Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:38])[N:9]([CH3:37])[C:10]=3[N:17]=[CH:16][C:15]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)=[CH:31][CH:32]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.091 mmol) in THF (2 ml) and water (2 mL) was added LiOH.H2O (7.6 mg, 0.183 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 40.5% yield) as a white solid. 1H NMR (CD3OD) δ: 8.52 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15-7.07 (m, 3H), 6.79 (d, J=8.4 Hz, 2H), 4.67 (s, 2H), 4.10 (t, J=6.8 Hz, 2H), 3.74 (s, 3H), 3.57 (t, J=6.4 Hz, 2H), 1.86-1.81 (m, 2H). LCMS: MH+ 520 and TR=3.195 min.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=2)[N:7]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1COCC1>[CH2:16]([N:18]([CH2:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=2)[N:7]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: COC(=O)c1cccc2oc(CCl)nc12
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)Cc1nc2c(C(=O)OC)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A mixture of methyl 2-(chloromethyl)benzoxazole-4-carboxylate (267 mg, 1.18 mmol) and diethylamine (2.0 mL, 27.4 mmol) in THF (15 mL) was stirred at ambient temperature overnight The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), followed by purification by preparative TLC (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford methyl 2-(diethylaminomethyl)benzoxazole-4-carboxylate (200 mg, 64%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.99 (dd, J=9.0, 1.0 Hz, 1H), 7.74 (dd, J=9.0, 1.0 (1H), 6.40 (t, J=8.1 Hz, 1H), 4.09 (s, 2H), 4.04 (s, 3H), 2.74-2.69 (m, 4H), 1.13 (t, J=6.6 Hz, 1H); MS (ESI+) m/z 263 (M+H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=1)C.[CH3:38][C:39]([C:41]1[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:42]=1[OH:48])=[O:40]>O1CCCC1>[CH2:30]([O:29][C:17]1[CH:16]=[C:15]([C:14](=[O:13])[CH2:38][C:39]([C:41]2[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:42]=2[OH:48])=[O:40])[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cc(O)ccc1O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (200.8 mL, 240 mmol), 2,5-dihydroxy acetophenone, 15 (9.12 g, 60 mmol) in tetrahydrofuran (150 mL) and ethyl-3,4-dibenzyloxy benzoate, 9 (21.7 g, 60 mmol) in tetrahydrofuran (100 mL) were reacted to afford 18, 1-(3,4-bis-benzyloxy-phenyl)-3-(2,5-dihydroxy-phenyl)-propane-1,3-dione (41 g), which was cyclized with Dowex-H+(12 g) in 2-propanol (300 mL) in a similar way as described for 22 to afford 24. Yield 12 g (44%); mp 196-197° C.; MS (FAB) 451 (M++1); IR (KBr) 3419, 1621; 1H NMR (200 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.75 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 7.55-7.22 (m, 13H), 6.94 (s, 1H), 5.30 (s, 2H), 5.27 (s, 2H).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.[CH3:47][O:48][CH2:49][CH2:50]NC>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[C:20](=[O:21])[CH2:19][CH2:18][CH:17]4[CH3:22])=[CH:15][C:10]=3[C:9]([N:8]([CH2:50][CH2:49][O:48][CH3:47])[CH3:6])=[O:39])=[O:24])[CH2:26][CH2:27]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1cc(N2C(=O)CCC2C)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 837 and (2-methoxyethyl)(methyl)amine (49 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (28 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH:2]([CH3:1])[CH3:3]
Reactant: NCc1ccc(F)cc1Cl
Reactant: CC(C)N1C(=O)CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
1-(1-Methylethyl)-5-oxo-proline (0.060 g, 0.35 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.052 g, 0.39 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.061 g, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.074 g, 0.39 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-(1-methylethyl)-5-oxo-prolinamide (0.032 g) as a white solid. LC/MS [M+H]+=313.1, retention time=2.26 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][C:26]([CH3:30])=[N:25]1>C(O)C>[NH2:14][C:13]1[O:29][C:28]2[N:24]([CH3:23])[N:25]=[C:26]([CH3:30])[C:27]=2[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:11]#[N:15]
Reactant: N#CCC#N
Reactant: CC1=NN(C)C(=O)C1
Reactant: COc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2c(C)nn3C)cc1
Reaction time: 0.02 h
Yield: 43.6 %

Procedure:
A mixture of anisaldehyde (350 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1,3-dimethyl-1H-pyrazol-5(4H)-one (321 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 24 h and the crude material was purified by column chromatography (25% ethyl acetate in hexanes to 100% ethyl acetate). The yellow solid was washed with ethanol and hexanes, and re-crystallized from ethanol to give 6-amino-4-(4-methoxyphenyl)-1,3-dimethyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (370 mg, 1.25 mmol, 44%) as a white solid. 1H-NMR (400 MHz) CDCl3: 7.12-7.10 (d, 2H), 6.85-6.83 (d, 2H), 4.61 (s, 2H), 4.55 (s, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 1.80 (s, 3H) 13C-NMR (100 MHz) CDCl3: 158.8, 157.9, 144.5, 144.4, 134.5, 128.8, 119.3, 114.0, 96.4, 64.2, 55.2, 36.7, 33.7, 12.7; LC/MS-MS: 297.0→231.2 m/z; GS1 and GS2 at 30, DP=61, CE=27, CXP=16, tR=3.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9]O.CCCCCC.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:20]1[CH:21]=[CH:22][C:17]([OH:23])=[CH:18][CH:19]=1
Reactant: Oc1ccccc1
Reactant: OCc1cc(I)ccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCCCCC
Product: Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 22.5 °C
Reaction time: 0.17 h

Procedure:
A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer was charged with (2-chloro-5-iodophenyl)methanol (268.5 mg, 1 mmol), anhydrous ZnCl2 (136.3 mg, 1 mmol), dichloromethane (5.0 mL) and n-hexane (29 mL) under argon. After stirring for 10 min at 20 to 25° C., HBr (gas) was bubbled into the mixture for 10 min and a solution of phenol (197.6 mg, 2.1 mmol) in dry dichloromethane (3.0 mL) was added dropwise over 30 min. After bubbling HBr for additional 2 h, the mixture was refluxed for 3 days. The conversion was about 65%. The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2×30 mL), washed with water (2×30 mL), brine (30 mL), concentrated and the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid. Yield: 180 mg (52%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J=8.4 Hz, 2H), 7.03˜7.09 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 4.76 (s, 1H), 3.95 (s, 2H), 3.82 (s, 2H). MS ESI (m/z): 345 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 154.1, 141.4, 139.5, 136.6, 134.2, 131.2, 130.9, 130.1, 115.5, 91.67, 38.07.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(I)cc1)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A mixture of 4-iodobenzyl bromide 14 (5.2 g, 17.51 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 3.27 g of 15 (53%). 1H NMR (200 MHz, CDCl3): δ1.24 (t, J=7.04 Hz, 6H), 3.07 (d, J=21.72 Hz, 2H), 4.01 (m, 4H), 7.04 (m, 2H), 7.62 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 16.24 (J=5.90 Hz), 33.21 (J=137.55 Hz), 62.04 (J=6.70 Hz), 92.15 (J=4.80 Hz), 131.31 (J=9.10 Hz), 131.57 (J=6.55 Hz), 137.43 (J=2.95 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(C)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cc(CBr)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of the ester 25 (2.26 g, 11.1 mmol), JV-bromosuccinimide (2.37 g, 13.3 mmol) and VAZO (271 mg, 1.11 mmol) was refluxed overnight in CCl4 (50 mL) under nitrogen. The reaction mixture was cooled to the room temperature, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 5% EtOAc in hexane) to give ethyl 5-bromomethyl-benzofuran-2-carboxylate. This compound was dissolved in dioxane (20 ml) and a solution of NaHCO3 (1.76 g, 20.9 mmol) in water (20 ml) was added. The reaction was stirred at 80° C. during 16 h. The solvent was evaporated and the product was dissolved in EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 20-40% EtOAc in hexane to give the title compound 26 (2.55 g, 61%) as a white solid. 1H-NMR (DMSO) δ: 7.74 (d, J=1.0 Hz, 1H), 7.71-7.70 (m, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.44 (dd, J=8.6, 1.8 Hz, 1H), 5.31 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H); 1.34 (t, J=7.0, 3H).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].[CH2:43](I)[CH3:44]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:43][CH3:44])[C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: CCI
Reactant: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1OC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methoxybenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (66 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[N:25][OH:26])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1.O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:12](=[N:25]/[O:26][CH2:36][CH:33]2[CH2:35][CH2:34]2)/[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(C(F)(F)F)cc1Cl
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
To 300 mg of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(hydroxyimino)ethyl]phthalimide in 5 ml of N,N-dimethylformamide, 324 mg of potassium carbonate and 158 mg of cyclopropylmethyl bromide were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), the resulting organic layers were combined, washed with water and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 1:19 to 4:16) as the eluent to obtain 98 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][NH:18][CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:19])[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CNC
Solvent: CN(C)C=O
Product: CCc1nnc2c(N(C)C)nc3ccccc3n12
Reaction time: 0.33 h
Yield: 42 %

Procedure:
4-Chloro-1-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, and 676 mg. (0.015 mole) of anhydrous dimethylamine in N,N-dimethylformamide (50 ml.) were stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 20 minutes. The precipitate which formed was separated by filtration, washed with water and air dried. Recrystallization from chloroform and then from chloroform/cyclohexane afforded 510 mg. (42% yield) of 4-dimethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 155°-158° C. Mass spectrum: m/e, 241 (P).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[N:12]([CH3:22])[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[OH:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].CN1C=NC(C2C=CC=CC=2)=N1.C(C1C=CC([F:45])=C(C=1)C=O)C>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:45])=[C:5]([CH:9]([C:11]2[N:12]([CH3:22])[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)[OH:10])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(F)c(C=O)c1
Reactant: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Agent: Cn1cnc(-c2ccccc2)n1
Product: CCc1ccc(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (105 mg, 0.66 mmol) and 5-ethyl-2-fluorobenzaldehyde (100 mg, 0.66 mmol) afforded 159 mg of Intermediate 385.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.12 (t, J=7.70 Hz, 3H) 2.47 (q, J=7.42 Hz, 2H) 2.95 (d, J=9.05 Hz, 1H) 5.48 (d, J=9.29 Hz, 1H) 6.67 (dd, J=9.90, 8.44 Hz, 1H) 6.87-6.99 (m, 1H) 7.03 (dd, J=7.34, 2.20 Hz, 1H) 7.08-7.15 (m, 6H) 7.15-7.22 (m, 10H) 7.30-7.48 (m, 5H) 8.04-8.16 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15]>>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1cccc(C)c1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,6-dimethylaniline to yield 2-[(2,6-dimethylphenyl]amino]phenylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[O:14]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (112 mg, 0.472 mmol) and K2CO3 (326 mg, 2.36 mmol) in acetone (3 mL) was added p-anisoyl chloride (0.066 mL, 0.472 mmol). The reaction vessel was sealed and heated to 80° C. for 4 days. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 15 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 9 mg (5%) of 5-hydroxy-2-(4-methoxy-phenyl)-7-morpholin-4-yl-chromen-4-one. Me is CH3—.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[CH:9][CH:8]=2)[N:3]=1.[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)no1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc([C@H]3CNCCO3)cc2)no1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of tert-butyl (2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl) morpholine-4-carboxylate (intermediate 18, 16.9 g, 49.0 mmol) in ethyl acetate (60 ml) was added 4N hydrogen chloride in ethyl acetate (150 ml) at room temperature and the solution was stirred for 3 hours. The solvent was evaporated under reduced pressure, and the resulting precipitate was filtered, washed with ethyl acetate, and dried under reduced pressure to afford (2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholine hydrochloride (intermediate 19, 13.3 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:22][C@H:21]([CH2:23][O:24]C4CCCCO4)[C@@H:13]([O:14]C4CCCCO4)[C@H:12]3[F:31])[C:6]=2[N:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO>[NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:13]([OH:14])[C@H:12]3[F:31])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@H]3F)c2n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Yield: 99.1 %

Procedure:
A solution of the compound from Step H (40 mg. 0.08 mmol) in EtOH (2 mL) was stirred with pyridinium p-toluenesulfonate (40 mg, 0.16 mmol) at 60° C. for 3 h. The mixture was then evaporated and the residue purified on a silica gel column with a solvent system of hexanes/EtOAc: 1/1 and 1/2 to give the desired compound (24 mg).
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])C(=O)[O-])(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1cccnc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@H](Cc1cccnc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 20 h
Yield: 68.4 %

Procedure:
To a solution of 1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(3-pyridinylmethyl)ethyl]carbamate (796.7 mg, 2.1 mmol) in DCM (10 mL) at RT was added 1M HCl in dioxane (10 mL). After 20 h, the solution was concentrated affording the title compound (404 mg, 68%) as the HCl salt: LCMS (ES) m/z 282 (M+H)+.