Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:15]([CH3:24])=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:13]=2)[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:15]([CH3:24])=[C:14]([S:25](=[O:27])(=[O:26])[NH2:28])[CH:13]=2)[CH:6]=1)[O:11][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCBr
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of compound 14 (202 mg, 0.5 mmol) in DMF (20 mL) were added Cs2CO3 (325 mg, 1 mmol) and methyl 4-bromobutanoate (99 mg, 0.55 mmol). The reaction mixture was stirred for 4 h at 40° C., then water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound 15 (176 mg, 70%).
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27].Cl>CN(C=O)C.O>[CH2:27]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:26]=[CH2:25]
Reactant: C=CCI
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (3 g, 0.011M) in DMF (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.5 g, 0.012M). The mixture was stirred at room temperature for 0.5 hours, and then allyl iodide (1.8 g, 0.01M) was added dropwise. The reaction mixture was warmed to 60° C. and stirred for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-allyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH2:22](Br)[C:23]#[CH:24]>CN(C)C=O>[CH2:24]([N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18])[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(C(C)=O)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 3.0 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, 0.6 g of sodium hydride (50% in oil), 250 ml of dimethylformamide and 1.38 ml of propargyl bromide was reacted as described in Example 5, giving 1.77 g of the desired product as orange crystals, mp 195°-198° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)c1ccccc1[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of the amide of example 49 (1.10 g, 5 mmol) in CH2Cl2 (50 mL) at 0° C. was added dropwise over 2 min, a cold mixture of 70% nitric acid (0.95 mL, 15 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ethyl acetate, the combined organic layers washed with brine, sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (2.68 g, 101%) consisting of a 2:1 ratio of 5-nitro and 3-nitro isomers. The title compound was obtained by RC (ethyl acetate/hexanes) in 60% yield as a white solid. m.p. 100-102° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1.C([O-])(O)=[O:24].[Na+]>>[F:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:24])[CH:17]=2)=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: Fc1cc(-c2nc(NC3CCOCC3)ncc2F)ccn1
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2nc(NC3CCOCC3)ncc2F)cc[nH]1
Reaction time: 2.5 h
Yield: 97 %

Procedure:
1M HCl (15 mL) was added to 5-fluoro-4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.26 g, 0.89 mmol). The suspension was heated at reflux. After 2.5 hours, the suspension was neutralized with NaHCO3, and the solid was collected by vacuum filtration. This was suspended in MeOH and evaporated to yield 4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.25 g, 0.86 mmol, 97% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.80 (br s, 1H), 8.48 (d, 1H), 7.52 (d, 1H), 7.40 (d, 1H), 6.83 (br s, 1H), 6.65-6.61 (m, 1H), 3.90-3.84 (m, 3H), 3.43-3.36 (m, 2H), 1.88-1.81 (m, 2H), 1.57-1.46 (m, 2H); m/z (APCI-pos) M+1=291.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:18]1([C:22]([C:24]2[CH:25]=[C:26]([Cl:31])[C:27](Cl)=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[CH:25]=[C:26]([Cl:31])[C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)OC)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (240 mg, 0.1 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (278 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was poured into water (30 mL) and acidified with 1N hydrochloric acid before being extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (as evidenced by LCMS data only m/z 435 (M+H)+) as a brownish oil (550 mg). The crude methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (434 mg, 1 mmol) was dissolved in THF (15 mL) and methanol (5 mL) then 1N aqueous Lithium hydroxide solution (2 mL) added followed by the dropwise addition of water until a clear solution obtained. The mixture was stirred was stirred for 4 hours at RT and the organics removed by evaporation. The aqueous solution was filtered, extracted with ethyl acetate (10 mL) and the aqueous layer acidified with 2N hydrochloric acid. The acidified layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired compound as a pale oil (375 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32 (quin, 2H), 3.34 (s, 3H), 3.42-3.55 (m, 2H), 4.13-4.34 (m, 4H), 4.54 (q, 1H), 6.93 (s, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), m/z 421 (M+H)+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: Sc1ncccn1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ncccn3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18].[I-].[K+]>CC(C)=O>[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[CH3:18]
Reactant: Oc1cccc2cc[nH]c12
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1cccc2cc[nH]c12
Yield: 88.7 %

Procedure:
To a solution of 7-hydroxyindole (2.65 g, 20 mmol) in acetone (20 ml) are added potassium carbonate (3.32 g), chloroacetic acid diethylamide (3.29 g, 22 mmol) and potassium iodide (0.33 g), and the mixture is refluxed for 4 hours. After cooling with ice, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to remove the solvent. To the residue are added chloroform (40 ml) and water (20 ml), and the mixture is stirred. The chloroform layer is separated, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and isopropyl ether (100 ml) is added to the residue. The precipitated crystals are collected by filtration, and dried to give the title compound N,N-diethyl-2-(1H-indol-7-yloxy)acetamide (4.37 g, yield: 89%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH:13]1[CH2:20][C:16]2([CH2:19][O:18][CH2:17]2)[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]1.CCN(CC)CC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH:13]2[CH2:20][C:16]3([CH2:17][O:18][CH2:19]3)[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(N)CC12COC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene (264 mg, 1.50 mmol), tert-butyl 7-amino-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (343 mg, 1.50 mmol) and NEt3 (0.44 mL, 3.12 mmol) in 10 mL of tetrahydrofuran was stirred at room temperature overnight and then heated under reflux for 5 hours. The resulting mixture was concentrated in vacuo and the residue was purified by flash column (eluting with 0-5% MeOH in DCM) to afford tert-butyl 7-[(4-chloro-2-nitrophenyl)amino]-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (438 mg, yield: 76.1%) as an orange solid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][NH:22][CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH:25](Br)([CH3:27])[CH3:26]>>[CH:25]([N:22]1[CH2:23][CH2:24][C:9]2[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])=[N:13][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[N:11][C:10]=2[CH2:21]1)([CH3:27])[CH3:26]
Reactant: CC(C)Br
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1CCNC2
Product: CC(C)N1CCc2c(nc(-c3cnc(N)nc3)nc2N2CCOC[C@@H]2C)C1

Procedure:
Compound fk was prepared according to the procedure described in Example 2 by reacting (S)-5-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrimidin-2-amine with isopropylbromide. LC-MS: m/z=+370 (M+H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)(=O)[CH3:15].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:14]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(=O)c1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCCCNC(=O)OC(C)(C)C)c1nccs1

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester and 2-acetyl thiazole in MeOH with NaBH4 gave [4-(1-thiazol-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.57 (m, 4H), 1.66 (d, 3H, J=6.5 Hz), 2.58-2.69 (m, 2H), 3.08-3.14 (m, 2H), 4.15 (q, 1H, J=6.7 Hz), 7.24 (d, 1H, J=3.3 Hz), 7.70 (d, 1H, J=3.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=C)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[O:35]1CCCC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:35])=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: C=Cc1ccc2nc(C)c(-c3nc(-c4ccccc4)c(-c4ncn(C5CCCCO5)n4)s3)n2c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reaction time: 72 h
Yield: 34.1 %

Procedure:
To the solution of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-6-vinylimidazo[1,2-a]pyridine (0.747 g, 1.59 mmol) in Tetrahydrofuran (55 mL, 680 mmol) and Water (16 mL, 890 mmol) was added Sodium metaperiodate (0.852 g, 3.98 mmol), followed by 0.157 M of Osmium tetraoxide in Water (0.53 mL, 0.083 mmol). The solution was stirred at r.t, for 3 days. The mixture was diluted with ˜100 mL of water, filtered to collect the solid product as the first crop of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.255 g, 24% yield). LCMS: (FA) ES+ 471. 1H NMR (400 MHz, d1-chloroform) δ 10.56 (σ, 1H), 10.00 (σ, 1H), 8.30 (σ, 1H), 7.94-7.97 (m, 2H), 7.82-7.85 (m, 1H), 7.69-7.71 (m, 1H), 7.46 (m, 3H), 5.48-5.51 (dd, J=8.78, 2.76 Hz, 1H), 4.06-4.09 (m, 1H), 3.73-3.77 (m, 1H), 2.85 (s, 3H), 2.02-2.15 (m, 3H), 1.59-1.69 (m, 3H). The filtrate was rotavaped to remove THF, extracted with 5% MeOH/DCM (4×60 mL). The combined DCM solution was dried over Na2SO4, filtered, rotavaped to give a crude material. Chromatograph in a 40 g ISCO column using MeOH/DCM (0/100 to 5/95) gave the second crop of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (fast fraction, 0.104 g, 14% yield), and 1-(2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridin-6-yl)ethane-1,2-diol (slow fraction, 0.243 g, 30.3% yield). LCMS: (FA) ES+ 503. 1H NMR (400 MHz, d1-chloroform & d4-methanol) δ 9.90 (σ, 1H), 8.28 (σ, 1H), 7.86-7.88 (m, 2H), 7.54-7.57 (d, J=9.29 Hz, 1H), 7.37-7.41 (m, 4H), 5.44-5.47 (m, 1H), 4.80-4.82 (m, 1H), 4.02-4.05 (m, 1H), 3.68-3.80 (m, 3H), 2.73 (s, 3H), 2.00-2.11 (m, 3H), 1.65-1.68 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: c1c[nH]cn1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Yield: 71 %

Procedure:
Similarly to Example 63, reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole and imidazole at 120° C. for 1 hr gave 2-(difluoromethyl)-1-[4-(1H-imidazol-1-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole in 71% yield: mp (CH2Cl2/hexanes) 272-275° C.; 1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.04 (t, J=1.4 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.78 (t, JHF=52.5 Hz, 1H), 7.50 (t, J=8.3 Hz, 1H), 7.22 (dd, J=1.5, 0.8 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.03 (m, 2H), 4.00 (s, 3H), 3.94 (m, 2H), 3.80-3.75 (m, 4H); Anal. Calcd. for C19H18F2N8O2: C, 53.3; H, 4.2: N, 26.2. Found: C, 53.6; H, 4.3; N, 26.7%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][C:55]=1[NH:56][C@@H:57]([CH3:61])[CH2:58][O:59][CH3:60])[N:52]([CH3:62])[C:51](=[O:63])[C:50]2([CH3:65])[CH3:64]>CN1C(=O)CCC1>[CH3:60][O:59][CH2:58][C@@H:57]([NH:56][C:55]1[CH:54]=[C:53]2[C:49]([C:50]([CH3:65])([CH3:64])[C:51](=[O:63])[N:52]2[CH3:62])=[CH:48][C:47]=1[NH:46][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[CH3:61]
Reactant: COC[C@H](C)Nc1cc2c(cc1N)C(C)(C)C(=O)N2C
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Nc1cc2c(cc1NC(=O)c1cc(C)c(=O)n(C)c1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (47 mg; 0.28 mmol), is dissolved in NMP (500 μl) and DIPEA (135 μl; 0.85 mmol) and HATU (111 mg; 0.29 mmol) is added. The reaction mixture is stirred at ambient temperature for 15 min. 5-Amino-6-((S)-2-methoxy-1-methyl-ethylamino)-1,3,3-trimethyl-1,3-dihydro-indol-2-one E-1.1 (85 mg; 0.31 mmol) dissolved in NMP (500 μl) is added and stirring is continued for 12 h at ambient temperature. The reaction mixture is poured on water and extracted with DCM once. The organic phase is dried with MgSO4 and concentrated under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1cccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCn1cccc1

Procedure:
The 1-(2-hydroxyethyl)pyrrole (TCI-US, 0.138 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]5[N:35]=[C:34]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[NH:33][N:32]=5)[CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[N:9][C:10]3[CH:11]=[CH:12][NH:13][C:14](=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:44].CN(C=O)C.C([O-])(O)=O.[Na+]>O>[Cl:44][C:14]1[N:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[NH:35][C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)=[N:33][N:32]=4)[CH2:29][CH2:30]3)=[CH:22][CH:23]=1)=[N:9]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 130 °C

Procedure:
A mixture of 8-7 (5.5 g, 10.2 mmol) and POCl3 (50.0 g, 326.1 mmol) and DMF (0.3 g, 4.1 mmol) was heated to reflux at 130° C. for 3 hr. The reaction mixture was cooled and concentrated to remove POCl3. 40 mL Toluene was added and concentrated to obtain a solid. To the solid was added 50 mL H2O and 40 mL NaHCO3 (saturated) and 20 mL 1NNaOH to pH=9. The mixture was stirred to precipitate a solid which was collected via filtration as the desired product 8-8. It was washed by water and CH3CN and dried under vacuum.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=[O:2].[CH2:27](O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([O:3][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:2])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: OCCc1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)OCCc3ccccc3)coc12
Yield: 36 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and phenethyl alcohol (0.7 ml) to give Compound 153 (0.14 g, 36%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccc(F)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Yield: 44.1 %

Procedure:
0.63 g (0.003 mol) of 1-(4-fluoro-benzyl)-piperidin-4-ol and 2.09 ml (0.015 mol) of triethylamine were dissolved in 30 ml of toluene, treated with 1.04 ml (0.009 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.415 g (44%) of 1-(4-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil. MS: me/e=314 (C19H21FNO2+).