Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: Nc1cccc(Br)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)Nc1cccc(Br)c1O
Yield: 99.9 %

Procedure:
2-Bromopropionyl chloride (1.47 ml, 14.6 mmol) was added dropwise to a vigorously stirred and ice-cooling mixture of 2-amino-6-bromophenol (2.74 g, 14.6 mmol) and sodium bicarbonate (3.06 g, 36.4 mmol) in ethyl acetate (50 ml)/water (15 ml). The mixture was stirred at 0° C. for 3 h and diluted with water. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue used for the following step without further purification to afford 4.71 g (99%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:9]([C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:18]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(Cl)ncn2)CC1

Procedure:
58.6 g (0.39 mol) of 4,6-dichloropyrimidine were placed in 400 ml of toluene, and a mixture of 61.0 g (0.39 mol) of cis-4-tert-butylcyclohexylamine and 50.0 g (0.50 mol) of triethylamine in 100 ml of toluene was added dropwise at from 70° to 80° C. The mixture was subsequently stirred at reflux for 4 hours. After cooling, it was extracted by stirring with water, the organic phase was dried and concentrated, to give a colorless oil which crystallized after trituration with petroleum ether. Filtration with suction left 70.5 g (67.0% of theory) of colorless crystals.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[C:22]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:23]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:26]([CH3:35])([CH3:34])[CH2:25][C:24]3=[O:36])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>ClCCl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([F:7])[C:21]2[C:22]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[C:23]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:32])[CH3:33])[O:27][C:26]([CH3:35])([CH3:34])[CH2:25][C:24]3=[O:36])=[CH:16][CH:15]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h

Procedure:
At −78° C., a solution of 46 μl (350 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 150 mg (320 μmol) of rac-6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 27A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −15° C. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→5:1) gives the target compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N+:72]([O-:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N+:72]([O-:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:31]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 14.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 2-methoxy-4-nitroaniline (Aldrich) (0.18 g, 1.1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide as a white solid (Yield 0.06 g, 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:24]([C:23]1[CH:26]=[C:27]([CH3:28])[C:20]([O:19][CH2:18][CH2:17][O:16][CH3:15])=[C:21]([CH3:29])[CH:22]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COCCOc1c(C)cc(C=O)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOc1c(C)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1C
Temperature: 150 °C
Yield: 43.4 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>[Ni](Cl)Cl.C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C[SiH](Cl)Cl
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: Cl[Ni]Cl
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 285.7 %

Procedure:
As described in Example 2, 3.01 g (0.0228 mol) of dicyclopentadiene, 5.19 g (0.0451 mol) of methyldichlorosilane, 0.032 g (0.000247 mol) of nickel dichloride, 57 μL (0.000230 mol) of tributylphosphine and 4 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 180° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (11.8 g) of (2-cyclopentenyl)methyldichlorosilane (3.1 g, 38%), other unreacted reactants, toluene, hexadecane, and unidentified compounds.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:20][CH:21]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Temperature: 180 °C
Yield: 50.4 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (320 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and NaH (65.3 mg) in DMF (5 mL) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as white crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][C:4]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:5]
Reactant: O=C(Cl)CCBr
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCBr)N1CC(c2ccccc2)c2ccccc21
Temperature: 10 °C

Procedure:
A solution of 9.1 ml of 3-bromopropionylchloride in 10 ml of dry benzene was added dropwise to a solution of 10.0 g of 3-phenylindoline and 10 ml of triethylamine in 100 ml of dry benzene cooled to 10° C. The precipitated triethylamine hydrochloride was separated by filtration, the benzene was removed from the filtrate in vacuo at room temperature and the residue recrystallized from ethanol to give 5.6 g of the desired N-(3-bromopropionyl)-3-phenylindoline having a melting point of 98°-9° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=3)[CH:8]=2)[NH:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=3)=[CH:6][CH:5]=2)[C@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:11][C@@H:2]1[CH3:1])(=[O:34])[CH3:33]
Reactant: CC(C)OC(=O)N[C@@H]1C[C@H](C)Nc2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 78 %

Procedure:
A solution of 1,1-dimethylethyl {(cis)-4-[2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (for a preparation see Intermediate 88) (1.0 g, 2.33 mmol) in acetic anhydride (2 mL) was allowed to stand at room temperature for 16 h then most of the solvent was concentrated in vacuo. The residue was co-evaporated twice with toluene. Purification of the resulting residue by flash chromatography on silica gel (gradient: 0 to 2% MeOH in DCM) gave 1,1-dimethylethyl {(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (862 mg, 1.832 mmol, 78%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:4].[CH2:16]([Mg]Br)[CH:17]=[CH2:18].O>O1CCCC1>[OH:4][CH:3]([CH2:18][CH:17]=[CH2:16])[C@@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:1]
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (30 mL) of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (3.0 g) in tetrahydrofuran was added 1.0 mol/L solution (28.8 mL) of allylmagnesium bromide in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate as a colorless oil. To a solution (10 mL) of the obtained benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate in tetrahydrofuran were added 2,6-lutidine (0.629 mL) and tert-butyldimethylsilane trifluoromethanesulfonate (0.91 mL) and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield: 610 mg).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]([CH3:39])[CH:31]=5)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:40])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]([CH3:39])[CH:31]=5)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:40][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
Acryloyl chloride (41.3 mg, 0.46 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 123, 195 mg, 0.42 mmol) in THF (3 mL), cooled in an ice/methanol bath to approximately −15° C. Upon slow addition of the acryloyl chloride a precipitate immediately formed. The mixture was stirred for 1 h while being gradually warmed to 0° C. The mixture was then diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL). The resulting aqueous solution was extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave crude solid product after concentration of appropriate fractions in vacuo. This solid was dissolved in the minimum amount of hot CH2Cl2 and triturated with diethyl ether to give the title compound (115 mg, 53%) as a white solid; 1H NMR (CDCl3) 1.77-1.96 (2H, m), 2.15-2.26 (1H, m), 2.29 (3H, s), 2.26-2.37 (1H, m), 2.73 (1H, d), 2.80 (1H, d), 2.83-2.90 (1H, m), 2.95 (1H, td), 3.21 (1H, t), 3.57-3.68 (1H, m), 3.88 (3H, s), 4.00 (3H, s), 5.68-5.74 (1H, m), 6.45 (2H, d), 6.81 (1H, s), 7.20 (1H, d), 7.23-7.31 (2H, m) partially obscured under CDCl3 signal, 7.37-7.43 (1H, m), 7.71 (1H, s), 8.02-8.10 (1H, m), 8.38 (1H, d), 9.09 (1H, s), 9.46 (1H, s), 9.85 (1H, s); m/z: ES+ MH+ 524.25.
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=1>ClCCl>[CH:7]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(C=O)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Solid trimethylamine N-oxide (241 mg; 3.20 mmol) was added to a solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1-1; 400 mg; 1.281 mmol) in dichloromethane, and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, washed with brine (2×), dried over MgSO4, and evaporated to give the title compound I-A as a white solid. MS M+1=148.1. 1H NMR (CDCl3): 1.75 (s, 9H), 7.42 (m, 1H), 8.64 (d, 1H), 8.80 (d, 1H), 10.28 (s, 1H).
Reaction SMILES: IC.[F:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:5]=1[O:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[N:10]=[CH:9][C:8]=1[OH:20].[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:5]=1[O:6][C:7]1[C:8]([O:20][CH3:26])=[CH:9][N:10]=[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(O)cn2)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.0362 g, 0.255 mmol) is added to a mixture of 4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ol (0.255 mmol and potassium carbonate (0.0794 g, 0.574 mmol) in DMF (3 mL) and stirred overnight at room temperature. The reaction mixture is partitioned between water and ether. The organic layer is washed with water, dried, and concentrated. The residue is purified by silica gel chromatography, eluting with 15-20% EtOAc in hexanes, to afford N-(4-(2,6-difluorophenoxy)-5-methoxypyridin-2-yl)-4-methylthiazol-2-amine.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:36]5[N:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(c2ncccn2)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in N,N-dimethylformade (2 mL) was added 2-chloropyrimidine (8.6 mg, 0.075 mmol) and triethylamine (21 μL, 0.15 mmol). The resulting mixture was stirred at 80° C. for 2.5 hours. After evaporation of the solvent, the crude product was directly purified by flash chromatography on silical gel, eluting with a gradient of 0-10% triethylamine in methanol to afford 2-methyl-1-{8-[2-(4-phenyl-1-pyrimidin-2-ylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole as amorphous solid (16.2 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J=6.0 Hz, 2H), 7.67 (dd, J=2.6, 7.0 Hz, 1H), 7.39-7.37 (m, 4H), 7.35-7.22 (m, 3H), 7.21-7.14 (m, 2H), 6.45 (t, J=4.7 Hz, 1H), 4.64 (m, 1H), 4.17-4.09 (m, 2H), 3.61-3.52 (m, 2H), 3.28-3.25 (m, 2H), 2.59 (s, 3H), 2.44-2.33 (m, 2H), 2.29-2.22 (m, 2H), 1.97-1.85 (m, 10H), 1.62 (d, J=7.7 Hz, 2H). HRMS m/z (M+H)+ calcd: 507.3236; obsd: 507.3248.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[CH2:17]([N:20]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26]O)[C:21]1=[O:28])[C:18]#[CH:19]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][CH2:26][N:22]1[C:23](=[O:25])[CH2:24][N:20]([CH2:17][C:18]#[CH:19])[C:21]1=[O:28])=[O:14]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C(/F)C(=O)OCC)C2(C)C)C1=O

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylic acid and 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methanol were reacted to obtain 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+12°±2° (c=0.5% in chloroform).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O=P(Cl)(Cl)[Cl:23]>N1C=CC=CC=1>[Cl:23][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Solvent: c1ccncc1
Product: ClCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 17) in dry pyridine (10 mL) was added dropwise POCl3 (2.4 g, 14.7 mmol) under N2 atmosphere. The resulting solution was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo. The residue was poured into ice-water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (400 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 3.90-3.86 (m, 1H), 3.81 (t, 2H), 3.77-3.70 (m, 1H), 2.93 (t, 2H), 2.41-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.75-1.71 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 289 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)(=O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C=O)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of methyl 5-formyl-2-hydroxybenzoate (21.76 g), triethylamine (13.46 g), ethyl acetate (300 mL) was added dropwise methanesulfonyl chloride (15.24 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-formyl-2-methanesulfonyloxybenzoate as a colorless oil (31.20 g, yield 100%).