Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][C@H:28]([C:30]([O:32]C)=[O:31])[CH3:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](C)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@@H](C)C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-L-alaninate (D76) (223 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (60 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then HCl aquous solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL) and water (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-L-alanine (E50) (82 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.34 (3H, d), 1.38 (6H, d), 3.33 (1H, m), 4.28 (2H, q), 4.88-4.94 (1H, m), 7.31 (1H, t), 7.47 (1H, d), 7.64 (1H, d), 8.00 (1H, d), 8.05 (1H, d), 8.22 (1H, dd), 8.40 (1H, d), 11.26 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 366.1 (M—NHC2H3COOH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][C:17]([NH2:19])=[O:18].[H-].[Na+].P([O-])([O-])([O-])=O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH2:16][C:17]([NH2:19])=[O:18])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2cccc(I)c2)C(=O)N1
Reactant: NC(=O)CBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)CN(c2cccc(I)c2)C1=O
Yield: 77.7 %

Procedure:
1-(3-Iodophenyl)imidazolidine-2,4-dione (0.302 g) was taken up in dry DMF (15 ml) and treated with bromoacetamide (0.399 g) and then with sodium hydride (60% oil dispersion, 48 mg). After 3 h pH 6.4 phosphate buffer (50 ml) was added and the reaction mixture extracted with EtOAc (3×25 ml), dried (MgSO4) and evaporated under reduced pressure. Thee residue was purified by Flash chromatography (Merck 9385, EtOAc then 9:1 EtOAc:MeOH) to give the title compound (0.279 g). LCMS RT=2.62 min.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)(C)(C)C>[CH2:10]([NH:17][CH2:6][CH2:5][N:4]([CH2:2][CH3:3])[CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CCCl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNCc1ccccc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
2-(diethylamino)-ethyl chloride hydrochloride (1 g, 5.81 mmol) and benzylamine (1.3 ml, 11.62 mmol) were dissolved in t-butanol (40 ml), triethylamine (3.2 ml, 23.24 mmol) was added thereto, and the resulting solution was refluxed for 12 hours. The solution was cooled to room temperature, and distilled under a reduced pressure to remove the solvent. The resulting solid was removed by filtration under a reduced pressure, and the residual solution was extracted with ethylacetate The separated organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, filtered and distilled under a reduced pressure to obtain the title compound 560 mg (yield: 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[C:33](Cl)(=[O:35])[CH3:34]>[Cl-].[Na+].O.C(OCC)(=O)C>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)NCc1ccc(CN2CCN(c3ccc(N)cc3)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccc(NC(C)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a-solution of N-(4-((4-(4-aminophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide (1.8 g) and potassium carbonate (3.1 g) in a mixed solvent of water (50 ml) and ethyl acetate (50 ml) was added dropwise acetyl chloride (0.43 ml) at room temperature over 10 min. This reaction mixture was stirred at room temperature for 4 hr and poured into saturated brine, which was followed by extraction with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give a purple solid (5.0 g). The obtained solid was subjected to column chromatography (elution solvent; chloroform:methanol=9:1) to give a pale-brown solid. The solid was recrystallized from methanol-water to give the title compound (0.75 g) as pale-red crystals, m.p.=225-226° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[C:13]([NH2:16])(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O>[C:13]([NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1)(=[O:15])[CH3:14]
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc2cc(C)ccc2n1
Temperature: 230 °C
Yield: 73.9 %

Procedure:
Chloride 44 (0.300 g, 1.69 mmol) was diluted with molten anhydrous acetamide (8 g, 135 mmol), and K2CO3 (1.17 g, 8.45 mmol) was added. The mixture was heated in a sand bath, at reflux (˜230° C.) for 16 h. The mixture was cooled, poured into H2O (120 mL) and extracted with EtOAc (4×30 mL). The organic layers were washed with H2O (3×100 mL) and sat. aq. NaCl (50 mL) and dried over anhydrous sodium sulfate and concentrated. Purification of the residue by flash column chromatography (SiO2), eluting with a gradient of 10% EtOAc in CH2Cl2 to 30% EtOAc in CH2Cl2 afforded the desired compound as a white solid (0.250 g, 74%). 1H NMR chemical shifts for this compound are consistent with those reported in the literature. 1H-NMR (500 MHz; CDCl3): δ 8.36 (br d, J=8.6 Hz, 1 H), 8.27 (br s, 1 H), 8.09 (d, J=8.9 Hz, 1 H), 7.70 (d, J=8.6 Hz, 1 H), 7.55 (s, 1 H), 7.50 (dd, J=8.6, 1.9 Hz, 1 H), 2.51 (s, 3 H), 2.24 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1.[CH:16](O)=[O:17]>>[CH3:1][O:2][C:3]1[C:8]([NH:9][CH:16]=[O:17])=[CH:7][CH:6]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: COc1nc(N2CCOCC2)ccc1N
Reactant: O=CO
Product: COc1nc(N2CCOCC2)ccc1NC=O
Yield: 88 %

Procedure:
A solution of 2-methoxy-6-morpholinopyridin-3-amine (Preparation 70, 40 mg, 0.191 mmol) in formic acid (3 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous saturated NaHCO3 (40 mL) and EtOAc (40 mL). The aqueous layer was re-extracted with EtOAc (40 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound (40 mg, 88%).
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](Cl)=[O:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.Br.Br.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:33]2[C:37]([CH3:38])=[N:36][N:35]=[C:34]2[CH2:39][NH2:40])=[C:23]([CH:32]=1)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.CN(C)C=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:33]2[C:37]([CH3:38])=[N:36][N:35]=[C:34]2[CH2:39][NH:40][C:7](=[O:8])[CH2:6][N:5]2[C:4](=[O:10])[C:3]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]3[C:1]2=[O:15])=[C:23]([CH:32]=1)[C:24]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25]
Reactant: Cc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 69.4 %

Procedure:
To a solution of 2-phthalimidoacetyl chloride (1.5 g) in benzene (20 ml) and dimethylformamide (10 ml), 5-chloro-2-(3-aminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone dihydrobromide (2.3 g) is added under ice cooling and stirring, and the temperature within the flask is gradually returned to room temperature. The reaction mixture is allowed to stand at room temperature, neutralized with saturated aqueous sodium bicarbonate, and shaken with ethyl acetate. The precipitated crystals are filtered, washed with methanol and dried to give 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.68 g) as crystals melting at 251°-253° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[NH2:20][C:21]1[C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[C:24]([C:31]2[O:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[N:32]=2)=[CH:23][C:22]=1[Cl:43]>C(#N)C>[NH2:20][C:21]1[C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[C:24]([C:31]2[O:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:38][CH2:39][N:40]([CH2:14][C:13]4[CH:16]=[CH:17][C:10]([C:9]([F:19])([F:18])[F:8])=[CH:11][CH:12]=4)[CH2:41][CH2:42]3)[N:32]=2)=[CH:23][C:22]=1[Cl:43]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Nc1c(Cl)cc(-c2nn(C3CCNCC3)c(=O)o2)c2c1OCCO2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(Cl)cc(-c2nn(C3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)c(=O)o2)c2c1OCCO2
Reaction time: 2 h

Procedure:
1.58 ml (11.38 mmol) of triethylamine and 0.88 g (5.68 mmol) of 4-(trifluoromethyl)benzyl bromide, in solution in 5 ml of acetonitrile, are successively added at room temperature, with magnetic stirring and under an argon atmosphere, to a solution of 1 g (2.84 mmol) of 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one in 60 ml of acetonitrile and the mixture is stirred for 2 h. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform, the solution is washed a number of times with water and dried and the solvent is evaporated under reduced pressure. The residue is crystallized from acetone and 1.14 g of white solid are obtained. Melting point: 198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCOCC2)c2c(C)cccc12
Reaction time: 8 h

Procedure:
To a mixture of 4-methoxy-8-methyl-1-naphthoic acid (above Step-5 intermediate) (1 equiv) in dry DMF (8 mL) was added, EDC.HCl (1.4 equiv) and HOBt (1.4 equiv) and the mixture was stirred for 10 min. To this, morpholine (1.5 equiv) and DIPEA (3 equiv) were added and the reaction mixture was stirred overnight. It was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (4×20 mL). The combined organic layer was washed with water (20 mL), 5% NaHCO3 solution (20 mL), brine (25 mL), dried (Na2SO4) and filtered. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to furnish the title compound.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl[C:29]([O:31][CH3:32])=[O:30].Cl>N1C(C)=CC(C)=CC=1C>[CH3:32][O:31][C:29]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[CH:27])=[CH:24][CH:25]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:30]
Reactant: COC(=O)Cl
Reactant: C#Cc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: C#Cc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(=O)OC)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg of 1-(β-D-glucopyranosyloxy)-2-(4-ethynylbenzyl)-benzene in 0.5 ml of 2,4,6-collidine are combined with 0.026 ml of methyl chloroformate in the ice bath and then stirred for 16 hours at ambient temperature. 5 ml of 0.1 N hydrochloric acid are added to the reaction mixture which is then extracted with 10 ml of ethyl acetate. The organic phase is separated off, washed with saturated saline solution and evaporated down. The residue is stirred with 8 ml of diethyl ether/petroleum ether (1:1), the solid is suction filtered and dried at 40° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 99 %

Procedure:
Following general procedure F, tert-butyl 4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]benzylcarbamate (58 mg, 0.117 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.176 mmol) to afford the crude product (67 mg) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[OH:14][C:11]1([CH3:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of N-Boc-piperidin-4-one (1.0 g, 5.0 mmol) was dissolved in THF (20 mL) and then cooled to −40° C. MeMgBr (2.8 M, 7.2 mL, 20 mmol) was added slowly over 10 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was cooled to 0° C. and saturated aqueous NH4Cl (50 mL) was added. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.0 g, 92% yield) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:37](=[O:39])[CH3:38])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: CC(=O)Cl
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.5 %

Procedure:
To a stirred suspension of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (46 mg, 0.127 mmol) and DIPEA (26 μL, 0.152 mmol) in anhydrous THF (3 mL) and anhydrous DCM (1 mL) was added acetyl chloride (9 μL, 0.127 mmol). Stirring at RT was continued for 3 h then volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc and water. The aqueous layer was further washed with DCM and the organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residues were combined, purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-70% 0.1% HCO2H in acetonitrile/water) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure affording 115 as a white solid (10 mg, 19%). LCMS: RT 2.13 min [M+H]+ 405.1. 1H NMR (CDCl3, 400 MHz): δ 8.35 (1H, s), 7.88 (1H, s), 7.78-7.70 (1H, m), 7.49-7.42 (1H, m), 7.28-7.20 (3H, m), 6.05 (1H, s), 4.98-4.82 (1.5H, m), 4.71-4.61 (0.5H, m), 4.09-3.99 (0.5H, m), 3.90-3.78 (0.5H, m), 3.42-3.37 (0.5H, m), 3.32-3.18 (0.5H, m), 2.88-2.37 (1H, m), 2.20-2.10 (4H, m), 2.06-1.96 (1H, m), 1.90-1.69 (5H, m). Signals split due to presence of rotamers
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H][H]>[Pd].CC1C=CC=CC=1C>[CH3:12][O:11][C:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: COC(=O)CC1CCC(=O)CC1
Temperature: 25 °C

Procedure:
A high pressure autoclave was charged with a mixture of methyl (4-hydroxyphenyl)acetate (50 g, 0.30 mol), palladium (5 g) (10%) on carbon (50% wet) and O-xylene (250 mL). The reaction mixture was stirred under 110 to 115 psi of hydrogen pressure for 7 to 8 h at 140° C. The reaction was monitored by HPLC. The reaction mixture was then cooled to room temperature, and the catalyst was filtered off. Filtrate was concentrated under reduced pressure to get 4-(methoxycarbonylmethyl)cyclohexanone as light yellow to colorless oily liquid (48.7 g, 97.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[O:40]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:39]([NH:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[F:31])=[O:40])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C=Nc1ccccc1F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4F)c(F)c3)CC2)c1
Yield: 9 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (100 mg, 0.242 mmol) and 2-fluorophenylisocyanate (37 mg, 0.267 mmol) were combined and heated in dichloromethane at 100° C. in the microwave for 10 minutes. The solvent was removed under reduced pressure and the residue purified by acidic reverse phase HPLC to afford the title compound (12 mg).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:2]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:11]2[CH:12]([C:7]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: Cc1cccc(C2(c3cccc(C)c3)C=CC(=O)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(Cc4ccccc4)CC32)c1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (12 drops) is added to a solution of 4,4-bis(3-tolyl)cyclohexenone (16.7 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (18.7 cc) in dry dichloromethane (150 cc). The reaction mixture is brought to reflux, then stirred for 3 hours while allowing the temperature the return to 25° C. and for a further 10 minutes after the addition of potassium carbonate (12 g). After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (85:15) and collecting 25-cc fractions. Fractions 14 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(3-tolyl)perhydro-4-isoindolone (13.9 g) in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2I.[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][O:25][C:26]2[CH:31]=[C:30]([Sn](C)(C)C)[N:29]=[C:28]([S:36]([CH3:39])(=[O:38])=[O:37])[N:27]=2)=[CH:22][CH:21]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:30]1[CH:31]=[C:26]([O:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:41][CH:40]=2)[N:27]=[C:28]([S:36]([CH3:39])(=[O:38])=[O:37])[N:29]=1
Reactant: COc1ccc(COc2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)cc1
Reactant: Brc1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 90 °C
Yield: 44 %

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.82 g, 2.015 mmol) and 4-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidine (1.013 g, 2.216 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (0.116 g, 0.101 mmol) and CuI (0.017 ml, 0.504 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 90° C. for 30 min. The mixture was diluted with DCM (5 mL), filtered through a plug of celite and washed with DCM. The filtrate was washed with water (25 mL×3) and the organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-10% EtOAc in Hexanes) to give 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (508 mg, 0.886 mmol, 44.0% yield) as a white foam. MS (ESI, pos. ion) m/z: 573/575 (1:1) (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.67-1.86 (m, 3 H) 2.06-2.26 (m, 2 H) 2.49-2.64 (m, 1 H) 3.48 (s, 3 H) 3.72-3.80 (m, 1 H) 3.82 (s, 3 H) 3.91-4.01 (m, 1H) 5.52 (s, 2 H) 5.79 (dd, J=8.41, 2.93 Hz, 1 H) 6.93 (m, J=8.80 Hz, 2 H) 7.45 (m, J=8.80 Hz, 2 H) 7.51-7.60 (m, 2 H) 7.70 (s, 1 H) 8.68-8.74 (m, 1 H).