Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)s2)C1

Procedure:
50.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chlorothiophene-2-carboxylic acid to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Brown oil. MS 345.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:48][CH2:49][C:50]1[S:54][C:53]([C:55](=[N:57]O)[NH2:56])=[C:52]([CH2:59][CH3:60])[CH:51]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:59]([C:52]1[CH:51]=[C:50]([CH2:49][OH:48])[S:54][C:53]=1[C:55]1[N:57]=[C:10]([C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[CH:14][CH:13]=2)[O:12][N:56]=1)[CH3:60]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: COc1ccccc1Oc1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 4-(2-methoxyphenoxy)benzoic acid (0.13 g, 0.53 mmol) that was obtained in Example 21 (21a), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.55 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), and 1.0 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (1.0 mL, 1.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:5) as the eluent to afford the title compound (0.15 g) in a yield of 72% as a yellowish white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13].Cl.[C:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.C1COCC1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:40]4[CH2:41][CH2:42][CH:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:38][CH2:39]4)=[O:25])=[CH:27][CH:28]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N4CCC(c5ccccc5)CC4)cc3)C2)C1=O
Yield: 56.7 %

Procedure:
To a solution of 4-[4-(5,6-dimethoxy-4,7-dioxoindan-2-yl)butoxy]benzoic acid (626 mg), 4-phenylpiperidinehydrochloride (617 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (598 mg), 1-hydroxybenzotriazole monohydrate (478 mg), triethylamine (1.30 ml), and THF (12 ml) was stirred at room temperature for 6 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from ethyl acetate-diethyl ether to yield the entitled compound (482 mg) as crystals.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[CH:24][C:23]([NH:22][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])=[CH:44][CH:43]=4)=[CH:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (197 mg, 973 μmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (80 μL, 973 μmol) and N,N-dimethylformamide (2 drops) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A solution of N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 649 μmol) in N,N-dimethylacetamide (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from ethanol/water to give the title compound (187 mg, 39%) as a white powder.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC.O1CCCC1>[Br:2][CH2:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrP(Br)Br
Reactant: CC(C)(C(=O)OCc1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C(=O)OCc1ccccc1)N1COC(CBr)=C(c2ccccc2)C1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of phosphorus tribromide (5.1 ml) in ether was added during 0.5 hour to a solution of benzyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (61.1 g) in a mixture of ether and tetrahydrofuran at -78° C. The mixture was then stirred at -10° C. for 4 hours and at room temperature for 1 hour, then washed (water), dried (magnesium sulphate) and evaporated. Purification of the residue by dry column chromatography on silica gel gave benzyl 2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (46.1 g), NMR(CDCl3) 1.5(s,6H), 3.8(s,2H), 5.05(s,2H), 5.3(s,2H), 7.2(s,5H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:15]4=[O:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.IC1C=CC2C3N=C(N4C(C)=NN(C)C4=O)SC=3CCOC=2C=1.[CH3:47][C:48]([OH:65])([CH3:64])[CH2:49][N:50]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[N:51]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C1COCC1>[OH:65][C:48]([CH3:64])([CH3:47])[CH2:49][N:50]1[CH:54]=[C:53]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]=[C:8]([N:14]5[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:15]5=[O:21])[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:52]=[N:51]1
Reactant: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2
Temperature: 80 °C
Reaction time: 20 h
Yield: 27 %

Procedure:
A microwave vial was charged with an approximately 1:1 mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one (41 mg), 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (33 mg, 0.13 mmol), PdCl2(dppf)2.DCM (3.5 mg, 0.004 mmol), cesium carbonate (68 mg, 0.21 mmol), THF (1 mL) and water (0.2 mL). The vial was sealed and the mixture evacuated and purged with argon (×3). The reaction mixture was heated at 80° C. for 17 hours then a further 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (15 mg) and PdCl2(dppf)2.DCM (4 mg) were added, the vial was re-filled with argon as before and stirring at 80° C. was continued for a further 20 hours. After cooling the reaction mixture was concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-4% MeOH in DCM) to give 473 as a white solid (12 mg, 27%). LCMS: RT=4.14 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.14 (1H, d, J=8.26 Hz), 8.08 (1H, s), 7.87 (1H, s), 7.33 (1H, dd, J=8.26, 1.84 Hz), 7.22 (1H, d, J=1.82 Hz), 4.68 (1H, s), 4.31 (2H, t, J=5.01 Hz), 3.98 (2H, s), 3.35 (3H, s), 3.28 (2H, m), 2.65 (3H, s), 1.04 (6H, s)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1ccnc(Cl)n1
Solvent: O
Solvent: CO
Product: Cc1ccnc(NN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (6.06 g, 47.1 mmol) in MeOH (40 mL) was added hydrazine monohydrate (10 mL, 206 mmol). The solution was stirred for 16 h at room temperature and then purified by reverse phase HPLC to provide 4.43 g of the title compound. (76%) as a white solid. MH+125.
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:17]1[NH:16][C:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:11](=[O:22])[C:12]=2[C:18]=1[CH3:19]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 59.14 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (44 mg, 59.14%) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].N1CC[CH2:23][CH2:22][CH2:21]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]1[CH2:18][CH2:23][CH2:22][CH2:21][CH2:19]1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CN(C)C)C2=O
Reactant: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)CCC(=CN1CCCCC1)C2=O

Procedure:
A mixture of 6-acetamido-2-(N,N-dimethylaminomethylidene)-1-tetralone (11 g) obtained in Example 41-1) and piperidine (100 ml) was refluxed with heating for 24 hours. After excess piperidine was distilled out under reduced pressure, the resulting residue was crystallized using tetrahydrofuran-isopropyl ether to give 6-acetamido-2-(1-piperidinylmethylidene)-1-tetralone (7 g) as a light yellow powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18]O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>O.C(OCC)(=O)C.CN(C)C=O.N1C=CC=CC=1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:13][CH2:14]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CCNC1
Reactant: OCCCO[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCCN3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-{[trans-4-(dibenzylamino)cyclohexyl]oxy}propan-1-ol (110 mg) were added tosyl chloride (60 mg) and pyridine (51 μL) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture were added N,N-dimethylformamide (1.1 mL), potassium carbonate (43 mg), and pyrrolidine (26 μL), followed by stirring at room temperature overnight. The reaction mixture were added ethyl acetate and water, and the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate-90:10-70:30) to obtain trans-N,N-dibenzyl-4-[3-(pyrrolidin-1-yl)propoxy]cyclohexanamine (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30](O)=[O:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=2)[CH2:16][CH2:15]1.O.O[N:35]1[C:39]2C=CC=[CH:43][C:38]=2N=N1.Cl.C(/N=N/CCCN(C)C)C.N1CCC1>C(Cl)Cl>[N:35]1([C:30](=[O:31])[CH2:29][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:18][CH2:19]3)=[C:2]([F:1])[CH:3]=2)[CH2:43][CH2:38][CH2:39]1
Reactant: On1nnc2ccccc21
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)O)cc3F)CC2)nc1
Agent: C1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)N4CCC4)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
2-(3-Fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetic acid (Step D product, 70 mg, 0.158 mmol), 1-HYDROXYBENZOTRIAZOLE HYDRATE (36.3 mg, 0.237 mmol) and (E)-3-(ETHYLDIAZENYL)-N,N-DIMETHYLPROPAN-1-AMINE HYDROCHLORIDE (42.5 mg, 0.237 mmol) were dissolved in CH2Cl2 (3 ml). The mixture was stirred at RT for 10 min., to which was added AZETIDINE (0.016 ml, 0.237 mmol). The reaction mixture was stirred at RT overnight. TLC and LC-MS showed the SM was completely consumed. The mixture was diluted with DCM, washed with water, dried over MgSO4, and evaporated to dryness. The crude product was purified by prep TLC (pure EtOAc) to afford 58.2 mg (76%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (S, 2H), 7.38 (m, 1H), 7.05 (m, 2H), 4.70 (m, 2H), 4.60-4.50 (m, 2H), 4.25 (s, 2H), 4.10˜4.00 (m, 4H), 3.70 (m, 1H), 3.40 (m, 3H), 3.32 (s, 3H), 2.83 (m, 2H), 2.25 (m, 2H), 2.05 (m, 2H), 1.82 (m, 1H), 1.40-1.20 (m, 3H), 1.05 (m, 1H), 0.70 (m, 2H), 0.40 (m, 1H). LC/MS (m/z): 483 (M+H)+, GPR119 Human EC50: 5.16 nM.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B(OC)(OC)OC.O1CCCC1.Cl>O>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1CO
Temperature: 65 °C
Yield: 98.1 %

Procedure:
A flask was purged with nitrogen and charged with 2-methyl-4-nitro-benzoic acid (45.3 g, 0.25 mol), trimethyl borate (103.9 g, 1.00 mol), and tetrahydrofuran (906 mL). Neat borane dimethyl sulfide complex (39.9 g, 49.8 mL, 0.525 mol) was added drop-wise at 20-35° C. over at least 30 min. An exotherm and effervescence were observed during this addition. When the addition was complete, the reaction mixture was stirred at 65° C. for at least 2 h or until in-process HPLC analysis showed that conversion was greater than 97%. The batch was quenched with cooling by drop-wise addition of methanol (46 mL), followed by a solution of 12.1 N aqueous hydrochloric acid (97 g, 82.1 mL, 1.00 mol) in water (138 mL) over at least 30 min. Batch temperature was held at 20-35° C. during quench; an exotherm and effervescence were observed during the quench. The mixture was stirred at 50° C. for at least 1 h and concentrated under reduced pressure to a volume of ˜230 mL (to remove tetrahydrofuran). The concentrate was diluted with water (453 mL) and extracted with ethyl acetate (2×453 mL). The organic layer was washed with saturated aqueous sodium chloride solution (230 mL), dried over anhydrous magnesium sulfate (23 g), filtered, and concentrated in vacuo to dryness to give the title compound as a beige solid (41 g, 98% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[O:10])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+].I[C:65]1[N:69]2[CH:70]=[CH:71][C:72]([C:74]3[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=3)=[CH:73][C:68]2=[N:67][CH:66]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[N:77]1[CH:76]=[CH:75][C:74]([C:72]2[CH:71]=[CH:70][N:69]3[C:65]([C:2]4[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=5)=[O:10])=[N:6][CH:7]=4)=[CH:66][N:67]=[C:68]3[CH:73]=2)=[CH:79][CH:78]=1
Reactant: Ic1cnc2cc(-c3ccncc3)ccn12
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cn1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-3-(m-trifluoromethylphenyl)-urea (0.520 g, 1.44 mmol, 1.0 eq.) in dioxane (12 mL), add bis(pinacolato)diboron (0.410 g, 1.59 mmol, 1.1 eq.), tricyclohexylphosphine (0.048 g, 12 mol %), potassium acetate (0.211 g, 1.5 eq.), and tris(dibenzylidineacetone)dipalladium (0) (0.066 g, 5 mmol %). Deoxygenate the reaction mixture and stir under nitrogen at 80° C. for approximately 16 h and cool to room temperature. Add 3-iodo-7-pyridin-4-yl-imidazo[1,2-a]pyridine (0.460 g, 1.44 mmol, 1.0 eq.), sodium carbonate solution (2 M, 3 mL) and tetralis(triphenylphosphine)palladium (0) (0.083 g, 5 mmol %). Deoxygenate the reaction mixture and stir at 80° C. for 6 hours, cool, then purify on a SCX cartridge (Varian) as in Example 115. Concentrate SCX-eluted materials and purify via silica gel flash chromatography employing a 0-4% gradient of methanol in dichloromethane to afford 0.450 g (0.99 mmol, 69%) of the title compound. MS (ES), m/z 475 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Br[C:44]1[CH:49]=[N:48][CH:47]=[C:46]2[N:50](S(C3C=CC=CC=3)(=O)=O)[CH:51]=[CH:52][C:45]=12.[OH-].[Na+]>O1CCOCC1.C(O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:16][CH2:17]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:44]1[CH:49]=[N:48][CH:47]=[C:46]3[NH:50][CH:51]=[CH:52][C:45]=13)=[N:6][C:7]=2[N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)CC3)n(C)c2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3cncc4[nH]ccc34)nc21
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a degassed mixture of 4-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (859 mg, 1.24 mmol), 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (385 mg, 1.14 mmol), copper(I)iodide (326 mg, 1.71 mmol) in 1,4-dioxane (10 mL) was added Pd(PPh3)4 (100 mg, 0.09 mmol). The reaction mixture was stirred at 110° C. for 18 hours. The reaction mixture was concentrated and then dissolved in DCM and filtered through a column of silica gel (20% MeOH in DCM). The elutant was concentrated to give a yellow paste which was taken up in ethanol (2 mL) and 1,4-dioxane (3 mL). A 12 M aqueous NaOH solution (0.5 mL) was then added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated and the crude product was purified by flash chromatography using a Biotage KP-NH column (10% MeOH in DCM) followed by RP-HPLC to give 124. LCMS: M+H+=518.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.70 (s, 1H), 9.14 (s, 1H), 8.79 (s, 1H), 7.70 (m, 1H), 7.43 (m, 1H), 4.30 (s, br, 4H), 3.88 (s, 3H), 3.78 (m, 4H), 3.70 (s, 2H), 3.54 (m, 4H), 2.86 (m, 2H), 2.43 (m, 4H), 2.09 (m, 2H), 1.75 (m, 2H), 1.36 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13](B(O)O)[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C(OCC)C>[CH2:13]([C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CB(O)O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
Under an argon gas atmosphere, 2-bromo-5-nitrobenzonitrile (2.0 g), isobutylboronic acid (988 mg), cesium carbonate (5.7 g), and PdCl2 (dppf)-CH2Cl2 (720 mg) were dissolved in toluene (25 ml) and water (1 ml). The mixture was stirred at 100° C. for 18 hours. After the mixture was cooled to room temperature, the mixture was diluted with diethyl ether and water followed by the step of extraction/separation. The organic layer was washed with 1 N-hydrochloric acid, 5 N-sodium hydroxide aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified on column chromatography (EtOAc:hexane=1:3) to obtain the title compound (1.06 g) as a pale yellow oily substance.