent was evaporated under vacuum. The resulted residue was purified by preparative HPLC. 1.1 g product was obtained. Yield: 74.7%; 1H NMR (500 MHz, DMSO-d6): δ 2.73412–2.76135(t, J=6.805 Hz, 2H), 4.14197–4.16922(t, J=6.815 Hz, 2H), 7.62305–7.64046(d, J=8.705 Hz, 1H), 7.96596–7.98797(dd, J1=8.635 Hz, J2=2.38 Hz, 1H), 8.2287–8.2335(d, J=2.4 Hz, 1H), 8.41991(s, 1H); ESI-MS: m/z 297, 299 (M++1)
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccccc1C(=O)CBr
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (5 g), 2-bromo-1-(2-methoxyphenyl)ethanone (3.3 g) and N,N-dimethylformamide (200 mL) was added 60% sodium hydride (1 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (4.12 g, 60%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([C:37]1[S:38][C:39]([CH2:42][NH2:43])=[CH:40][CH:41]=1)=[O:36])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([C:37]1[S:38][C:39]([CH2:42][NH:43][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])=[CH:40][CH:41]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CN)s1
Reactant: CCC(C)CC(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)CC(=O)NCc1ccc(C(=O)Nc2ccccc2N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a solution of 33.43 mg (0.288 mmol) 3-methylpentanoic acid in 1 ml THF were added 46.67 mg (0.288 mmol) 1,1′-carbonyldiimidazol. After 1 h at rt 100 mg (0.288 mmol) {2-[(5-aminomethyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester were added and the reaction mixture was stirred for 3 h at rt. 1.7 ml trifluoroacetic acid were added and after 2 h at rt sat. aqueous NaHCO3 was added carefully and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/heptane 6:4) to yield 59.3 mg (0.171 mmol) 5-[(3-Methyl-pentanoylamino)-methyl]-thiophene-2-carboxylic acid (2-amino-phenyl)-amide; exact MW [M+H] calc'd: 346.16; MW found [M+H]: 346.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:40][CH:39]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
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: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide which was further purified using preparative HPLC which gave the TFA salt.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH2:17])=[C:5]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:4]=1.Cl[CH2:30][C:31](Cl)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]([C:10]2[C:11]3[NH:17][C:31](=[O:32])[CH2:30][O:16][C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:18])=[C:5]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3N3CCCCC3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2-amino-3-hydroxybenzamide 22b (2.5 g, 6.4 mmol) was dissolved in 20 ml of DMF and at 0° C. TEA (1.8 ml, 2 equiv.) and chloroacetyl chloride (0.6 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 2 hours. K2CO3 (1.77 g, 2 equiv.) was added and the reaction was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 1 as eluant gave 1 g of a white solid. Yield=36% 1HNMR (DMSO, 200 MHz) δ 1.57 (2H, bs), 1.69 (4H, bs), 2.82 (4H, m), 4.60 (2H, d, J=5.4 Hz), 4.67 (2H, s), 7.09 (1H, t, J=7.8 Hz), 7.20 (1H, dd, J=8 Hz, J′=1.2 Hz), 7.33 (1H, m), 7.41 (2H, m), 7.57 (1H, m), 9.38 (1H, bt), 11.02 (1H, bs); [M+1] 434.3 (C22H22F3N3O3 requires 433.4).
Reaction SMILES: [OH: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]([OH:14])=O.Cl.C[N:17](C)CCCN=C=NCC.O[N:28]1C2C=CC=CC=2N=N1.N>O1CCCC1>[NH3:17].[OH: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]([NH2:28])=[O:14]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1c(O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of 2-hydroxy-1-napthoic acid (5.0 g, 26.6 mmol), 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol), and 1-hydroxybenzotriazole (3.95 g, 29.2 mmol) in tetrahydrofuran (70 ml) was stirred at room temperature for 30 minutes prior to the addition of 0.880 NH3 (6 ml). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate diluted with water (80 ml) and extracted with ethyl acetate (4×80 ml). The combined organic extracts were washed with water (50 ml×2), saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give an orange oil. Purification by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia 95:5:0.5 gave the title compound as a pink solid (1.83 g).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[NH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=[O:19].[N-:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C=O)C>[N:20]1([C:14]([C:15]2[CH:16]=[C:17]([C:18]#[N:13])[C:1](=[O:2])[NH:8][C:12]=2[CH3:11])=[O:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=c1cccc[nH]1
Reactant: c1c[n-]cn1
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1C(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To 0.20 g (1.1 mmol) of 11 in 10 ml DMF was added carbonyldiimidazole (0.223 g, 1.4 mmol). The solution was stirred for 24 hours at room temperature. Dimethylformamide was stripped off under reduced pressure giving an oil which crystallized upon further drying. The solid was washed with water and dried in the vacuum dessicator. Yellow solids were obtained: 0.11 g, 40% yield; mp=237°-238° C. with decomposition; NMR (DMSO-d6) δ 2.5 (s, 3H), 7.2 (d, 1H), 7.8 (d, 1H), 8.4 (2s, 2H); IR (KRr) 1670 cm-1 (C=O of pyridone), 1710 cm-1 (C=O of imidazolide).