Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cncnc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cc1cncnc1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
Under nitrogen atmosphere to a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(pyrimidin-5-ylmethyl)pyrrolidine (21.0 g) in dichloromethane (105 ml) were added triethylamine (16.1 g) firstly and methanesulfonyl chloride (13.7 g) secondly at 5° to 10° C. After the reaction mixture was stirred for an hour at the same temperature, dichloromethane (50 ml) and ice-water (150 ml) were added thereto, and then the solution was stirred vigorously for twenty minutes. The organic layer was separated and washed with 1N-hydrochloric acid (100 ml), 1N-sodium hydroxide (200 ml), and brine (200 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(pyrimidin-5-ylmethyl) pyrrolidine (25.2 g) as an oil.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([O-:10])(C)[CH3:8].[K+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.C1OC1C>CCCCCC.C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:14]=1[CH2:6][CH:7]([OH:10])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: CC1CO1
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.5 M of n-BuLi in hexane (4.4 mL) was added to THF (10.0 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M of KOtBu in THF (11 mL). The mixture was stirred at −78° C. for 30 min, then 1-fluoro-3-(trifluoromethyl)benzene (1.5 g, 9.1 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of propylene oxide (640 mg, 11 mmol) in THF (5 mL) was added at −78° C. The mixture was allowed to slowly warmed to rt and stirred overnight. The mixture was quenched with water (10 mL), and then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield a brown oil. The crude material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ=1.22 (d, J=6.3 Hz, 3H), 2.90-2.97 (m, 1H), 3.06-3.13 (m, 1H), 4.05-4.13 (m, 1H), 7.37-7.44 (m, 1H), 7.47 (td, J=7.9, 5.7 Hz, 1H), 7.54-7.59 (m, 1H). 1H NMR (CDCl3, 400 MHz): δ=1.30 (d, J=6.1 Hz, 3H), 1.41 (d, J=6.1 Hz, 1H), 2.93-3.07 (m, 1H), 4.08-4.17 (m, 1H), 7.23-7.27 (m, 1H), 7.29 (s, 1H), 7.30-7.37 (m, 1H), 7.48 (d, J=7.8 Hz, 1H).
Reaction SMILES: ClC1C=C(C=[CH:10][CH:11]=1)C(OO)=O.C([C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:22]=2[N:23]=1)C.[S:32]([O-])([O-:35])(=[O:34])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:10]([S:32]([C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:22]=2[N:23]=1)(=[O:35])=[O:34])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccsc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccsc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.87 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.6 g of 2-(3-ethylthiophen-2-yl)-5-(trifluoromethyl)benzoxazole and 6 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.53 g of 2-(3-ethylsulfonylthiophen-2-yl)-5-(trifluoromethyl)benzoxazole (Compound of Present Invention (33)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH2:22][O:21]1>CN(C)C=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([OH:21])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH2:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CN1NCc2ccccc21)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a suspension of Indazole (0.27 g, 2.32 mmol) in N, N-dimethylformamide (10 ml) was slowly added sodium hydride (0.093 g, 2.32 mmol) at 0° C., followed by stirring for 30 min and then for an additional 30 min at room temperature. Then, 1-((2-(2,4-difluorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole (0.50 g, 2.11 mmol) was added, followed by stirring for 2 hrs at 60° C. The reaction was quenched with the addition of water (1 ml) at 0° C. Following dilution with ethyl acetate (20 ml), the reaction mixture was washed with saturated ammonium chloride solution (20 ml) and then with brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum condition. The product was purified by chromatography on silica gel to give the title compound (Yield 44%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4](C)(C)C)=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:28]=[C:29]([C:31]1[C:32]([CH3:50])=[CH:33][C:34]([CH3:49])=[C:35]([NH:37][C:38]([C:40]2[N:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]3=[N:42][CH:41]=2)=[O:39])[CH:36]=1)[NH2:30].ClC(OC)=O>CN1C(=O)CCC1.C(O)(C(F)(F)F)=O.O>[N:42]1[CH:41]=[C:40]([C:38]([NH:37][C:35]2[C:34]([CH3:49])=[CH:33][C:32]([CH3:50])=[C:31]([C:29]3[N:28]=[C:12]([CH:10]4[CH2:9][N:8]([C:1]([O:3][CH3:4])=[O:2])[CH2:11]4)[O:14][N:30]=3)[CH:36]=2)=[O:39])[N:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=12
Reactant: Cc1cc(C)c(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: COC(=O)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CC(c2nc(-c3cc(NC(=O)c4cnc5ccccn45)c(C)cc3C)no2)C1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of Boc-azetidine-3-carboxylic acid (20 mg, 0.1 mmol) in anhydrous NMP (1 mL) was added CDI (16.3 mg, 0.1 mmol). The reaction was stirred for 10 minutes. Then, N-(5-(N′-hydroxycarbamimidoyl)-2,4-dimethylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (50c) (15 mg, 0.05 mmol) was added and the reaction was stirred for 15 minutes. The reaction was heated in the microwave at 125° C. for 15 minutes. The reaction mixture was added dropwise to water (20 mL) and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was dissolved in 0.5 mL of TFA and stirred for 10 minutes. Then TFA was removed under vacuum and the residue was dissolved in DCM (1 mL) followed by addition of TEA (15 mg, 0.15 mmol) and methyl chloroformate (6 mg, 0.06 mmol). The solvent was removed and the residue was purified by HPLC to give methyl 3-(3-(5-(imidazo[1,2-a]pyridine-3-carboxamido)-2,4-dimethylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F79). MS m/z 447.1 (M+1)+.
Reaction SMILES: C([C:4]1SC(N2CCN(CC3C=CC(C(N4CCCCC4)=O)=CC=3)C2=O)=[N:6][C:5]=1C)(=O)C.[C:31]([C:34]1[S:38][C:37]([N:39]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:40]2=[O:52])=[N:36][C:35]=1[CH3:53])(=O)[CH3:32].COC(OC)([N:58](C)C)C.O.NN>>[F:51][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][N:41]2[CH2:42][CH2:43][N:39]([C:37]3[S:38][C:34]([C:31]4[CH:32]=[C:5]([CH3:4])[NH:6][N:58]=4)=[C:35]([CH3:53])[N:36]=3)[C:40]2=[O:52])=[CH:46][CH:47]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)nc1C
Agent: NN
Solvent: O
Product: Cc1cc(-c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)n[nH]1
Yield: 46 %

Procedure:
Following the procedure as described in Example 40, making variations as required to replace 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(piperidine-1-carbonyl)benzyl)imidazolidin-2-one with 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-fluorobenzyl)imidazolidin-2-one to react with N,N-dimethylacetamide dimethyl acetal and further with hydrazine monohydrate, the title compound was obtained as a colorless solid in 46% yield: mp 218-221° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.05-6.97 (m, 2H), 6.15 (s, 1H), 4.44 (s, 2H), 4.09-4.02 (m, 2H), 3.43-3.38 (m, 2H), 2.52 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 160.8, 156.5, 155.7, 143.4, 131.7, 130.1, 129.9, 115.8, 115.6, 103.7, 47.3, 42.0, 41.7, 16.5, 11.4; MS (ES+) m/z 372.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.F[C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:19][C:15]1[CH:14]=[C:13]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:2]2)[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc(Cl)c1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cccc(-n2ccc(-c3ccccn3)n2)c1
Temperature: 145 °C

Procedure:
2-(1H-Pyrazol-3-yl)pyridine (435 mg, 3 mmol), 3-fluoro-1-chlorobenzene (0.32 mL, 3 mmol) and K2CO3 (830 mg, 6 mmol) were dissolved in DMF (10 mL) under Ar (g) and heated at 145° C. for 18 h. After cooling to ambient temperature, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were washed with brine (3×40 mL), dried over Na2SO4 and concentrated onto silica gel. The crude material was purified by liquid chromatography on silica gel, eluting with EtOAc:hexane (1:1) to afford 2-[1-(3-chlorophenyl)-1H-pyrazol-3-yl]pyridine as as solid. 1H NMR (CD3Cl, 300 MHz) δ 8.68-8.69 (1H, m), 8.13-8.16 (1H, m), 8.01 (1H, m), 7.88 (11H, m), 7.79 (1H, ddd), 7.66-7.68 (1H, m), 7.42 (1H, dd), 7.26-7.31 (2H, m), 7.16 (1H, d). MS (ESI) 256 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[CH:20](Br)([CH3:22])[CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: CC(C)Br
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 99.9 %

Procedure:
N-(2-Fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI) (20 g), isopropyl bromide (25 g), potassium iodide (5 g) and anhydrous potassium carbonate (11 g) were dissolved in a mixture of acetonitrile (135 g) and dimethylformamide (15 g), and the resultant solution was heated under reflux for 7 hours. After cooling, the reaction mixture was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 23.2 g of N-(2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl). M.P. 62.8° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#N)=[CH:10][C:9]=1[C:16]([F:19])([F:18])[F:17].[OH-:20].[Na+].Cl.C[OH:24]>O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:24])=[O:20])=[CH:10][C:9]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CO
Reactant: C[C@H]1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
4-[(2S)-2-methylpiperidin-1-yl]-3-(trifluoromethyl)benzonitrile (1.40 g; 5.22 mmol; 1 eq.) was dissolved in MeOH (7 mL) to which was added NaOH (5 N solution in water, 7 mL). The reaction mixture was heated to 100° C. for 7 hours. The reaction mixture was acidified to pH 2 with 5N HCl solution in water. The resulting precipitate was filtered and washed with water to give a light brown solid. It was recrystallized from Et2O/cHex to give a beige solid (851 mg; 57% over 2 steps). 1H NMR (DMSO-d6) δ 13.29 (s, 1H), 8.23-8.12 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 3.07 (m, 1H), 2.94-2.81 (m, 1H), 2.61-2.45 (m, 2H), 1.75 (m, 1H), 1.67-1.18 (m, 4H), 0.71 (d, J=6.1 Hz, 3H). HPLC (Method A), Rt 4.79 min (Purity: 99.9%). LC/MS (Method B): 286.2 (M+H)−; 288.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH2:12].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH2:11][NH2:12]
Reactant: NCCc1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NCCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
To a solution of 2-(indol-2-yl)ethylamine (2.7 g) in acetic acid (25 ml) at 15° C. was added sodium cyanoborohydride (2.22 g) in one portion. The solution was stirred at room temperature for 15 hours and diluted with chilled water. The mixture was made basic with sodium hydroxide pellets and extracted three times with ether. The ether layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 2-(2,3-dihydroindol-2-yl)ethylamine (1.41 g) as an oil. The oil was dissolved in tetrahydrofuran (50 ml) and treated with 1,1'-carboxyldiimidazole (1.13 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (30%-ethyl acetate-chloroform) to give crystals. The crystals were washed with ether to give 3,4,4a,5-tetrahydropyrimido[1,6-a]indol-1(2H)-one (0.74 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH:11]([OH:14])[CH2:12][CH3:13])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:16]>CN(C=O)C>[CH3:16][O:14][CH:11]([CH2:12][CH3:13])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:10]
Reactant: CCC(O)C(C)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(OC)C(C)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A 2 L reaction flask was charged with NaH (29.5 g, 0.73 mol) in oil dispersion (60%) and DMF (500 mL) under N2. The mixture was heated to 40° C. 2-Phenyl-pentan-3-ol (100 g, 0.61 mol) was fed to the mixture over 1 hour. The reaction was aged for 1 hour at 40° C. Iodomethane (103 g, 0.73 mol) was then fed into the reaction mixture over 2 hours. The reaction mixture was further aged for 8 hours, and quenched subsequently with saturated NH4Cl solution (300 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (300 mL) and brine (300 mL) to provide a crude product, which was purified by distillation to afford (2-methoxy-1-methylbutyl)-benzene (63 g, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][C:12]([O:15]CC1C=CC=CC=1)=[CH:11][CH:10]=3.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3
Reactant: Cc1ccccc1-c1nc2c3cc(OCc4ccccc4)ccc3ccn2c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1-c1nc2c3cc(O)ccc3ccn2c1N
Yield: 83.9 %

Procedure:
To a solution of 5.0 g of 3-amino-9-benzyloxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 40) in 100 ml of ethanol was added 0.5 g of palladium on activated carbon (Pd 10%). After introduction of hydrogen, the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. Resultant residue was purified by column chromatography on silica gel and recrystallized from water/methanol to give 3.2 g of the title compound as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13](CC3C=CC(OC)=CC=3)[C:12]([C:25]([NH:27]CC3C=CC(OC)=CC=3)=[O:26])=[C:11]([Cl:37])[CH:10]=2)[CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.CO>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[NH:13][C:12]([C:25]([NH2:27])=[O:26])=[C:11]([Cl:37])[CH:10]=2)[CH:3]=1
Reactant: COc1ccc(CNC(=O)c2c(Cl)cc(Nc3cc(N)ncn3)c(=O)n2Cc2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c(=O)c(Nc2cc(N)ncn2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxamide (6, 0.40 g, 0.77 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL) and trifluoromethanesulfonic acid (1 mL) at 0° C. The reaction mixture was stirred at 70° C. for 2 h. After completion, the reaction mixture was concentrated and basified by aq. ammonia at 0° C. The precipitate obtained was collected by filtration, washed with water and dried to obtain the crude. The crude was stirred with methanol, filtered, washed with pentane and dried to afford 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (Cpd. No. 214) as yellow solid. Yield: 0.035 g, 16%; MS (ESI) m/z 281.05 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 6.53 (s, 2H), 6.18 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.Cl.[F:21][C:22]1[CH:23]=[N:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:25]4[N:26]=[CH:27][C:22]([F:21])=[CH:23][N:24]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 17, 0.35 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.25 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.3 g of desired product. MS (electrospray): 386 (M+1) for C16H16FN9O2. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.4 (s, 1H) 11.30 (s, 1H) 9.15 (s, 1H) 9.00 (s, 1H) 8.80 (s, 2H) 6.10 (d, 1H) 5.25 (m, 1H), 1.90 (m, 1H) 1.60 (d, 3H) 1.00 (m, 2H) 0.80 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:17][CH3:18]>CC(C)=O.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH2:17][CH3:18]
Reactant: CCI
Reactant: Nc1ncnc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1c(N)ncnc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A reaction mixture of 4-amino-6-chloro-pyrimidin-5-ol (1000.0 mg; 6.8 mmol; 1.0 eq.), cesium carbonate (2686.3 mg; 8.24 mmol; 1.2 eq.), and iodoethane (1285.9 mg; 8.24 mmol; 1.2 eq.) in acetone (10 ml) was stirred at 50° C. overnight. The reaction solution was diluted with ethyl acetate (50 ml), washed with water, then brine, dried and concentrated. The residue was treated with ether, stirred for 30 min, filtered, collected white off solid as title compound (1165 mg in yield 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:22]1[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.9 %

Procedure:
To a cold (0° C.) solution of 5-hydroxyindole-2-carboxylic acid ethyl ester (purchased at Biosynth, ref H-6350, 20 g, 1.0 eq.), 1-isopropylpiperidin-4-ol (intermediate 1, step 1, 16.75 g, 1.2 eq.) and triphenylphosphine (30.68 g, 1.2 eq.) in tetrahydrofuran (500 mL) was slowly added a solution of di-tert-butylazodicarboxylate (26.93 g, 1.2 eq.) in tetrahydrofuran (100 mL). The reaction mixture was stirred at room temperature for 48 h then evaporated to dryness in vacuo and purified on silica, eluting with a gradient of solvent from dichloromethane/ethyl acetate 19:1 to dichloromethane/methanol/ammonium hydroxide 95:5:0.25. One fraction was isolated and dried in vacuo, to yield 21.53 g (66%) of the desired product as white solid. MS (m/e): 331.1 (MH+, 100%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH2:10]([O:13][CH:14]([CH3:19])[C:15]([O:17]C)=O)[CH:11]=[CH2:12].O>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:15](=[O:17])[CH:14]([O:13][CH2:10][CH:11]=[CH2:12])[CH3:19]
Reactant: C=CCOC(C)C(=O)OC
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CCOC(C)C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of N-methyl-O-methyl hydroxylamine hydrochloride (10.0 g, 104 mmol, 2 equiv) in dichloromethane (100 mL) was treated with trimethylaluminum (52.0 mL, 104 mmol, 2 equiv) at 0° C. After stirring for 1 hour at 0° C., a dichloromethane (50 mL) solution of (±)-methyl 2-(prop-2-en-1-yloxy)propanoate (7.50 g, 52.0 mmol) was added over 15 minutes. The mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with water (500 mL) and extracted with dichloromethane (2×300 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[CH3:1][CH:2]([CH3:7])[CH2:3][C:4]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:22]([C:20]3[CH:21]=[C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]4)[N:17]=[C:18]([NH2:32])[N:19]=3)=[CH:23][CH:24]=2)[CH2:29]1)=[O:5]
Reactant: CC(C)CC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 3-methylbutanoyl chloride (Aldrich, Cat. #157422) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=409.2.