Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[CH:40][NH:41]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH:39]=[CH:40][NH:41]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc4[nH]ccc34)n(-c3ccccc3)c(=O)c12
Yield: 3.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (140 mg, 0.32 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (116 mg, 0.48 mmol), sodium carbonate (2M, 715 μl, 1.43 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40 mg, 0.05 mmol) according to the method described in Example 3 to give 6 mg (4% yield) of the title compound as a mixture of diastereoisomers. Purity 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH3:10])=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=1
Reactant: CSc1ccc(C)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
(2-Bromo-4-methylphenyl)(methyl)sulfane (700 mg, 3.20 mmol) was dissolved in THF (5.0 mL) and cooled to −78° C. To the cooled solution was added n-butyl lithium (2.2 mL, 3.60 mmol) dropwise. The reaction was stirred for 2 min at −78° C. then the triisopropyl borate (0.82 mL, 3.56 mmol) was added dropwise and the reaction mixture was allowed to warm to 0° C. over a period of approximately 90 min. The reaction was quenched by addition of 1N HCl solution and was stirred for 5 min. The mixture was then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (1×30 mL), brine (1×30 mL) and dried over MgSO4. The crude product was then triturated with EtOAc and hexanes to give 5-methyl-2-(methylthio)phenylboronic acid. The mother liquor was purified by column chromatography (silica gel, 0 to 30% EtOAc:hexanes) to give more desired product. Mass Spectrum (ESI) m/e=183.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH3:10])[C:7](O)=[O:8]>>[CH3:5][C:6]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH3:10])[C:7]([Cl:3])=[O:8]
Reactant: CC(C)(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Product: CC(C)(C(=O)Cl)N1C(=O)c2ccccc2C1=O
Yield: 98.3 %

Procedure:
Thionyl chloride (750 ml, 10.28 mol) was added to 2-methyl-2-phthalimidopropanoic acid (385 g, 1.65 mol) and the mixture refluxed under nitrogen for 3 hours. Excess thionyl chloride was removed under reduced pressure to yield a solid. The solid was washed with diethyl ether (2×250 ml) to yield the title compound as a white crystalline solid (408.2 g, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.Cl[CH2:38][C:39]([NH2:41])=[O:40].CCN(CC)CC>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Reactant: NC(=O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC(N)=O)CC3(C)C)n(C)c2n1
Reaction time: 84 h
Yield: 47.6 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (120 mg, 0.25 mmol), 2-chloroacetamide (50 mg, 0.54 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (5 mL) was allowed to stir at r.t. for 5 h before further 2-chloroacetamide (100 mg, 1.07 mmol) and NEt3 (100 μL, 0.72 mmol) was added. The resulting mixture was allowed to stir for 84 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 717 (65 mg, 49%). LCMS (method I): RT 2.54 min, [M+H]+ 547.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.99 (1 H, m), 7.77-7.74 (1 H, m), 7.32-7.22 (2 H, m), 6.95 (1 H, brd s), 5.43 (1 H, brd s), 4.34 (4 H, brd s), 3.90 (3 H, s), 3.86 (6 H, t, J=4.76 Hz), 3.35 (2 H, q, J=7.48 Hz), 2.96 (2 H, s), 2.62-2.45 (4 H, m), 2.38 (2 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.25 (6 H, s)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])=[CH:33][CH:32]=1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])=[CH:35][CH:36]=3)[N:3]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Reactant: C=CC(=O)Nc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(Nc2ncnc(Nc3cc(OC)c(OC)c(OC)c3)n2)cc1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (29.9 mg, 0.101 mmol) in IpOH (2.5 ml) was added DIEA (0.026 mL, 0.151 mmol) and N-(4-aminophenyl)acrylamide (Step 2) (18 mg, 0.111 mmol). The mixture was heated at 100° C. for 18 h. The solution was cooled to RT. The organics were evaporated in vacuo and the residue was purified by column chromatography using 9:1 CH2Cl2/MeOH as the solvent to give N-(4-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-ylamino]phenyl}-acrylamide: MS m/z 423[M+H]+. Calc'd for C21H22N6O4: 422.17.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and methyl bromoacetate (16 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 100° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 followed by trituration with diethyl ether afforded 10 mg (26%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxy-2-oxoethoxy) phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.92 (t, 1H), 7.50 (t, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.C(Cl)Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared by analogy to Example 48 except that 1-(4-chloro-phenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C

Procedure:
To a mixture of 60% sodium hydride and THF were added dropwise ethyl diethylphosphonoacetate and further 4-[4-(t-butoxycarbonyl)piperazin-1-yl]benzaldehyde under cooling to 0° C., followed by stirring. Then, post-treatment and purification were carried out in a usual way to obtain ethyl 3-{4-[4-(t-butoxycarbonyl)piperazin-1-yl]phenyl}acrylate. Further, catalytic reduction was carried out using palladium/carbon to obtain an objective compound.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][C:27]=2[F:34])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:4]3[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH2:9][CH3:10])=[CH:28][C:27]=2[F:34])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1F
Reactant: CCCOc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
5-Bromo-2-propoxy-3H-imidazole-4-carbaldehyde (3.7 g, 15.7 mmol), 4′-bromomethyl-2′-fluorobiphenyl-2-carboxylic acid t-butyl ester (5.7 g, 15.7 mmol) and potassium carbonate (6.5 g, 47.0 mmol) were dissolved in DMF (50 mL, 646 mmol), and stirred at room temperature until the reaction was complete, as determined by HPLC. Water (100 mL) was added and the mixture was extracted with EtOAc (2×), washed with saturated aqueous NaCl (2×), dried over MgSO4, filtered and concentrated to yield a yellow oil. The oil was purified by flash chromatography (2-20% EtOAc/hexanes) to yield compound A (4.8 g) as a colorless oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][N:19]3[C:24]=2[C:23]([NH:25][C:26]2[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=2)[N:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[N:30]=[CH:29]4)=[N:22][CH:21]=[N:20]3)[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CO>[F:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:24]4=[C:16]([CH2:15][N:12]5[CH2:11][CH2:10][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:14][CH2:13]5)[CH:17]=[CH:18][N:19]4[N:20]=[CH:21][N:22]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Acetic anhydride (25 uL, 2.3 equiv.) was added to a mixture of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) and K2CO3 (21 mg 0.15 mmole) in MeOH (3 mL) at 0° C. under nitrogen. After 1 h, the reaction was removed from the ice bath and the mixture was left stirred at RT overnight. The solvent was removed and the residue was taken up in DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (41 mg, 80%). MS: 513 (M+H)+; HPLC Ret Time: 1.12 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][N:9]=2)=[CH:4][C:3]=1[F:19].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:20]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:19])[CH:4]=2)[CH2:12]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 75 °C
Yield: 92.6 %

Procedure:
Methanesulfonic acid 3-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl ester (38.6 g, 111.9 mmol) was added to dimethyl formamide (100 ml) followed by addition of sodium azide (14.5 g, 223.8 mmol). The mixture was heated to 75° C. for five hours and then added to aqueous sodium chloride (200 ml) followed by extraction with ethyl acetate (3×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (31 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].[N:22]1([C:27]2[CH:28]=[CH:29][C:30](O)=[N:31][CH:32]=2)[CH:26]=[N:25][CH:24]=[N:23]1>CN(C=O)C>[N:22]1([C:27]2[CH:28]=[CH:29][C:30]([O:1][CH2:2][CH2:3][C@@H:4]3[CH2:6][C@@H:5]3[CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]4([CH3:19])[CH2:18][CH2:17]4)=[O:14])[CH2:9][CH2:8]3)=[N:31][CH:32]=2)[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: Oc1ccc(-n2cncn2)cn1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCO)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4cncn4)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (100 mg, 0.37 mmol) in DMF (5 mL) was added NaH (22 mg, 0.56 mmol) in small portions. After total addition, the grey solution was stirred at RT for 10 minutes and then cooled to −26° C. via dry ice/methanol bath. A solution of 5-(1H-1,2,4-triazole-1-yl)pyridin-2-ol (120 mg, 0.74 mmol) in DMF (0.5+0.5 mL) was added via syringe drop-wise and the resulting mixture was stirred for 30 minutes. The reaction was quenched with a cold solution of NH4Cl (10 mL) via syringe. Water (10 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organics were combined, dried by MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (80 g silica gel, ISCO, eluant 5% methanol in DCM) to afford the product after being concentrated to dryness under reduced pressure. LC/MS (m/z): 412 (M+H)±. LC/MS (m/z): 424 (M+H)+. GPR119 Human EC50: 0.88 nM
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[F:6][C:7]([CH3:38])([CH3:37])[CH2:8][CH2:9][C@H:10]1[C:14](=[O:15])[O:13][C@H:12]([C@@H:16]([NH:24][C:25]([C:27]2[CH:36]=[N:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11]1>CO>[CH2:17]([CH:16]([NH:24][C:25]([C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH:12]([OH:13])[CH2:11][CH:10]([C:14](=[O:15])[NH:2][OH:3])[CH2:9][CH2:8][C:7]([F:6])([CH3:38])[CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NO
Reactant: CC(C)(F)CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NO
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Hydroxylamine hydrochloride (1.55 g, 22.4 mmol) and KOH (1.51 g, 26.7 mmol) were combined in anhydrous methanol (20 mL) and stirred for 30 minutes under a dry nitrogen atmosphere, and then filtered. To the resulting filtrate was added the product from Method E (500 mg, 1.17 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue solvated in EtOAc (50 mL) and transferred to a separated funnel. The organic layer was washed with water and brine and dried (MgSO4). After filtration the solvent was removed in vacuo and the remaining residue recrystallized (methylene chloride/Hexanes) to give a pale yellow solid (330 mg, 58%) m.p. 165-166° C.
Reaction SMILES: O.C(=O)(O)[O-:3].[Na+].[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>C(OCC)C>[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[OH:3])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=C(C)C(=O)OCCC[Si](C)(C)O

Procedure:
After 60 mL of water, 60 ml of diethyl ether, and 7 g (83 mmol) of sodium bicarbonate had been placed into a four-necked flask, the temperature was lowered to 0° C. Next, 15 g (68 mmol) of 3-methacryloxypropyldimethylchlorosilane were added dropwise into the resulting mixture, which was being agitated, via a dropping funnel. After the reaction had been completed, the ether layer was separated and then washed with water once. After the ether had subsequently been distilled and removed at room temperature and reduced pressure, 3-methacryloxypropyldimethylsilanol (hereafter, "MPOH") was obtained. The structure of said compound was verified by gas chromatographic analysis (GLC) and nuclear magnetic resonance analysis (NMR).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[C:18]=2[C:19]#[N:20])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl.CO>[Cl:25][C:21]1[CH:22]=[N:23][CH:24]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:3]([OH:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:16][CH:15]=2)[C:18]=1[C:19]#[N:20]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(Cl)cncc1-c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Granular sodium borohydride (225 mg, 5.94 mmol) was added to a solution of 3-(4-benzoylphenyl)-5-chloroisonicotinonitrile (473 mg, 1.187 mmol, 80% pure) in dichloromethane (10 mL) and methanol (10 mL). After 30 min at room temperature, the mixture was quenched with saturated ammonium chloride (30 mL). The organic solvents were evaporated in vacuo. The aqueous residue was extracted with ethyl acetate (2×40 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane and eluting with 20-60% ethyl acetate in hexanes, gave 3-chloro-5-(4-(hydroxy(phenyl)methyl)phenyl)isonicotinonitrile as white solid (327 mg, 69% yield), which was approximately 80% pure. MS (ES+) m/z: 303 (M−water+H); LC retention time: 3.798 min (analytical HPLC Method A).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(OC(Cl)(Cl)Cl)=[O:15]>O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[O:9][C:10]1=[O:15]
Reactant: COC(=O)c1sccc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2ccsc2c(=O)o1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (31.0 g, 0.20 mol) was added to a solution of potassium hydroxide (22.68 g, 0.40 mol) in 1 L water. The solution was heated at 90° C. for 2 hours. The solution was then cooled to 0° C. and trichloromethyl chloroformate (35.7 mL, 0.30 mol) was added slowly, maintaining the temperature between 0° C. and 10° C. The solution was stirred at 0° C. for 4 hours, and then allowed to warm up gradually to room temperature and stirred for another 3 hours. The precipitated solid product was collected by vacuum filtration to give 28.5 g (85% yield) 1H-thieno[3,2-d][1,3]oxazine-2,4-dione. 1H-NMR (DMSO-d6) δ 6.94 (d, J=5.0 Hz, 1H), 8.24 (d, J=5.0 Hz, 1H), 12.26 (b, 1H) ppm; EIMS m/z 170 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19]C)=[O:18].[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:33]([F:36])([F:35])[F:34])=[C:26]([CH:32]=1)[CH:27]=[CH:28][C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][N:12]([C:29](=[O:30])/[CH:28]=[CH:27]/[C:26]3[CH:32]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=3[C:33]([F:34])([F:35])[F:36])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)C=Cc1cc(F)ccc1C(F)(F)F
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3cc(F)ccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared employing a procedure analogous to that described in Example 1 using methyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 5-fluoro-2-(trifluoromethyl)cinnamic acid followed by a procedure analogous to that described in Example 2. LC-MS Method 1 tR=1.93, min, m/z=496, 498; 1H NMR (CDCl3) 1.20-1.40 (3H), 1.70 (m, 1H), 2.39 (m, 1H), 2.51 (m, 1H), 2.65-3.05 (4H), 3.36 (m, 1H), 3.62 (br s, 1H), 4.06 (d, 1H), 4.79 (d, 1H), 6.83 (d, 1H), 7.0-7.5 (5H), 7.70 (m, 1H), 7.87 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:45][CH2:46][CH2:47][CH2:48]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:45][CH2:46][CH2:47][CH2:48][O:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:39])([CH3:40])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Yield: 30.7 %

Procedure:
A suspenssion of tert-butyl (3-(6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (30 mg), 1,3-dibromopropane (14.7 mg) and K2CO3 (13.4 mg) in acetone (6 mL) was heated to reflux for 16 hours. The mixture was diluted with EtOAc (200 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give desired product tert-butyl 3-(6-(6-(4-(3-bromopropoxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate (11 mg).