Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:28])[C@H:5]([CH3:27])[NH:6][C:7](=[O:26])[C@H:8]([CH3:25])[NH:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:2].[CH2:29](OC(N1CCC[C@H]1C(N[C@H](C(NN)=O)C)=O)=O)[C:30]1C=CC=CC=1.C(NC(=O)[C@H](C)N)C>CN(C)C=O>[CH2:1]([NH:3][C:4](=[O:28])[C@H:5]([CH3:27])[NH:6][C:7](=[O:26])[C@H:8]([CH3:25])[NH:9][C:10](=[O:24])[C@@H:11]1[CH2:23][CH2:30][CH2:29][N:12]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:2]
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NN
Agent: CCNC(=O)[C@H](C)N
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 49 %

Procedure:
This product was prepared by a process analogous to that employed in preparing the corresponding benzyloxycarbonylalanylalanyl alanine ethylamide described in Example 1 from benzyloxycarbonylprolyl alanine hydrazide and alanine ethylamide in a 49% yield with a melting point of 219 to 220 degrees C. [α]D20 -36.2 degrees (c 0.3; dimethylformamide).
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]=1[CH3:38])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:15]=1[CH3:38])#[N:13]
Reactant: COCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)CCOC)oc23)C1
Reaction time: 0.83 h
Yield: 30.6 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(methylamino)pyrrolidine (109 μl, 1.03 mmol) was added at 140 to 150° C. to a dimethyl sulfoxide (8 ml) solution of 4-cyano-7-fluoro-N-(2-methoxyethyl)-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-122) (314 mg, 855 μmol) and triethylamine (155 μl, 1.11 mmol), followed by stirring at the same temperature for 50 minutes. After cooling, saturated brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=10:1, v/v) to obtain a rough product of the entitled compound. The rough product of the entitled compound was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, then the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (117 mg, 31%) as an amorphous substance.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2)[NH2:2].CO[CH:15](OC)[CH2:16][CH:17](OC)OC>CCO.C(Cl)Cl>[N:1]1([C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][N:7]=[CH:8]3)[CH:17]=[CH:16][CH:15]=[N:2]1
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1cccc2cnccc12
Solvent: ClCCl
Solvent: CCO
Product: c1cc(-n2cccn2)c2ccncc2c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A suspension of 5-hydrazinylisoquinoline (22.0 g, 112 mmol) in EtOH (300 mL) was treated with 1,1,3,3-tetramethoxypropane (27.7 g, 169 mmol) and the mixture was heated to 100° C. for 10 h. The reaction mixture was then concentrated in vacuo and the residue obtained taken up in DCM (500 mL) and washed with a saturated aqueous solution of NaHCO3 gas formation. The aqueous layer was extracted twice with DCM and the combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 95:5 to DCM/MeOH 9:1) to give the title compound (16.1 g). UPLC-MS: MS 196.1 (M+H+); UPLC rt 0.62 min.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH:6]1([N:5]([CH2:11][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][N:21]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH3:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:7]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: C1CCNCC1
Solvent: CC#N
Product: CN(CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2ccccc21)C1CCCCC1

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[[cyclohexyl)(methyl)amino]methyl]piperidine to give colorless crystals, mp. 146°-148° C. (acetonitrile activated charcoal).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].O=[CH:15][CH2:16][CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27]([O:29][CH3:30])=[O:28])[CH:20]=[CH:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@@H:4]([NH:3][CH2:15][CH2:16][CH2:17][N:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[C:27]([O:29][CH3:30])=[O:28])[CH:20]=[CH:19]1)[CH2:5]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc2ccn(CCC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a stirred solution of (R)-(+)-3-aminoquinuclidine dihydrochloride (287 mg, 1.4 mmol) in 1,4-dioxane (10 mL) was added 60% sodium hydride (86 mg, 3.6 mmol) in portions. The mixture was heated at 60° C. for 1 h and then a solution of methyl 1-(3-oxopropyl)-1H-indole-7-carboxylate (278 mg, 1.2 mmol) from Step B above in 1,4-dioxane (20 mL) was added, followed by glacial acetic acid (1% of total solvent used). The reaction mixture was stirred at 60° C. for 2 h and cooled to room temperature. Sodium triacetoxyborohydride (763 mg, 3.6 mmol) was then added in portions and the reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give (R)-methyl 1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (317 mg, 77%) as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.78 (d, J=13.0 Hz, 1H), 7.62 (d, J=12.5 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 7.10 (t, J=13.0 Hz, 1H), 6.56 (d, J=5.5 Hz, 1H), 4.49 (t, J=11.5 Hz, 2H), 3.96 (s, 3H), 3.07-2.99 (m, 1H), 2.82-2.65 (m, 5H), 2.44-2.27 (m, 3H), 1.89-1.64 (m, 5H), 1.53-1.32 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:32])[NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:26]1([CH2:25][CH2:24][NH:23][C:22]([C:18]2([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[CH:17]=[CH:16][CH:21]=[CH:20][NH:19]2)=[O:32])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(NCCN1CCOCC1)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OC2(C(=O)NCCN3CCOCC3)C=CC=CN2)cc1
Temperature: 75 °C
Yield: 64.2 %

Procedure:
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75° C. overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3×25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf 0.32.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.I.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](SC)=[NH:30]>>[CH3:20][N:12]([CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:2]([NH:1][C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[NH:30])=[CH:3][C:4]1=2)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: CN(CCN1CCOc2ccc(N)cc21)C(=O)OC(C)(C)C
Reactant: CSC(=N)c1cccs1
Agent: I
Product: CN(CCN1CCOc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 44 h
Yield: 50 %

Procedure:
To a stirred ethanolic solution of tert-butyl 2-(6-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl(methyl)carbamate (0.118 g, 0.384 mmol) under an argon atmosphere was charged methyl thiophene-2-carbimidothioate hydroiodide (0.219 g, 0.768 mmol), and the resulting yellow solution stirred at room temperature. After 44 hours, argon was bubbled through the mixture, which was then concentrated to residue and partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (10 mL). The aqueous layer (pH˜9) was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to yield an orange residue. The residue was purified on silica gel twice, with the first purification using 100% EtOAc as the eluent and the second purification using 5% (2M NH3 in MeOH)/CH2Cl2 to yield the title compound as a yellow solid (80 mg, 50.0%). 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=2.9 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.10-7.03 (m, 1H), 6.60 (d, 1H, J=8.1 Hz), 6.30 (m, 3H), 6.00 (dd, 1H, J=8.1, 1.6 Hz), 4.18-4.02 (m, 2H), 3.40-3.21 (m, 6H, merged with H2O peak), 2.81 (s, 3H), 1.34, 1.29 (2×s, 9H); ESI-MS (m/z, %): 417 (MH+, 100).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11]([S:15][CH2:23][CH3:24])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 5-benzyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.2 g) and potassium carbonate (0.24 g) in N,N-dimethylformamide (4 mL) was added ethyl iodide (0.035 mL), and the mixture was stirred for 4 hr. The insoluble material was filtered off. The filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.22 g, 97%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(Cl)(=O)C(Cl)=O.C[N:33](C=O)C>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:33])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C(N)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of EXAMPLE 1E in dichloromethane (20 mL) was treated with oxalyl chloride (0.305 mL, 3.50 mmol) and a drop of DMF, stirred for 6 hours at room temperature, and concentrated. The resulting residue was dissolved in dichloromethane (20 mL), cooled to 0° C., treated with aqueous NH3 (3 mL), stirred for 6 hours, and partitioned between ethyl acetate and saturated aqueous sodium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4) and filtered. Concentration of the filtrate gave the desired product as a residue that was utilized directly in the next step without further purification. MS
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:7]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 99.8 %

Procedure:
2-Chloro-4-methoxy-5-nitropyridine (Frontier Scientific, Newark, Del.; 1.02 g, 5.40 mmol) and K2CO3 (895 mg, 6.48 mmol) were purged with argon, treated with DMF (10 mL) followed by 1-methylpiperazine (0.66 mL, 5.94 mmol). The reaction mixture was then heated to 60° C. for 3 h. The reaction mixture was cooled to RT and treated with water, extracted with EtOAc (2×100 mL), washed with brine (2×25 mL) and dried over MgSO4, filtered and concentrated affording crude 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol, 99% yield). m/z (ESI, +ve ion) 252.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1H, s), 5.97 (1H, s), 3.97 (3H, s), 3.70-3.78 (4H, m), 2.47-2.55 (4H, m), 2.36 (3H, s). Pd/C (10 wt. %, 586 mg, 0.55 mmol) and 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol) were treated with EtOH (20 mL) and EtOAc (20 mL) and stirred at RT overnight (18 h) under an atmosphere of hydrogen (balloon). The reaction mixture was filtered through a pad of Celite, washed with MeOH, and concentrated to dryness affording 4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a) (1.22 g, 5.77 mmol, 99% yield) as a purple viscous oil. m/z (ESI, +ve ion) 223.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s), 6.17 (1H, s), 3.87 (3H, s), 3.37-3.45 (4H, m), 3.32 (2H, br. s.), 2.51-2.60 (4H, m), 2.36 (3H, s).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:28][CH3:29])[C:25]([OH:27])=O)[C:5]1=[O:30])[CH:2]=[CH2:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([NH2:60])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C>[CH2:1]([C:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:28][CH3:29])[C:25]([NH:60][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CC(C)(C)N
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)NC(C)(C)C)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoic acid (81 mg, 0.176 mmol) (Example 101, Step A) in dry DMF (880 μL) with 3 eq TEA (73.6 μL, 0.528 mmol) at 0° was added 2 eq HATU (134 mg, 0.352 mmol). The reaction was stirred at 0° for 5 min, followed by addition of t-butyl amine (25.7 mg, 0.352 mmol). It was stirred for 30 min at 0°, quenched with sat. NaHCO3 and extracted to EtOAc. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 0-30% EtOAc/hexanes, gradient elution) provided the title compound as a mixture of stereoisomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[N:10][C:9]2=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=[C:8]2[C:7]=1Cl)=[O:5])[CH3:2].[NH3:26]>CCO.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[N:10][C:9]2=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=[C:8]2[C:7]=1[NH2:26])=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)c1c(Cl)nc2nn(Cc3ccc(OC)cc3)cc2c1Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(Cl)nc2nn(Cc3ccc(OC)cc3)cc2c1N
Reaction time: 288 h

Procedure:
A solution of 4,6-dichloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.21 g) in EtOH/THF was saturated with NH3. Then solution was then stirred for 12 days (the solution was resaturated several times during that time). The solvent was removed and the residue was dissolved in EtOAc (250 mL). The solution was washed with aqueous NaCHCO3 and dried. Removal of the solvent gave the product (1 g) as a white solid. LC: 3.84 (Gradient 1); MH+: 347.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][N:38]2[CH3:43])=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][N:38]2[CH3:43])=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CN1CCCCC1c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCCC1c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-phenylbenzoate (0.040 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and methanol and water were added to the residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 0.034 g of 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH2:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:28])[C@H:21]([C:25](O)=[O:26])[CH:22]([CH3:24])[CH3:23].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:25](=[O:26])[CH:21]([N:20]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH3:28])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 2-(3-tert-butyl-4-hydroxylphenyl)-1-(thiazol-2-yl)ethylamine (4.67 g, 16.64 mmol), Boc-N-Me-Val-OH (5.0 g, 21.63 mmol) and CMPI (5.53 g, 21.63 mmol) in THF (110 ml), TEA (5.33 ml, 38.27 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (8.10 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[Cl:20])#[N:2].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[Cl:20])#[N:2]
Reactant: N#Cc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccccc1NC(=O)c1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 17.3 %

Procedure:
N-(2-Cyanophenyl)-2-chloro-4-nitrobenzamide (1.30 g, 4.04 mmol) was added to a stirred suspension of tin (II) chloride dihydrate (4.42 g, 23 mmol) in hydrochloric acid (52 ml) at 0° C. The reaction was allowed to warm to ambient temperature over 2 hours and aqueous sodium hydroxide was added to take the reaction to pH 10. Extraction of the aqueous layer with dichloromethane (3×50 ml), followed by solvent evaporation in vacuo, yielded N-(2-cyanophenyl)-4-amino-2-chlorobenzamide (0.19 g, 16% yield) as a white solid:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCBr)C=CC=CC=1.[Mg].Cl[Si:22]([CH2:25][Cl:26])([CH3:24])[CH3:23].Cl>O1CCCC1.O>[Cl:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: C[Si](C)(Cl)CCl
Agent: BrCCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(CCl)CCc1ccccc1
Yield: 48.5 %

Procedure:
To a solution of 2-phenylethylmagnesium bromide, prepared from 2-phenylethyl bromide (9.25 g, 50 mmol) and magnesium (1.34 g, 55 mmol) in tetrahydrofuran (50 ml), is added chlorochlormethyldimethylsilane (6.43 g, 45 mmol) in tetrahydrofuran (25 ml). The mixture is refluxed for 18 hours, cooled to 0° C. and hydrolyzed with 3N HCl (50 ml). The mixture is then poured in water (50 ml) and diethyl ether (50 ml), the organic layer is washed with water, brine, dried over MgSO4 and the solvents removed in vacuo. Fractional distillation affords the title compound (5.15 g, 48.5% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH3:17]
Reactant: Oc1ccccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added iodoethane (6.7 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-ethoxybenzene (12.2 g).