Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH2:16][CH2:15][CH:14]([CH2:17]O)[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:17][CH:14]2[CH2:15][CH2:16][O:12][CH2:13]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OCC1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(CC3CCOC3)c2n1
Yield: 142.6 %

Procedure:
2,6-Dichloropurine (21 g, 113 mmol) and (tetrahydrofuran-3-yl)methanol (11.5 g, 113 mmol) were dissolved in tetrahydrofuran (250 ml) followed by the dropwise addition of triphenylphosphine (33 g, 125 mmol) and a diisopropyl azodicarboxylate (24.5 ml, 125 mmol)-tetrahydrofuran (50 ml) solution with ice cooling and the resulting mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure and then the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1 to 1:1 to 0:1) to give the title compound (44 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([CH2:36][C:37](O)=[O:38])[N:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[C:37](=[O:38])[CH2:36][C:33]1[NH:34][N:35]=[C:31]([CH3:30])[N:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)n[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 12 %

Procedure:
Prepared using the same procedure described in Example 189 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (17 mg, 12%). LC/MS (Method B) 3.22 min, [M+1]+ 525.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:10]([CH3:21])=[N:11][O:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=[O:5])C.CO.[OH-].[Na+].Cl>C1COCC1>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:12][N:11]=[C:10]([CH3:21])[C:9]=2[CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CC1c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid ethyl ester (more polar isomer, 0.164 g, 0.468 mmol) was dissolved in THF (3 mL) then MeOH (1 mL) and NaOH (1N aq., 1 mL) were added. The reaction stirred at room temperature overnight and was then acidified with 1N aq. HCl and submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 11H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+-cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:33][C:31]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:32]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) and sodium bicarbonate (75 mg) in dry tetrahydrofuran (6 mL) at 0° C. under N2 is treated with methyl chloroformate (38 μL), and the resulting mixture is stirred at 0° C. for one hour. The reaction is then diluted with ethyl acetate (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-166° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].C(OCC)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:10](=[O:12])[CH2:11][C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C(C)=O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.2 mmol) was added portionwise to a stirred solution of 1-(5-chloro-2-methoxy-phenyl)-ethanone (10.0 g, 54.2 mmol) in THF (100 mL) at 0° C. The mixture was then stirred for 10 minutes before addition of diethyl carbonate (7.68 g, 65.0 mmol) and then for an additional 1 hour. The mixture was warmed to room temperature for 2 hours and then heated to 65° C. for 2 hours. Diethyl ether was added, the organics washed with water and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (50 to 100% dichloromethane in cyclohexane) to yield 3.41 g of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=257.2; NMR (400 MHz, CDCl3): δ 7.59 (d, 1H); 7.38 (dd, 1H); 6.89 (d, 1H); 4.18 (q, 2H); 3.95 (s, 2H); 3.88 (s, 3H); 1.24 (t, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH:20]=1.C(Cl)Cl>C(Cl)Cl.CO>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH:17][CH:28]4[CH2:29][CH2:30][N:25]([C:21]5[CH:20]=[C:19]([CH3:18])[N:24]=[CH:23][N:22]=5)[CH2:26][CH2:27]4)[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:5][CH2:6]1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Cc1cc(C2=CCOCC2)c2nc(N)nn2c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C2=CCOCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3,6-dihydro-2H-pyran-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a yellow oil (yield: 5%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 406.5 (100) [(M+H)+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: OCCCBr
Solvent: Cc1ccccc1
Product: OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C., ice bath) solution of morpholine (31.5 ml, 0.36 mole) in toluene (300 ml) was added 3-bromopropanol (25 g, 0.18 mole) under argon. The cooling bath was then removed, the resulting mixture was warmed to room temperature, and stirred at room temperature for 1 hr. The mixture was heated at 100° C. (bath temperature) for 3 hrs under argon. After cooling, the mixture was diluted with ethyl acetate. The organic layer was washed (brine), dried (MgSO4), and concentrated. The residue was chromatographed (silica gel, elution by 1:1 CH2Cl2-hexane) to give the title compound as a clear oil.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:12]([CH:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:15])#[C-:13].C([O-])([O-])=O.[K+].[K+]>CO>[F:1][CH:2]([F:11])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][CH:13]=[N:12][C:14]=2[CH3:15])=[CH:9][CH:10]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)F)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A mixture of Example 38C (3.68 g, 23.6 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (4.93 g, 23.6 mmol), and K2CO3 (3.26 g, 23.6 mmol) in MeOH (110 mL) was heated to reflux. After 1 hr the reaction mixture was cooled to ambient temperature and the volatiles evaporated at reduced pressure. The residue was partitioned between Et2O and H2O. The separated aqueous phase was extracted with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 5% to 25% EtOAc/hexanes eluant; SF40-150 g column) afforded 4.39 g (89%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.80-7.73 (m, 2H), 7.69 (d, J=8.6, 2H), 7.09 (t, J=55.3, 1H), 2.40 (s, 3H). MS (DCI+) m/z 210 (M+H).
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([CH3:9])[C:7](=[O:10])OC1=O)(=[O:3])[CH3:2].[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([C@@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=1.Cl>C(OCC)(=O)C>[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:7](=[O:10])[C@H:8]([CH3:9])[NH:4][C:1](=[O:3])[CH3:2])[CH3:19])=[CH:14][CH:13]=1
Reactant: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
(S)-3-Acetyl-4-methyl-2,5-oxazolidinedione (N-acetyl-L-alanine-NCA)(424 mg, 2.7 mmol) was dissolved in ethyl acetate (10 mL), followed by the addition of (S)-1-(p-tolyl)ethylamine (406 mg, 3 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (25 mL), followed by extraction with ethyl acetate (25 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting white solid was washed with hexane-ethyl acetate to afford the title compound (380 mg, 57%) as white crystals.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[S:2].[Na+:6].[Na+].[I-].[Na+].Cl[CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[CH:16]([CH3:24])[CH2:15][C:14]1([CH3:26])[CH3:25].O>C(O)C>[S:1]([O-:5])([S:2][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[CH:16]([CH3:24])[CH2:15][C:14]1([CH3:25])[CH3:26])(=[O:4])=[O:3].[Na+:6]
Reactant: Cc1ccc2c(c1)N(CCCl)C(C)(C)CC2C
Reactant: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)N(CCSS(=O)(=O)[O-])C(C)(C)CC2C

Procedure:
A mixture of sodium thiosulfate (49.6 g, 0.2 m), sodium iodide (1 g), N-(2-chloroethyl)-2,2,4,7-tetramethyl-1,2,3,4-tetrahydroquinoline (25.2 g, 0.1 m), water (100 ml), and ethanol (100 ml) was refluxed fro 3 hrs. The mixture was cooled and extracted with 2-75 ml portions of toluene. The aqueous layer then contained essentially pure product and aliquots were used to prepare dyes without further purification.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.[OH-].[K+]>O>[N:12]1([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cccc(-n3cccn3)n2n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3); 1.06 g; 5.0 mmol; 1.0 eq.), pyrazole (3.40 g; 50.0 mmol; 10 eq.) and potassium hydroxide (842 mg; 15.0 mmol; 3.0 eq.) were melted and stirred overnight at 110° C. After this time, reaction mixture was cooled to rt poured into water and extracted with Et2O. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (650 mg, 65%). HPLC, Rt: 1.22 min. (purity 96.6%). LC/MS, M+(ESI): 201.0.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:14])([O-:4])=[O:3].[CH3:15]I.[Cl-].[Li+]>CN(C)C=O>[N+:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([O:10][CH3:15])=[O:9])[C:6]=1[OH:14])([O-:4])=[O:3]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: CI
Agent: [Cl-]
Agent: [Li+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
In a flask are placed 5.0 g (0.024 mole) of the sodium salt of 3-nitrosalicylic acid, 3.58g (0.0252 mole) of methyl iodide, and 40 mL of N,N-dimethylformamide. This mixture is stirred at ambient temperature for approximately sixteen hours. At the conclusion of this period 200 mL of a 10% aqueous solution of lithium chloride is added to the reaction mixture. This mixture is extracted three times with ethyl acetate. The combined extracts are washed with 200 mL of the 10% aqueous solution of lithium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, leaving a residue which is then passed through a column of silica gel, eluting with ethyl acetate. The product-containing fractions are combined, and the solvent is evaporated under reduced pressure leaving methyl 3-nitrosalicylate as a residue.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8](=O)[N:9]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[NH:11][C:12]=1[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:8]1[C:7]([Cl:6])=[C:12]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[N:11]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(OCC)c1[nH]c(C2CC2)nc(=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(OCC)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
Phosphorus oxychloride (35.1 g, 0.229 mol) in toluene (93 mL) was added to 5-chloro-2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone (i.e. the product of Example 4) (51.75 g, 0.190 mol) and N,N-dimethylformamide (34.7 g, 0.475 mol) in toluene (186 mL) at −5 to 0° C. The mixture was allowed to warm to room temperature over about 2 h. Then the mixture was added to aqueous sodium carbonate solution (saturated, 600 mL). The aqueous phase was further extracted with ethyl acetate (4×50 mL), and the organic extracts were combined, dried and evaporated to leave the product as an oil (52.9 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29](O)=[O:30].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:32]1([C:29](=[O:30])[CH2:28][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:35][CH2:34][CH2:33]1
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)n1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-fluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (80.0 mg, 0.185 mmol) in 1 ml anhydrous DMF at RT was added azetidine (12.6.2 mg, 0.221 mmol) and N,N-diisopropylethylamine (0.097 ml, 0.554 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.369 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 473.2 (M+H)+. GPR119 Human EC50: 5.8 nM
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]1)[CH2:2][CH3:3]>[Pd].C(OCC)(=O)C.[H][H]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C:7](=[O:9])[CH2:8]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1C=CC(=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CCC(=O)C1
Yield: 87.4 %

Procedure:
A mixture of 2 (1.2 g, 9.7 mmol) and 10% palladium on charcoal (catalytic quantity) in ethyl acetate (30 ml) was shaken in hydrogen at 55 psi and at 30° C. for 6 hours. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 1:0 to 9:1) to give the 3-propylcyclopentanone 3 (1.07 g, 88%). νmax(film)/cm−1 1744 (C═O).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH2:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>ClCCl.C(=O)([O-])O.[Na+]>[CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH:15][C:23](=[O:26])[CH2:24][CH3:25])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: NC/C=C1\CCc2ncc3c(c21)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC/C=C1\CCc2ncc3c(c21)CCO3
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a mixture of (2E)-2-(1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylidene)ethanamine (220 mg, 0.999 mmol) and triethylamine (167 μL, 1.20 mmol) in dichloromethane (10 mL) was added propionyl chloride (104 μL, 1.20 mmol) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→10/90) and recrystallization (chloroform/hexane) to give the title compound (195 mg, yield 75%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[Li]CCCC.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:43]=[CH:44][C:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:46][CH:47]=1)=O.[NH4+].[Cl-]>C1COCC1.O>[O:38]1[CH2:39][CH2:40][N:35]([C:34]2[C:29]3[N:30]([C:41]([C:42]4[CH:43]=[CH:44][C:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:46][CH:47]=4)=[C:27](/[CH:25]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:28]=3)[N:31]=[CH:32][CH:33]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 58a (218 mg, 0.771 mmol) in 3 mL of THF at rt was added n-BuLi (482 μL, 0.771 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 61a (263 mg, 0.642 mmol) in 5 mL of THF. The resulting mixture was stirred at rt for 1 h then 2 mL of saturated NH4Cl was added. The mixture was diluted with 10 mL of water, and the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc-DCM) to afford compound 61b as a pale yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 9.07 (d, J=2.0 Hz, 1H), 8.25-8.31 (m, 1H), 8.17-8.25 (m, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.77 (d, J=15.6 Hz, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.29-7.37 (m, 1H), 7.23-7.29 (m, 1H), 6.13 (d, J=5.9 Hz, 1H), 4.02-4.11 (m, 4H), 3.91-4.02 (m, 4H), 2.88-2.98 (m, 2H), 2.69-2.83 (m, 2H), 1.86-1.96 (m, 2H), 1.77-1.86 (m, 2H), 1.68 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C31H34N6O3, 539.3 (M+H). found 539.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-(tert-butyloxycarbonylaminomethyl)nicotinate from Example G3 (1.56 g, 5.84 mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.37 g, 8.76 mmol). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The aqueous residue was acidified by addition of 1M citric acid solution and extracted with chloroform/IPA (3 times). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated in vacuo to give a white solid; yield 1.38 g (94%).