Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH:9]([C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH3:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: CCc1ccncc1CC
Product: CCc1cnccc1C(C)CCc1ccccc1
Yield: 57.2 %

Procedure:
1.26 g (9.35 mmol) of 3,4-diethylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.28 g of the desired compound (yield: 57.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O-:12].[K+].OP([O-])(O)=O.[Na+].C(#N)C.[O:23]1[C:25]2([CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)[CH2:24]1>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:24][C:25]1([OH:23])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1
Reactant: COc1cc([N+](=O)[O-])ccc1[O-]
Reactant: C1CC2(CCS1)CO2
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC1(O)CCSCC1
Temperature: 150 °C
Yield: 41.9 %

Procedure:
A mixture of potassium 2-methoxy-4-nitrophenolate (3.02 g, 14.59 mmol), sodium phosphate monobasic, monohydrate (2.014 g, 14.59 mmol), acetonitrile (12 mL), water (3 mL) and 1-oxa-6-thiaspiro[2.5]octane (1.90 g, 14.59 mmol), prepared as described in patent WO 2005/063729 A1, was heated at 150° C. for 3.5 h in a microwave reactor. After cooling to RT, acetonitrile was mostly removed under vacuum, the remaining material was partitioned between EtOAc (100 mL) and H2O (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 60:40) to afford 1.83 g (42%) of the title compound as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J=9.07, 2.47 Hz, 1H), 7.73 (d, J=2.75 Hz, 1H), 7.18 (d, J=9.35 Hz, 1H), 4.75 (s, 1H), 3.89 (s, 3H), 3.85 (s, 2H), 2.87-2.97 (m, 2H), 2.49 (s, 1H), 2.38 (d, J=13.20 Hz, 2H), 1.82-1.89 (m, 2H), 1.72-1.82 (m, 2H). HPLC retention time: 2.985 min; LCMS (ES): m/z 282 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CO
Reactant: COc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1OC
Reaction time: 24 h

Procedure:
500 g of 2-methoxy-benzeneacetic acid are dissolved in 4 1 of methanol and 150 ml of sulfuric acid (d 1.84). The solution is boiled for 24 hours and poured onto ice water. The aqueous phase is extracted with chloroform which is then shaken against water and a solution of sodium hydrogen carbonate, whereupon the chloroform solution is evaporated.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:29][OH:30].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:30][NH:29][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 12g (125 mg, 0.303 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (210 mg, 3.03 mmol) and a freshly prepared solution of sodium methoxide in methanol (104 mg, 4.50 mmol of sodium dissolved in 1 mL of methanol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13g
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH:13]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O1CCOCC1>[CH:13]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (30 mg, 0.166 mmol) in dioxane was added 4-isopropoxyaniline (125 mg, 0.829 mmol). The mixture was heated in microwave for 20 minutes at 120° C. The solid formed was isolated by filtration and air dried to yield 5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde with impurities that will be removed in the final step. LCMS (M+1=297)
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]3[C:9]2=[O:18])=[C:6]([F:19])[CH:5]=[C:4]([Cl:20])[C:3]=1[OH:21].[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([O:21][CH2:24][C:23]#[CH:22])=[C:4]([Cl:20])[CH:5]=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[CH:11]2[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]2[C:9]1=[O:18]
Reactant: C#CCBr
Reactant: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)cc(F)c(N2C(=O)C3C=CCCC3C2=O)c1N

Procedure:
A mixture of 2-amino-6-chloro-4-fluoro-3-(tetrahydrophthalimido)phenol (0.31 g), propargyl bromide (0.2 ml), potassium carbonate (0.14 g), and acetonitrile (5 ml) was heated under reflux for 0.5 hr. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the title product (0.2 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]2[C:18]([N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22]2=[O:31])=[CH:17]1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([CH:7]2[NH:9][C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:16]3[C:17]2=[C:18]2[N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22](=[O:31])[C:23]2=[C:24]3[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(-c3ccccc3N)cc2n(C)c1=O
Reactant: Cc1ccc(C=O)o1
Solvent: CCO
Product: Cc1ccc(C2Nc3ccccc3-n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 170 °C
Yield: 40.1 %

Procedure:
A mixture of 5-methylfuran-2-carbaldehyde (32 mg, 29 μl, 0.29 mmol), compound 6 (101 mg, 0.29 mmol), and ethanol (1 mL) were heated in a microwave reactor at 170° C. for 10 min. A white product was isolated, washed and recrystallized from ethanol to afford 51 mg of 7 (42% yield); m.p.>300° C.; 1H NMR (DMSO-d6): δ 7.41 (broad m, 4H), 6.95 (d, 2H, J=8.42 Hz), 6.90-6.83 (m, 2H), 6.29 (d, 2H, J=2.93 Hz), 6.08 (d, 1H, J=2.19 Hz), 5.80 (d, 1H, J=2.93 Hz), 5.69 (d, 1H, J=2.93 Hz), 3.50 (s, 3H), 3.12 (s, 3H), 2.11 (s, 3H). 13C NMR (DMSO): 159.2, 153.1, 151.9, 151.9, 139.2, 131.5, 129.6, 129.4, 128.8, 126.9, 124.3, 122.8, 120.6, 118.2, 117.6, 111.9, 108.9, 107.1, 105.2, 47.8, 32.3, 28.2, 13.9. HRMS (ES+) (m/z): [M+1]+ calculated for C26H23N4O3, 439.1765. found, 439.1771.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1.[H-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:21]#[N:22])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]2)[C:21]#[N:22])=[CH:18][CH:17]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC1CN(CCCCl)CC(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1CN(CCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (2.0 g.) was prepared using the procedure described in Example 2a except using 2.3 g. (11 moles) of 4-(3-chloropropyl)-2,6-dimethylmorpholine, 0.48 g. of sodium hydride, and 1.69 g. (11 mmoles) of 4-chlorobenzyl cyanide in 15 ml. of a 2 to 1 mixture of toluene and DMF and was isolated as a pale yellow oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[N-:15]=[N+]=[N-].[Na+]>CO.C(O)C>[N+:7]1([O-:9])[O:8][N:15]=[C:2]2[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=12
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cc2c(no[n+]2[O-])s1
Temperature: 70 °C
Yield: 33.7 %

Procedure:
A suspension of 25.0 g (90 mmol) of ethyl 2-bromo-3-nitro-5-thiophenecarboxylate (Tetrahedron 21 (1965) 1061) and 29.0 g (450 mmol) of sodium azide in 300 ml of methanol is stirred at room temperature for 4 hours in 300 ml of ethanol. The mixture is poured into 4 l of ice-water, the precipitate is filtered off and the residue is heated at 70° C. for 3 hours in 700 ml of toluene. Subsequent purification by flash chromatography yields 6.5 g (34%) of ethyl thieno[2,3-c][1,2,5]oxadiazole-5-carboxylate-1-oxide and -3-oxide, m.p. 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18](OC)=[CH:17][CH:16]=1.ClC1C=CC(O)=CC=1[N+]([O-])=O>>[CH2:14]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 10C substituting benzyl bromide and the product from Example 47C for 1-chloromethyl-4-methoxy-benzene and 4-chloro-3-nitro-phenol (0.72 g, 79%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][CH2:9][C@H:8]2[NH:12]C(=O)[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:9][C@H:8]2[NH2:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C([O-])N[C@@H]1CNC[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H]1CN(CC(F)(F)F)C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Racemic tert-butyl (3R,4S) and (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate (260 mg, 0.991 mmol) was taken up in DMF (5 ml) and cooled to 0° C. NaH (59.5 mg, 1.487 mmol) was added slowly. The reaction was allowed to stir for 10 minutes at 0° C. before adding 2,2,2-trifluoroethyl trifluoromethanesulfonate (345 mg, 1.487 mmol). The reaction continued to stir at 0° C. for 1 hour and was then allowed to reach room temperature and continue stirring for 16 hours. LC/MS in showed full conversion to desired product. Saturated NH4Cl was added slowly. EtOAc and water were added. Our products were extracted into EtOAc (3×). The combined organic layers were then washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by MPLC SNAP 25 g 0-25% EtOAc/hexanes gave racemic tert-butyl (3R,4S) and (3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)carbamate (258 mg, 0.749 mmol, 76% yield). MS ESI calc'd. For C17H24F3N2O2 [M+1]+ 345, found 345.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>ClCCl>[S:10]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CN1CCC[C@@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.3 %

Procedure:
A solution of (R)-3-hydroxymethyl-1 -methylpiperidine (2.6 g, 20 mmol) in dichloromethane (70 mL) was cooled to 5° C. and tosyl chloride (3.8 g, 20 mmol) was added in portions during 15 minutes. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred for 20 hours. The reaction mixture was then concentrated and the residue partitioned between 10% potassium hydroxide (50 mL) and ether (100 mL). The ether layer was removed and the aqueous phase extracted once again with ether (50 mL). The combined ether layers were dried over magnesium sulfate and concentrated to afford (R)-3-tosyloxymethyl-1 -methylpiperidine as a white solid (2.4 g, 42%), m.p. 74.5-81.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][C:14](Br)=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].C[Zn+].[CH3:22]N1CCN(C)C1=O>C(N1C=CN(C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C.O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][C:14]([CH3:22])=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN1CCN(C)C1=O
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Br)s2)CC1
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(C)s2)CC1
Temperature: 50 °C

Procedure:
To a solution of cis/trans-4-(5-bromo-4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (371 mg, 1.12 mmol) and 2 M methyl zinc chloride solution in tetrahydrofuran (0.837 ml, 1.67 mmol) in a 5:1 mixture of tetrahydrofuran and 1,3-dimethyl-2-imidazolidinone (6 ml) was added (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) chloride (15.2 mg, 22.3 μmol) at room temperature. The reaction mixture was heated at 50° C. for 2 h. After cooling to room temperature the reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (170 mg, 57%) as colorless oil, with a purity of 80% according to GC. MS m/e: 268 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1nc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 92.8 %

Procedure:
A solution of 3-nitro-1H-1,2,4-triazole (1.00 g, 8.77 mmol), trityl chloride (4.89 g, 17.5 mmol) and diisopropylethylamine (3.05 mL, 17.5 mmol) in THF (50 mL) was stirred at room temperature for 15 hr. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (15-30% ethyl acetate/hexane) to give the title compound as a white powder (2.90 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1.Cl>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NC1CCN(CCc2ccccc2)CC1
Agent: Cl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(CCc2ccccc2)CC1

Procedure:
9.66 Grams of 4-nitrophthalic anhydride and 10.11 grams of 4-amino-1-(2-phenylethyl)piperidine were reacted in a similar manner to that described in Example 12 to give 10.51 grams of the title compound as the monohydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:32]([O:33][C:2]2[C:7]3[O:8][CH2:9][CH2:10][N:11]([CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[C:6]=3[N:5]=[CH:4][N:3]=2)=[C:25]([F:24])[CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Oc4ccc(C#N)cc4F)ncnc32)CC1
Temperature: 120 °C
Reaction time: 72 h
Yield: 7.8 %

Procedure:
To a solution of isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A (10.0 mg, 0.029 mmol) and 3-fluoro-4-hydroxybenzonitrile (12.07 mg, 0.088 mmol) in DMF (0.4 mL) was added K2CO3 (12.17 mg, 0.088 mmol). The reaction mixture was stirred in a sealed vial for 3 days at 120° C. The reaction mixture was cooled to RT. The reaction mixture was diluted with MeOH, filtered and purified by reverse phase HPLC (H2O/CH3CN) to give isopropyl 4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate (1.0 mg, 2.265 μmol, 7.72% yield) as Example 148 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J=6.05 Hz, 6 H) 1.55-1.79 (m, 4 H) 2.85-2.95 (m, 2 H) 3.44-3.54 (m, 2 H) 4.05-4.15 (m, 2 H) 4.24-4.35 (m, 2 H) 4.84-4.95 (m, 2 H) 7.29-7.40 (m, 1 H) 7.45-7.52 (m, 2 H) 7.88 (s, 1 H). LRMS (ESI): 442.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1)#[N:19]>C(#N)C>[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][S:11][C:8]2[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][N:9]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)cc2)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution 4-ethoxycarbonylimidazole-2-thiol (8.22 g, 47.8 mmol) and potassium carbonate (19.8 g, 143 mmol) in dry acetonitrile (100 mL) at room temperature was added 4-cyanophenacyl bromide (10.7 g, 47.8 mmol). The reaction mixture was stirred for 20 hours, during which time a white precipitate formed. To the solution was added 100 mL ice water. The resulting solid was filtered and washed with water (2×25 mL) to provide the title product as an off-white solid which was sufficiently pure for use in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[O:22]=[C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][NH:31][C:32](=[O:48])[C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH:26]=[CH:25][NH:24]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:27]4[CH:26]=[CH:25][NH:24][C:23](=[O:22])[CH:28]=4)=[O:48])=[CH:34][CH:35]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CC1(C)OB(c2ccc(C(=O)NCCc3cc[nH]c(=O)c3)cc2)OC1(C)C
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4cc[nH]c(=O)c4)cc3)nc3scnc23)cc1OC
Yield: 9.2 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol), N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (140 mg, 0.38 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol) was added in 20 mL of 1,4-dioxane. Na2CO3 (100 mg, 0.94 mmol) in 3 mL of water was added and then the mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (15 mg, 9%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 11.34 (s, 1H), 10.15 (s, 1H), 9.38 (s, 1H), 8.67-8.65 (m, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 7.95-7.81 (m, 3H), 7.51-7.47 (m, 1H), 7.26 (d, 1H, J=6.6 Hz), 7.01 (d, 1H, J=8.7 Hz), 6.15 (s, 1H), 6.08 (d, 1H, J=6.6 Hz), 3.83 (s, 3H), 3.78 (s, 3H), 3.50-3.48 (m, 2H), 2.72-2.65 (m, 2H). LC-MS: 528.9 [M+H]+, tR=1.35 min. HPLC: 98.40% at 214 nm, 99.86% at 254 nm, tR=5.18 min.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:14](=[O:17])[NH:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1COCC1>[CH:18]([NH:21][C:2]1[C:3]2[N:4]([C:14](=[O:17])[NH:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)([CH3:20])[CH3:19]
Reactant: O=c1[nH]nc2c(Br)nc(-c3ccccc3)cn12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2ccccc2)cn2c(=O)[nH]nc12

Procedure:
A solution of 29 mg of the product of Step A and 118 mg of isopropylamine in THF (5.0 mL) was heated at reflux for 16 h. The reaction was concentrated to one-quarter volume, diluted with water, and the pH was adjusted to pH 2 with 2N HCl. The solid was collected and triturated for one h in isopropyl ether at 60° C. before being collected and dried to give the title compound as a tan solid. MS (M+H+)=270.1.