Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=3[CH:34]=2)[C@@H:15]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][O:42][CH2:43][C@H:44]([O:46][CH2:47][CH3:48])[CH3:45])=[CH:37][CH:36]=2)[C@H:14]([CH2:49][OH:50])[CH2:13]1)=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH2:47]([O:46][C@H:44]([CH3:45])[CH2:43][O:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C@@H:15]2[C@@H:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=4[CH:34]=3)[CH2:17][NH:12][CH2:13][C@H:14]2[CH2:49][O:50][C:1](=[O:3])[CH3:2])=[CH:36][CH:37]=1)[CH3:48]
Reactant: CC(=O)Cl
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COC(C)=O)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
0.89 mmol of acetyl chloride are added to a solution of 0.81 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) and 0.97 mmol of Et3N in 7 ml of CH2Cl2 under argon at 0° C. After 1 h, the reaction mixture is diluted with CH2Cl2 and washed with successively with saturated aqueous NaHCO3 solution and brine. The combined aqueous phases are extracted with CH2Cl2—the combined organic layers are dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and is identified based on the Rf value.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:79]=[CH:78][C:77]([N:80]2[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]2)=[CH:76][C:56]=1[C:57]([NH:59][C:60]1[CH:65]=[N:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:74])[F:73])[CH:67]=2)=[CH:62][N:61]=1)=[O:58]>CN(C)C=O.C(OCC)(=O)C>[N:80]1([C:77]2[CH:78]=[CH:79][C:55]([NH:54][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[C:56]([C:57](=[O:58])[NH:59][C:60]3[CH:65]=[N:64][C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:73])([F:74])[F:75])[CH:67]=4)=[CH:62][N:61]=3)[CH:76]=2)[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.1 %

Procedure:
To 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (53.7 mg, 0.18 mmol, 0.80 equiv) in N,N-dimethylformamide (2 mL) was added HATU (172.3 mg, 0.45 mmol, 2.00 equiv) and DIEA (117.0 mg, 0.91 mmol, 4.00 equiv) followed by the dropwise addition of a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide 6d (100 mg, 0.23 mmol, 1.00 equiv) in N,N-dimethylformamide (1 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of water and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 140 mg of crude product as a brown solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccncc2)CC1
Yield: 100.7 %

Procedure:
Amine preparation: a mixture of 1-BOC-piperazine (2 g), 4-pyridine carboxaldehyde (1.26 g), sodium triacetoxyborohydride (2.96 g) and acetic acid (0.6 mL) was stirred together in dry 1,2-dichloroethane (15 mL) at room temperature. After 4 h the reaction was quenched with saturated NaHCO3 solution and extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo to give 4-pyridin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (3 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(O)(=[O:29])C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:29])=[CH:21][CH:20]=3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)o2)cc1
Reactant: CC(=O)O
Solvent: O
Product: CS(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)o2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-(4-fluorophenyl)-2-(4methylthiophenyl)-5-(4-pyridyl)oxazole (0.056 g, 0.15 mmol) in glacial acetic acid (12 mL) was added a solution of K2S2O8 (0.07 g, 024 mmol) in H2O (2 mL). After stirring at rt for 48 hr, the precipitate was filtered. Purification by column chromatography (25:1 CH2Cl2/MeOH), followed by trituration with Et2O afforded the title compound (0.014 g) as a white solid: ESMS (m/z)=379.0 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2F)n1
Temperature: 50 °C

Procedure:
200 mg (0.85 mmol) of 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester were dissolved in 5 ml of DMF. 552 mg (1.7 mmol) of cesium carbonate and 152 mg (0.85 mmol) of 1-bromo-3,3-dimethyl-butan-2-one were added and the mixture was heated to 50° C. for 6 h. Then the mixture was filtered and the solvent removed in vacuo. The obtained crude title compound was subjected to hydrolysis without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]3)=[N:17][N:16]=1)[CH2:7][CH2:6]2
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(c1nnc(N(C)C3CC(C)(C)NC(C)(C)C3)s1)C2=O
Temperature: 150 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.282 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (132 mg, 0.395 mmol) in DMF (0.7 mL) under nitrogen was added K2CO3 (78 mg, 0.564 mmol) followed by CuI (32 mg, 0.169 mmol). The reaction mixture was heated at 150° C. for ˜18 hours. A further 1.4 eq of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (132 mg, 0.395 mmol) and 0.6 eq of CuI (32 mg, 0.169 mmol) were added and stirring was continued at 150° C. for an additional 48 hours. The reaction mixture was diluted with EtOAc (10 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product as a dark brown oil. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified) collecting at 312 nm. The product containing fractions were combined and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (˜20 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (12 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as a pale yellow/brown glass-like solid (28 mg, 23% yield). LC-MS: Rt 0.91 min; MS m/z 430.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88-7.97 (m, 1H), 6.96-7.03 (m, 2H), 4.35 (t, J=6.57 Hz, 2H), 4.16 (tt, J=12.19, 3.22 Hz, 1H), 3.85 (s, 3H), 3.14 (t, J=6.57 Hz, 2H), 2.91 (s, 3H), 1.58 (dd, J=12.13, 3.03 Hz, 2H), 1.42 (t, J=11.87 Hz, 2H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[I:22])[CH:13]1[CH2:23][C:24]([O-:26])=O)=[O:11])=O)(C)(C)C.[Na+].C(OC(NCC(N1CCC2C(=CC=CC=2I)C1CC(OCC)=O)=O)=O)(C)(C)C.[OH-].[Na+]>CCO>[I:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][N:12]1[C:10](=[O:11])[CH2:9][NH:8][C:24](=[O:26])[CH:23]=[C:13]12
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(I)cccc2C1CC(=O)[O-]
Agent: CCOC(=O)CC1c2cccc(I)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
sodium 2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. To an orange solution of ethyl 2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (57.4 mmol, 114 mmol) in EtOH (800 mL) was added an aqueous solution of NaOH (4M, 33 mL, 132 mmol) and the mixture was stirred at RT for 60 h. The mixture was then filtered and the filter cake was washed with Et2O. The filtrate was then concentrated down in vacuo until the formation of another precipitate. The mixture was then filtered again and the filter cake washed with Et2O. The combined filter cakes were then dried in vacuo to give the title compound (49.8 g) as a beige powder that was used as it is in the next step. UPLC-MS: MS 475.2 (M+H+); UPLC rt 1.00 min.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([C:13]2[CH:33]=[CH:32][C:16]([O:17][C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3C(OCC)=O)=[CH:15][CH:14]=2)[C:4]1=[O:34])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([C:13]2[CH:33]=[CH:32][C:16]([O:17][C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[CH:26]=3)=[CH:15][CH:14]=2)[C:4]1=[O:34])[CH3:2]
Reactant: CCOC(=O)c1c(Oc2ccc(-n3c(=O)n(CC)c4cc(C)cnc43)cc2)nc2ccccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3cn4ccccc4n3)cc2)c2ncc(C)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of ethyl 2-[4-(1-ethyl-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]imidazo[1,2-a]pyridine-3-carboxylate (62 mg) in EtOH (4 mL) was added sodium hydroxide (1.084 mL). The mixture was stirred at 50° C. for 2 h. Hydrochloric acid (2.168 mL) was added to the mixture, and the mixture was stirred at 60° C. for 10 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (42.0 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8]I)(=[O:5])=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])(=[O:5])=[O:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)S(=O)(=O)CCCI
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
To a solution of 3-iodo-propane-1-sulfonic acid dimethylamide (600 mg) in DMF (10 mL) was added potassium phthalimide (590 mg) and the reaction heated at 100° C. for 16 h. After cooling to room temperature, the reaction was partitioned between dichloromethane (30 mL) and water (30 mL). The organic layer was washed with aqueous brine solution (3×30 mL), dried (MgSO4) and reduced in vacuo to give 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propane-1-sulfonic acid dimethylamide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[OH-].[Na+:15]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O-:13])=[O:12].[Na+:15]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccccc1CC(=O)[O-]

Procedure:
A solution of (2-nitrophenyl)acetic acid (18.1 g) in normal sodium hydroxide solution (120 cc) is hydrogenated in an autoclave under a pressure of 5 bar for 2.5 hours at 20° C. in the presence of 3% palladium-on-carbon black (1.5 g). The solution of sodium (2-aminophenyl)acetate thus obtained is cooled to +5° C. and then treated with a solution of di-tert-butyl dicarbonate (26.16 g) in tetrahydrofuran (100 cc) and then with normal sodium hydroxide solution (80 cc). The reaction mixture is stirred at 20° C. for 80 hours, partially concentrated under reduced pressure (2.7 kPa), diluted with water (200 cc) and washed with ethyl ether (3×200 cc). The aqueous phase is acidified to pH 3 by addition of 4N hydrochloric acid and extracted with ethyl acetate (2×200 cc). The combined organic phases are washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). (2-tert-Butoxycarbonylaminophenyl)acetic acid (25 g) is obtained in the form of a cream-white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([CH:17]=[CH2:18])=[C:5]([CH2:19][CH3:20])[N:4]=1)[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([CH2:17][CH3:18])=[C:5]([CH2:19][CH3:20])[N:4]=1)[CH3:2]
Reactant: C=Cc1c(CC)nc(CC)c(CO)c1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1nc(CC)c(CO)c(-c2ccccc2)c1CC

Procedure:
The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-ethenyl)pyridine (Example 8) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.44 (m, 3 H), 7.18 (m, 2 H), 4.33 (d, J=6 Hz, 2 H), 2.97 (q, J=8 Hz, 2 H), 2.86 (q, J=8 Hz, 2 H), 2.36 (q, J=328 Hz, 2 H), 1.34 (m, 7 H), 0.93 (t, J=8 Hz, 3 H). FAB-MS: calculated for (C18H23NO) 269, found 270 (M+H). Anal. Calcd for C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 79.70; H, 8.54; N, 5.08. mp 100° C. Rf=0.4 (50% ethyl acetate/hexane).
Reaction SMILES: NC(=O)[C@H:3]([NH:7][C:8]1[N:9]=[N:10][C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[CH3:24])[N:13]=1)[CH:4]([CH3:6])C.NCC1[NH:35][C:34](=[O:36])[CH2:33]C1.N[C@H](C(C)C)C(N)=O>>[CH3:24][N:19]1[C:20]2[C:16](=[C:15]([NH:14][C:12]3[N:13]=[C:8]([NH:7][CH2:3][CH:4]4[CH2:6][CH2:33][C:34](=[O:36])[NH:35]4)[N:9]=[N:10][C:11]=3[C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: CC(C)[C@@H](Nc1nnc(C(N)=O)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Reactant: NCC1CCC(=O)N1
Agent: CC(C)[C@@H](N)C(N)=O
Product: Cn1ccc2c(Nc3nc(NCC4CCC(=O)N4)nnc3C(N)=O)cccc21

Procedure:
The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 5-(aminomethyl)pyrrolidin-2-one was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C18H20N8O2 as (M+H)+ 381.3. UV: λ=219, 239, 292 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.36-7.22 (3H, m), 6.60 (1H, dd, J=0.8 Hz, 2.8 Hz), 3.98 (1H, m), 3.84 (3H, s), 3.62-3.51 (2H, m), 2.40, −2.20 (3H, m), 1.90 (1H, m) ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[C:24]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CNCc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
2.2 g (0.01 mole) of N-methyl-9-anthrylmethylamine was dissolved in 40 ml of toluene, and 1.7 g (0.012 mole) of anhydrous potassium carbonate was added. With continued stirring at room temperature, 2.49 g (0.011 mole) of p-t-butylbenzylbromide was added, and the mixture was reacted at 40° to 50° C. for 4 hours. The reaction mixture was mixed with ice water, and distributed. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 4% ethyl acetate/n-hexane. The eluate was concentrated to give 3.3 g (yield 91%) of an oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][NH:4][CH2:3]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:3]1
Reactant: CC1(C)CCNC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCC(C)(C)C2)n1
Yield: 20 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3,3-dimethyl-pyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (20%) as amorphous yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([C:13]([CH2:20][CH3:21])([C:17](Cl)=[O:18])[C:14](Cl)=[O:15])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[CH2:11]([C:13]1([CH2:20][CH3:21])[C:14](=[O:15])[C:6]2[C:5](=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH3:1])[C:7]=2[CH3:8])[C:17]1=[O:18])[CH3:12]
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: COc1cccc(C)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CCC1(CC)C(=O)c2cc(OC)c(C)c(C)c2C1=O
Temperature: 0 °C

Procedure:
A stirred mixture of 2,3-dimethylanisole (6.8 g., 0.05 mole) and 2,2-diethylmalonyl chloride (10 g., 0.051 mole) in hexane (75ml.) is cooled to 0°C. and treated with aluminum chloride (13.5 g., 0.11 mole) in several portions over a 15 minute period. The reaction is heated at reflux for 2 hours, the hexane is distilled at reduced pressure, the product treated with cold 1N-hydrochloric acid, extracted into ether, washed with water, 5% sodium hydroxide, water then dried over magnesium sulfate. Evaporation of the ether at reduced pressure affords 6.3 g. of 2,2-diethyl-4,5-dimethyl-6-methoxy-indan-1,3-dione which melts at 80°-81°C. after recrystallization from petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=1.O(C)[Na]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Nc1cc(Cl)ccn1
Agent: CO[Na]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc(N)c2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
To a mixture of 4-aminophenol (218 mg, 2 mmol) and 4-chloropyridin-2-amine (256 mg, 2 mmol) in DMSO (2.5 mL) was added NaOCH3 (216 mg, 4 mmol). The reaction was microwaved at 180° C. for 40 minutes, then cooled down to rt and quenched with water (10 mL). The mixture was extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=30/1) to give the title compound as a brown solid (103 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(N)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: NC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A mixture of 4'-methylbiphenyl-2-carboxamide (2.1 g), N-bromo-succinimide (2.5 g) and azobisisobutyronitrate (AIBN; 82 mg) in benzene (20 ml) was stirred for 20 hours at 60 to 70° C. Resulting crystalline precipitates were collected by filtration, washed with isopropylether and suspended in water. The suspension was stirred for 30 minutes, and insoluble materials were collected by filtration and dried to give crude crystals. Recrystallization from ethyl acetate-methanol afforded colorless needles (1.6 g, 55%), m.p. 220-221° C.(decomp.).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: BrBr
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]cc(C(F)(F)F)cc1Br
Yield: 75.8 %

Procedure:
0.4 g of 5-trifluoromethyl-2-pyridone was dissolved in 10 ml of acetic acid, and 0.4 g of bromine was added to the solution which was subsequently reacted for 4 hours while stirring. After completion of the reaction, the acetic acid was distilled off, and recrystallization was carried out from a mixed solvent of methylene chloride and n-hexane to obtain 0.45 g of the titled compound having a melting point of 162° to 165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[O:14]1[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])=[CH:11][N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1cccc(-c2cnco2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2cnco2)c1
Yield: 98.7 %

Procedure:
10% Pd/C (0.60 gm, 0.56 mmol) was added to a solution of 5-(3-Nitrophenyl)oxazole (5.80 gm, 30.50 mmol) in MeOH (122 mL). A H2 atmosphere was then introduced via balloon. After 24 h the reaction mixture was filtered through Celite. The catalyst was rinsed with MeOH and the filtrate was concentrated to give the product 3-(oxazol-5-yl)aniline (4.82 gm, 30.10 mmol, 99% yield) as a white solid. Anal. Calcd. for C9H6N2O3 m/z 160.1, found: 161.1 (M+H)+. Crude product was used without purification.