Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:13](Cl)=[O:14].C(N(CC)CC)C>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:13]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: NCCc1cccs1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1cccs1)c1cc(Cl)cc(Cl)c1
Yield: 92.9 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 3,5-dichlorobenzoyl chloride (120 mg, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 3,5-dichloro-N-(2-thiophen-2-yl-ethyl)-benzamide (118 mg, 0.39 mmol, 92% yield) as a white powder after purification by chromatography on silica gel (eluent: EtOAc/hexane 2/8).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][C:32]([F:31])([F:44])[F:43])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4OC(F)(F)F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-trifluoromethoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H11F3N4O4, 416.1; m/z found, 417.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.02 (s, 1H), 12.95 (s, 1H), 8.99 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.69-7.66 (m, 1H), 7.61-7.53 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[H-].[Na+].[Cl:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl>CN(C=O)C>[Cl:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: ClC/C=C\CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C/C=C\CCl)c2ccccc21
Temperature: 40 °C

Procedure:
A solution of 1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2 g, 13 mmoles) in DMF (50 ml) was added dropwise and at room temperature to a suspension of 80% sodium hydride (0.4 g, 13 mmoles) in DMF (25 ml). The mixture was heated at 40° C. for 30 minutes and cis-1,4-dichloro-2-butene (2.84 ml, 27 mmoles) in DMF (30 ml) was dropped in 4 hours under stirring. After stirring overnight at room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was evaporated and the crude residue was purified by flash chromatography (hexane-ethyl acetate 55-45) to give 1.4 of the title compound as a thick yellowish oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C([Li])CCC.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CCOCC>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccccn1
Reactant: Ic1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Ic1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
A solution of 1,4-diiodobenzene (46.8 g, 142 mmol) in dry ether (450 mL) under argon was cooled in a salt-ice bath. n-Butyllithium (2.0 M in pentane, 72 mL, 142 mmol) was added, and the solution was stirred for 10 minutes. 2-Fluoropyridine (13 mL, 150 mmol) was added and the reaction was allowed to warm to room temperature over 2 hours. Water (500 mL) was added and the organic layer was separated. The aqueous layer was extracted with ether (3×200 mL) and the combined organic layers were washed with brine (1000 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent completely removed. The residue was purified in two steps; first by column chromatography over silica using a dichloromethane/light petroleum mixture (1:1) followed by recrystallisation of the main fraction from a dichloromethane/light petroleum mixture to give (1) (17.0 g, 40%).
Reaction SMILES: CN(C=O)C.[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:28]([C:32]1[NH:36][C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=1)[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:36]3[C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=[C:32]3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a DMF (75 mL) solution of 4′-bromomethylbiphenyl-2-sulfonic acid t-butylamide (4.7 g, 12.2 mmol), was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (2.3 g, 12.2 mmol) and potassium carbonate (1.7 g, 12.2 mmol). The mixture was stirred at room temperature overnight. EtOAc (400 mL) was added and the organic was washed 3 times with a sodium bicarbonate solution (200 mL) followed by saturated aqueous NaCl (200 mL). The solvent was removed and purification was achieved by silica gel chromatography (50/50 hexanes/EtOAc) using an isocratic gradient yielding intermediate (1a) as an off-white solid (5.0 g). Anal. HPLC: retention time=5.2 minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C25H30ClN3O3S, 488.18. found 488.6.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]3[N:22]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[C:18]3[CH2:17]2)=[O:15])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:1][C:24]1[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:22][N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:34][CH:33]=3)=[O:15])[CH2:17][C:18]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(Cl)c2C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
N-chlorosuccinimide (21 mg, 0.16 mmol) was added to a solution of 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (50 mg, 0.14 mmol) in chloroform (1 mL). The mixture was stirred at 80° C. for 1 hour. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% CH3CN) to yield (3-chloro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (26 mg, 47% yield). C20H17ClFN3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.05 (br. s., 2H), 4.24 (br. s., 2H), 4.75 (br. s., 2H), 5.04 (s, 2H), 6.98 (t, J=7.4 Hz, 1H), 7.03 (d, J=7.8 Hz, 2H), 7.17 (t, J=8.5 Hz, 2H), 7.30 (dd, J=8.5, 7.4 Hz, 2H), 7.50 (dd, J=8.7, 5.2 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NCCCCCCCNC(=O)OCc1ccccc1
Yield: 32.4 %

Procedure:
On an ice-water bath, to the solution of 1,7-diaminoheptane (1.433 g, 11 mmol) in CH2Cl2/MeOH (125 mL/125 mL) was added the solution of CbzCl (1.71 g, 10 mmol) in CH2Cl2 (250 mL) dropwise within 12 h while keeping the temperature below 5° C. The mixture was allowed to stir at the same temperature for another half of an hour before concentrated under reduced pressure to remove most of the MeOH. Water (150 mL) was then added, and the aqueous layer was adjusted to pH=2 using 6 N HCl. The layers were separated. The aqueous layer was washed with DCM (50 mL×3), then adjusted to pH=12 with 10 N NaOH and extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by flash column using DCM/MeOH (9/1) to give 856 mg white solid in 32% yield. 1H NMR (400 MHz, CDCl3): δ7.35-7.29 (m, 5H), 5.09 (s, 2H), 4.73 (brs, 1H), 3.18 (q, J=6.64 Hz, 2H), 2.67 (t, J=6.94 Hz, 2H), 1.55-1.44 (m, 2H), 1.44-1.40 (m, 2H), 1.32 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 156.40, 136.70, 128.50, 128.09, 128.06, 66.55, 42.18, 41.06, 33.71, 29.91, 29.09, 26.76, 26.68. mp 78-80° C. IR v (Diamond, cm−1): 3327, 1686, 1532, 1263, 1144. MS (ESI) m/z found 264.8 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:15]([O:17]C)=[O:16])[C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[OH-].[K+].O>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: COC(=O)c1cc2nc(C)n(C)c2cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc(C(=O)O)c(C(=O)O)cc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of dimethyl 1,2-dimethyl-5,6-benzimidazoledicarboxylate (2.80 g, 10.7 mmol), potassium hydroxide (1.49 g, 26.7 mmol), water and methanol is stirred at room temperature for 16 hours and then concentrated in vacuo. The resultant residue is taken up in a minimal amount of water, cooled, acidified to pH 3 with hydrochloric acid and filtered to give the title product as pink crystals (2.28 g, 91.2%), mp 308°-312° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>C(O)(C)C>[Br:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: C1CSCCN1
Reactant: Cc1nc(C)c([N+](=O)[O-])c(Cl)c1Br
Solvent: CC(C)O
Product: Cc1nc(C)c([N+](=O)[O-])c(N2CCSCC2)c1Br

Procedure:
11.68 Grams (0.044 mol) of 5-bromo-4-chloro-2,6-dimethyl-3-nitro-pyridine and 9.11 g (0.088 mol) of thiomorpholine are heated at boiling point for 18 hours in 50 ml of isopropanol. Upon completion of the reaction the solvent is removed, the residue is digested with water, and the yellow precipitate is filtered off with suction and recrystallized from isopropanol.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[CH:14][CH:13]=1.Cl>O1CCCC1.CCCCCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:3]([O:7][CH2:8][CH3:9])=[O:10])[C:19]2=[O:23])=[CH:14][CH:13]=1
Reactant: O=C1CCCN1c1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1CCN(c2ccc(Cl)cc2)C1=O
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a suspension of 25 g of sodium hydride (60% oil dispersion) in 100 mL of tetrahydrofuran was added 37 g of diethyl carbonate. Under reflux, to the mixture was added dropwise a solution of 52.0 g of 1-(4-chlorophenyl)-2-pyrrolidinone in 150 mL of tetrahydrofuran over about 1.5 hours. After refluxing for 4.5 hours, the reaction mixture was cooled, and carefully poured into ice-water. The mixture was made to weakly alkaline with diluted hydrochloric acid and extracted with 300 mL of ethyl acetate. The organic layer was washed sequentially with water, aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and concentrated to give an oil. To the residue was added 200 mL of n-hexane, and the precipitated crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 60 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:22])[C:17](OCC)=[O:18])#[N:14]>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17](=[O:18])[C:16](=[O:22])[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]#[N:14])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC(C(=O)C(=O)C(C#N)c1ccc(Cl)cc1)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of 6.6 g. (0.044 mol.) of p-chlorophenylacetonitrile and 20 ml. of dry glyme was added 6.2 g. (0.13 mol.) of sodium hydride (50% in oil). Ethyl 3-cyano-3-phenylpyruvate (9.55 g., 0.044 mol.) was added in portions at -10° and the reaction mixture was stirred at 25° for 12 hours. The mixture was diluted with 150 ml. of water, extracted with ether, acidified with 15 ml. of acetic acid and the solid was collected by filtration to yield 2-(p-chlorophenyl)-5-phenyl- 3,4-dioxoadiponitrile, m.p. 210° dec.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[C:17]([OH:30])[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[N:33]1([CH2:39][CH2:40][CH2:41]O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=[C:17]([O:30][CH2:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCc3ccccc3)c2)cc1C
Reactant: OCCCN1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 3-morpholin-4-yl-propan-1-ol (97.6 mg; 0.67 mmol), tributylphosphine (0.27 mg; 1.34 mmol) and 1,1′-(Azodicarbonyl)dipiperidine (0.34 g; 1.34 mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 1 h and purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 574.3 (M+H); Rt: 2.07 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:9]=[C:8]2[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CCCCCBr
Reactant: COc1ccc2[nH]cc(C(=O)c3cccc4ccccc34)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OC)ccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (1.54 g, 45.7 mmol, 60% in mineral oil) in DMF (100 ml) under nitrogen was added dropwise a solution of 5-methoxy-3-(1-naphthoyl)-1H-indole 4 (9.83 g, 32.6 mmol) in DMF (50 ml) and the mixture was stirred at 40° C. for 1 h. The solution was then cooled to room temperature and to this mixture was added a solution of 1-bromopentane (8.2 g, 54.3 mmol) in DMF (25 ml). The mixture was stirred at 60° C. for 1 h. The solvent was removed under high vacuum and the crude product was suspended in water (200 ml) and extracted by ethyl acetate (2×200 ml). The combined ethyl acetate phases were washed by water (1×100 ml), brine (1×100 ml), dried over sodium sulphate, filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (7/3) to give the title compound 5 as an oil which solidified upon cooling (7.1 g, 59%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O-:42])=[O:41])[C:29]2=[O:43])[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:43])[C:22]([OH:24])=[O:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CCc2ccccc2N(CC(=O)[O-])C1=O
Agent: Br
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)CCc2ccccc21

Procedure:
3(S)-[5-(1-Benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate is treated with hydrogen bromide, subjected to alkaline hydrolysis and purified by XAD-2 column chromatography in the same manner as described in Example 30 to give 0.03 g of 3(S)-[5-(4-piperidyl)-1(S)-carboxypentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid as a colorless powder.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([O:11]C)[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:21]=3)=[C:15]([CH3:32])[N:14]=2)=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br>C(O)(=O)C>[CH:1]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:21]=3)=[C:15]([CH3:32])[N:14]=2)=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1nc(NC(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(NC(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 42.8 %

Procedure:
A solution of N-isopropyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.063 g, 0.14 mmol) in acetic acid (5 mL) was treated with HBr (0.066 mL, 0.58 mmol), heated at 90° C. for 4 h, cooled to RT and quenched with ice water. The solution was treated with NaHCO3 and NaCl, extracted with 1:1 THF/EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN (1 mL), allowed to stand at RT and the resulting solid was collected via filtration to afford 2-(isopropylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (25 mg, 38%). 1H NMR (400 MHz, DMSO-d6): δ 10.8 (br s, 1H), 8.68 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.67 (br s, 1H), 6.61 (d, J=5.6 Hz, 1H), 4.07 (m, 1H), 3.85 (s, 3H), 2.34 (s, 3H), 1.17 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[C:37]([CH3:39])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][CH:51]1[CH2:56][NH:55][CH2:54][CH:53]([CH3:57])[NH:52]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[CH:36]=[C:37]([CH3:39])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(C)cc(-c3cccc(C=O)c3)c2)c1
Reactant: CC1CNCC(C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(C)cc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-5-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added 2,6-dimethylpiperazine (predominantly cis) (26 mg, 0.23 mmol), and AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified using a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 90% CH3CN in water at a flowrate of 20 mL/min. Fractions containing product were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}-5-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide as a white solid (50 mg, 43%). LC-MS m/z 757 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[OH:4][CH2:3][C@@H:2]([NH:1][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)[C@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of D-Ser-OMe (LXXXVIII) in dry DCM was added TEA (1.2 eq). After the solution became clear, trityl chloride (1 eq in dry DCM) was added dropwise and stirred for 2 hours. The reaction mixture was washed with 2M HCl, brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give the crude product as a colorless oil. The oil crystallized from Et2O/hexane to produce pure (R)-methyl 3-hydroxy-2-(tritylamino)propanoate (LXXXIX) as white solid (85% yield).
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].[CH3:12][NH2:13]>C1COCC1.C(O)C>[Br:11][C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:13][CH3:12])=[O:4])=[N:10][CH:9]=1
Reactant: COC(=O)c1ncc(Br)cn1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1ncc(Br)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid methyl ester (5.0 g, 23.0 mmol) in THF (10 mL) was added 8 N solution of methyl amine in ethanol (11.5 mL). The reaction mixture was heated 20 min in a microwave oven, cooled down to room temperature and concentrated under pressure to give 5 g of 5-bromo-N-methylpyrimidine-2-carboxamide as a solid LCMS: 216, 218 (M+1).