Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]([C:12]2[N:13]([CH3:22])[N:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=2[Cl:17])=O)=[N:4][CH:5]=[C:6](Br)[N:7]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.CCOC(C)=O.O>[C:18]([C:15]1[C:16]([Cl:17])=[C:12]([C:10]2[NH:9][C:3]3=[N:4][CH:5]=[C:6]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][C:24]([F:23])([F:36])[F:35])[N:7]=[C:2]3[N:1]=2)[N:13]([CH3:22])[N:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1ncc(Br)nc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2nc(-c3ccccc3OC(F)(F)F)cnc2[nH]1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (3-amino-5-bromo-pyrazin-2-yl)-amide (45.0 mg, 0.116 mmol, prepared as described in the previous step), 2-trifluoromethoxy-phenyl-boronic acid (28.7 mg, 0.139 mmol), Cs2CO3 (95 mg, 0.29 mmol) and Pd(dppf)2.DCM (9.5 mg, 0.012 mmol) in 1,4-dioxane (3 mL) was added water (1.5 mL). After stirring at 100° C. for 16 h, the resulting mixture was cooled to room temperature and treated with EtOAc (50 mL), washed with H2O (20 mL), brine (20 mL) and then dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0:100-35:65 EtOAc-hexanes) yielded 2-(5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-5-(2-trifluoromethoxy-phenyl)-1H-imidazo[4,5-b]pyrazine as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 8.79 (s, 1H), 7.87-7.94 (m, 1H), 7.45-7.64 (m, 3H), 4.14 (s, 3H), 1.44 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C20H18ClF3N6O: 451.1 (M+H), Measured: 451.1.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:25](=[O:28])[CH2:26][CH3:27])[N:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[OH:22][C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([CH3:11])[C:25](=[O:28])[C:26]=1[CH3:27]
Reactant: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of LiHMDS (0.78 mL, 0.78 mmol, 1 M solution in THF) in THF (1 mL) at −78° C. was added a solution of diethyl 2-(2-methyl-2-propionylhydrazono)malonate (50 mg, 0.19 mmol) in THF (1 mL). The resulting mixture was slowly warmed to −40° C. and stirred for 1.5 hours at −40° C. The reaction mixture was quenched with 10% aqueous HCl and diluted with water. The resulting mixture was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 20% EtOAc in hexanes) to afford 25 mg (61%) of the desired product.
Reaction SMILES: C[CH:2]1[C:7]2[CH:8]=[C:9]3C(C)(C)C(C)C(C)(C)[C:10]3=[CH:11][C:6]=2[CH2:5][O:4][CH2:3]1>C(O)C>[O:4]1[C:3]2[CH:2]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=[CH:6][CH2:5]1
Reactant: CC1COCc2cc3c(cc21)C(C)(C)C(C)C3(C)C
Solvent: CCO
Product: C1=Cc2ccccc2OC1
Reaction time: 2 h

Procedure:
200 grams of the liquid phase benzopyran mixture was prepared according to Example 15 of U.S. Pat. No. 3,360,530 containing 78% by weight of 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta[G]-2-benzopyran and 100 grams of 10% aqueous ethanol were admixed and cooled to a temperature of +5° C. with stirring. Stirring continued for a period of 2 hours at which point in time solid particles began to precipitate. The mixture was stirred for an additional 3 hours at 5° C. 42 grams of white crystalline material were filtered at 5° C. The resulting composition was a solid phase benzopyran mixture containing 91 weight % of 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[G]-2-benzopyran having a melting point of 31° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:4]([CH:5]([C:13]([OH:15])=O)[CH2:6]2)[N:3]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][Li]>CCOCC>[CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:4]([CH:5]([C:13](=[O:15])[CH3:23])[CH2:6]2)[N:3]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C1CC2C(C(=O)O)CC1C(C)N2Cc1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C1CC2C(C(C)C)CC1N(Cc1ccccc1)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylic acid (30.1 g, 100 mmol) and ether (300 mL) was cooled to 0° C. and methyllithium (330 mL, 1.2N solution in ether) was added dropwise over 2 hours. The mixture was stirred for 1 hour at 0° C. and quenched by the addition of saturated NH4Cl (100 mL). The mixture was poured into water (1 L), and the aqueous layer was separated and extracted with ether (1×200 mL). The ether extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ether/hexane to afford 14.3 g (48%) of 1-[3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octan-6-yl]-ethanone. The product was treated with ethereal.HCl to afford 15.2 g of the hydrochloride salt as a white solid, m.p. 208.5°-210° C. (dec.) when recrystallized from ethanol/ether.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:34][CH2:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCC1CCCCC1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCC2CCCCC2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), cyclohexanemethylamine (0.53 mL, 6.1 mmol) and MeOH (0.11 mL) is heated at 100° C. for 48 h. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-50:50) gives 0.23 g of the product 79. 1H NMR (CDCl3) δ 7.80-7.35 (m, 2 H), 7.18 9s, 1 H), 7.10-6.90 (m, 6 H), 6.90-6.70 (m, 2 H), 5.45-5.30 (m, 2 H), 3.45-3.15 (m, 2 H), 2.00-1.50 (m, 5 H), 1.45-0.95 (m, 15H); MS: m/z 434 (M++1).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[O:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.CCCCCC.[C].[Pd]>[F:47][C:2]([F:1])([F:46])[O:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)ncc3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
To a mixed solution of the compound (66 mg) obtained in Step 5, ammonium formate (28 mg) and ethanol (1.3 ml) was added 10% palladium carbon (33 mg) with heating under reflux. The mixture was stirred at the same temperature for 10 min and ammonium formate (28 mg) and 10% palladium carbon (33 mg) were added and the mixture was stirred for 10 min. Ammonium formate (28 mg) and 10% palladium carbon (33 mg) were further added. The reaction mixture was allowed to return to room temperature, and diluted with ethanol. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), and the obtained crude product was suspended in hexane, collected by filtration, and dried to give the title compound (31 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[H-].[Na+].Cl[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:16][CH2:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH3:11])=[N:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(COCc2ccccc2)c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a 0° C. stirred solution of 5-bromo-3-methyl-indazole (from Preparation 1, 1.00 g, 4.33 mmol) in anhydrous DMF (30 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.21 g, 5.19 mmol). After 30 min, benzyl chloromethyl ether (60%, 1.47 g, 5.63 mmol) was added vial syringe in about 1 min. Stirring was continued for 1 h. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give an oil that was purified by chromatography on silica gel (hexane/ethyl acetate 10:1) to give the title compound (0.72 g, 50%) that was pure by NMR.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:39][CH:40]=3)=[N:3][CH:4]=[C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (60.7 mg, 0.13 mmol), 4-(methylsulfonyl)phenylboronic acid (40.1 mg, 0.2 mmol), tricyclohexylphosphine (6.2 mg, 0.022 mmol), and tris(dibenzylideneacetone)dipalladium (0) (10.4 mg, 0.011 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.3 mL, 0.39 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-60% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that was triturated with MeOH to afford a light yellow solid as 5,7-difluoro-3-methyl-N-(2-(4-(methylsulfonyl)phenyl)-5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.8, 1.2 Hz), 8.12 (5H, m), 7.96 (2H, m), 7.62 (1H, d, J=8.8 Hz), 7.39 (1H, ddd, J=6.8, 4.8, 2.1 Hz), 7.02 (2H, m), 6.55 (1H, d, J=2.4 Hz), 3.91 (4H, m), 3.28 (4H, m), 3.09 (3H, s), 2.25 (3H, s). Mass Spectrum (pos.) m/e: 602.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][C@@H:33]([CH3:35])[N:32](C(=O)C(F)(F)F)[CH2:31][C:30]2=[O:42])[CH:26]=[CH:27][CH:28]=1>Cl>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C:30]3=[O:42])[CH:24]=2)=[N:3][CH:4]=1
Reactant: C[C@@H]1CN(c2cccc(N)c2)C(=O)CN1C(=O)C(F)(F)F
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Agent: Cl
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3C[C@@H](C)NCC3=O)c2)ncc1F
Temperature: 95 °C
Yield: 55 %

Procedure:
To the suspension solution of 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (100 mg, 0.32 mmol) and (5R)-1-(3-aminophenyl)-5-methyl-4-(trifluoroacetyl)-2-piperazinone (147 mg, 0.48 mmol) was added 2 drops of 12N HCl. The reaction mixture was then sealed and heated in a 95° C. oil bath for 16 h. The reaction was followed by LC/MS. The reaction was evaporated to dryness. The residue was then dissolved in THF (10 mL) with LiOH (1.0 M solution 0.64 mL). The reaction mixture was heated at 50° C. for 3 h. Then the solvent was evaporated to dryness on high vacuum and the residue was loaded on silica gel column and eluted with 2.0 to 9.0% MeOH (with 0.1% NH4OH) in CH2Cl2. Oil was then recrystallized from hot EtOH to yield the pure title compound (84 mg, 55%). MS: M(C25H28FN7O2)=477.54 (M+H)+=478.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]1[CH2:20][CH3:21].Cl.ClC1C([F:31])=C(F)C=CC=1CN>>[Cl:1][C:2]1[C:7]([F:31])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]1[CH2:20][CH3:21]
Reactant: NCc1ccc(F)c(F)c1Cl
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Agent: Cl
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)c(F)c1Cl

Procedure:
N-[(2-chloro-3,4-difluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (E130) but using [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (prepared as described above for Example 36) in the place of [(2-chloro-4-fluorophenyl)methyl]amine.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([F:47])[C:12]2[O:16][C:15]([NH:17][C@H:18]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]4[NH:33][CH2:34][CH2:35][CH2:36][N:37]=4)=[CH:22][CH:21]=3)=[N:14][C:13]=2[CH:46]=1.C1(C)C=CC=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([F:47])[C:12]2[O:16][C:15]([NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]4[NH:33][CH2:34][CH2:35][CH2:36][N:37]=4)=[CH:24][CH:25]=3)=[N:14][C:13]=2[CH:46]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2cc(Br)cc(F)c2o1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3cc(Br)cc(F)c3o2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
3.5 ml of trifluoroacetic acid is added to 260 mg of ester 9-2 in 5 ml of dichloromethane, agitation is carried out for 3 hours at ambient temperature then 10 ml of toluene is added. Evaporation is then carried out under reduced pressure and 236 mg of expected acid 9-3 is obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[C:24](=[N:32]O)([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:32]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:31]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Reactant: NC(=NO)c1ccccc1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCCc2nc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 1.5 h
Yield: 34.9 %

Procedure:
CDl (0.98 g, 6.1 mmol) was added to a solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (1.89 g, 5.5 mmol) in DMF (15 ml) and stirred under nitrogen for 1.5 h. Benzamidoxime (0.91 g, 6.1 mmol) was added and the mixture stirred at 110° C. overnight. The reaction mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The crude product was crystallised from methanol and then further purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a white solid (850 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=4)[C:11]=3[CH:24]=2)=[N:4][N:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([CH:21]([OH:23])[CH3:22])=[CH:19][CH:20]=4)[C:11]=3[CH:24]=2)=[N:4][N:3]=1
Reactant: CC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(C)O)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 1-[4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenyl]ethanone (0.30 g, 0.94 mmol) in ethanol (3 mL) was added sodium borohydride (90%, 59 mg, 1.41 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/2-1/3) and recrystallized from hexane/ethyl acetate to give the title compound (0.23 g, yield 76%) as colorless crystals.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=4)=[CH:26][CH:27]=3)[N:22]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([S:44][CH3:45])[N:39]=3)[CH:21]=2)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=4)=[CH:26][CH:27]=3)[N:22]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([S:44]([CH3:45])=[O:6])[N:39]=3)[CH:21]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2cn(-c3ccnc(SC)n3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cn(-c3ccnc(S(C)=O)n3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Yield: 96.7 %

Procedure:
m-Chloroperoxybenzoic acid (m-CPBA; 70%, 95 mg, 0.384 mmol) was added to a mixture solution of 3-(4-methoxyphenyl)-1-(2-(methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (90 mg, 0.192 mmol) in methylene chloride (10 mL) at 0° C. 2 hours later, after adding saturated sodium bicarbonate aqueous solution at 0° C., the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound (90 mg) was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:3]=1.[C:20]([O-])(O)=O.[Na+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:20])=[O:10])=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1cccc(Nc2nc(Cl)nc(Cl)c2C(=O)O)c1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.8 %

Procedure:
To a solution of 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylic acid (7.67 g, 25.7 mmol) in DMF (80 mL) was added NaHCO3 (3.30 g, 39.3 mmol) and iodomethane (1.605 mL, 25.7 mmol) at 0° C. The mixture was stirred at RT for 14 h, after which saturated aq NaHCO3 was added. The mixture was extracted with EtOAc. The organic layers were washed with aqueous NaHOC3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure. The residue was triturated with isopropyl ether and filtered to give a first batch (5.28 g) of the title compound. The filtrate was concentrated, triturated with IPE, and filtered to give a second batch (0.66 g) of the title compound as a yellow solid (total 5.94 g, 74%). 1H NMR (500 MHz, CDCl3) δ ppm 2.38 (s, 3H), 4.00 (s, 3H), 7.02-7.03 (m, 1H), 7.27-7.33 (m, 2H), 7.44-7.46 (m, 1H), 10.30 (br s, 1H). [M+H] calc'd for C13H12Cl2N3O2, 312. found, 312.