Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([N:7]2[CH:12]=[CH:16][CH:15]=[CH:14]2)[CH:8]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(Br)ccc1F
Solvent: CC(=O)O
Product: Fc1ccc(Br)cc1-n1cccc1
Yield: 99 %

Procedure:
A mixture of 5-bromo-2-fluoroaniline (prepared according to the procedure of Roe et al. in J. Org. Chem., 1956, 21, 28-29) (200 mg, 1.05 mmol) and 2,5-dimethoxytetrahydrofuran (171 μl, 1.32 mmol) in glacial acetic acid (1.5 ml) was heated at 130° C. for 20 min and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with 10% diethyl ether in isohexane yielded 1-(5-bromo-2-fluorophenyl)-1H-pyrrole (335 mg, 99%): δH (360 MHz, CDCl3) 7.53 (1H, dd, J 7 and 3), 7.33 (1H, ddd, J 9, 4 and 3), 7.10 (1H, dd, J 11 and 9), 7.04-6.95 (2H, m), 6.36 (2H, t, J 2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:11])=[N:9][N:10]=1.[Cl-].[C:16]([O:20][C:21](=[O:24])[CH2:22][Zn+])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:11][C:8]1[O:7][C:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])[CH:14]=[CH:13][CH:12]=2)=[N:10][N:9]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1nnc(Cc2cccc(Br)c2)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1nnc(Cc2cccc(CC(=O)OC(C)(C)C)c2)o1
Reaction time: 20 h
Yield: 59.5 %

Procedure:
To a solution of 2-(3-bromobenzyl)-5-methyl-1,3,4-oxadiazole 1105 (0.50 g, 1.97 mmol) in dioxane (1 mL), under an atmosphere of Argon, was added Bis(tri-t-butylphosphine)palladium(0) (0.15 g, 0.295 mmol) followed by the addition of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 4.92 mmol, 9.84 mL). The mixture was allowed to stir under Argon for 20 hours and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (10 mL) and washed with water (2×5 mL), brine (2×5 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by normal phase chromatography 0-50% EtOAc/Hexanes to give 0.338 g of tert-butyl 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetate 1106. 1H NMR 300 MHz CDCl3: δ 7.24 (m, 4H), 4.12 (s, 2H), 3.51 (s, 2H), 2.46 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C.C(OCC)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:1]([C:9]1[NH:10][C:11]([CH2:15][C:16]([O:18][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:17])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(OC(=O)Cc1ccc(C(=O)c2ccccc2)[nH]1)C(=O)OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 150.8 %

Procedure:
A mixture of 2-benzoylpyrrole (855 mg, 5 mmol), diethyl chloromalonate (973 mg, 5 mmol) and manganese(III) acetate dihydrate (4560 mg, 15 mmol) in acetic acid (30 mL) was stirred at 80° C. for four hours. The reaction was cooled to room temperature, diluted with diethyl ether and filtered. The filtrate was washed with 10% aqueous sodium hydroxide and saturated aqueous sodium chloride, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica (70-30, hexanes-ethyl acetate) to provide 1.46 g (75%) of diethyl (5-benzoylpyrrol-2-yl)acetoxymethane-dicarboxylate.
Reaction SMILES: [CH3:1][Mg]Br.[OH:4][C@H:5]1[CH2:15][C@@:14]2([CH3:17])[O:16][C@@:6]31[C@@H:18]1[C@@H:10]([N:11]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=4)[C:12](=[O:19])[C@H:13]21)[O:9][CH2:8][CH2:7]3>C1COCC1>[OH:4][C@:5]1([CH3:1])[CH2:15][C@@:14]2([CH3:17])[O:16][C@@:6]31[C@@H:18]1[C@@H:10]([N:11]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:21]=4)[C:12](=[O:19])[C@H:13]21)[O:9][CH2:8][CH2:7]3
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@]12C[C@@](C)(O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reaction time: 1 h
Yield: 21.9 %

Procedure:
Methylmagnesium bromide (3M in ether, 0.476 mL, 1.427 mmol) was added drop wise to a solution of Example 3 (280 mg, 0.714 mmol) in THF (10 mL) at −30° C. The resulting reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10-100% EtOAc/hexane, Flow rate: 40 mL/min) to give Example 37 (64 mg, 22% yield) as a white solid along with 204 mg of recovered starting material.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[CH2:3][CH:4]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)=[O:7])[CH2:5]1
Reactant: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(C(=O)c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a flask containing ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (3.00 g, 12.0 mmol) was added anhydrous tetrahydrofuran (28.8 mL), methanol (28.8 mL), and 1 N sodium hydroxide (28.8 mL, 28.8 mmol). After 1 h, the reaction was concentrated to a white solid. The solid was the redissolved in 700 mL of water. With vigorous stirring, 1 N HCl (29.0 mL) was added dropwise and the suspension was stirred for 30 min. at room temperature. The solid was then collected with a Buchner funnel and the solid was washed two times with water. The solid was then azeotrophed with toluene to give 4-(3,3-dimethylcyclobutanecarbonyl)benzoic acid (2.15 g, 92% yield) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.21-8.15 (m, 2H), 8.01-7.94 (m, 2H), 3.91 (quin, J=8.9 Hz, 1H), 2.28-2.17 (m, 2H), 2.15-2.04 (m, 2H), 1.28 (s, 3H), 1.09 (s, 3H). MS (M−1): 231.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[H-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH2:10][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)(C)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 3-(4-chlorophenyl)-3-methyl-2-butanone (197 mg, 1 mmol) in diethyl carbonate (1.32 g, 11 mmol) was added at 20° C. under an atmosphere of nitrogen portion wise a dispersion of 55% sodium hydride in mineral oil (91 mg, 2.1 mmol). The reaction turned yellow and was heated to 50° C. After the gas evolution stopped the reaction was stirred at 85° C. for 30 min. After cooling to 20° C. the reaction was poured onto ice-water (2 mL) and then acetic acid (0.14 mL) was added. The reaction was extracted twice with diethyl ether. The combined organic layers were washed with water and with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using heptene/ethyl acetate (9:1 v/v) as eluent to yield the title compound as a pale-yellow oil (79 mg, 29%).
Reaction SMILES: [CH3:1]COC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:27][C@H:26]([OH:28])[CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:29]1([C:35]2[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:23][C:22](=[O:24])[C@@H:21]1[CH2:25][C@@H:26]([O:28][C:31]2[CH:30]=[C:29]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=[CH:33][CH:32]=2)[CH2:27][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](Oc2cccc(-c3ccccc3)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A solution of diethylazodicarboxylate (829 μL) in tetrahydrofuran (10 mL) was added to a cold (−15° C.) stirred solution of N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline (1.23 g), 3-phenylphenol (896 mg), and triphenyl phosphine (1.38 g) in tetrahydrofuran (30 mL) under argon, After stirring at room temperature for 15.5 hr, the solvent was evaporated and coevaporated several times with toluene in vacuo. The residue was diluted with toluene and precipitated solids were removed by filtration, which was washed with toluene. The combined organic layers were evaporated in vacuo and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, v/v) to give title compound (837 mg): 1H-NMR (400 MHz, CDCl3) δ 1.36-1.50 (m, 9H), 2.18-2.29 (m, 1H), 2.51-2.64 (m, 1H), 3.68-3.89 (m, 5H), 4.40-4.56 (m, 1H), 4.91-5.01 (m, 1H), 6.79-6.87 (m, 1H), 7.04-7.10 (m, 1H), 7.17-7.24 (m, 1H), 7.29-7.39 (m, 2H), 7.39-7.49 (m, 2H), and 7.49-7.60 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(F)c1
Yield: 81.7 %

Procedure:
The title compound (D44) (239.7 mg) was prepared according to the experimental procedure described in Description 40 starting from (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (D43) (200 mg, 0.993 mmol) and 3-Fluorophenol (0.089 ml, 0.993 mmol).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:35])[C:5]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30]CC)=[O:29])[CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])=[CH:15][CH:14]=2)=[C:6]([NH2:8])[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:35])[C:5]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:33][CH:34]=2)=[C:6]([NH2:8])[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(SCCCc2c(N)nc(N)[nH]c2=O)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(N)c(CCCSc2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)c(=O)[nH]1
Yield: 41.6 %

Procedure:
A sample of compound 1E (0.50 g, 0.99 mmole) was stirred at 50° C. in 0.1N NaOH (18 mL) for 2 hours. The pH was adjusted to 8.0 with 1.0 N HCl and the mixture evaporated to dryness in vacuo. The resulting solid was dissolved in a minimum of ethanol/water (35% ethanol v/v) and chromatographed in 5 injections on a Regis C18 2.1 cm×50 cm, 10 micron, preparative reverse phase column. The combined fractions were reduced in vacuo to 5 mL volume and acidified with concentrated HCl to pH 3.0. Filtration gave a white solid which was dried in vacuo at 50° C. to yield the title compound, 1F, (0.185 g, 41%) as a white powder. Anal: C19H23N5O6S.3/2 H2O: C, 47.89; H, 5.48; N, 14.70. Found: C, 47.99; H, 5.51; N, 14.61. NMR (DMSO-d6) δ1.6 (t, 2H, CH2 --CH2 --CH2), 2.0 (m, 2H, --CH2 --CH2 --CO2H), 2.35 (m, 4H, CH2 --CH2 --CH2 --S and CH2 --CO2H), 2.95 (t, 2H, --CH2 --S), 4.35 (m, 1H, methine), 5.8 (br, 2H, NH2), 6.1 (br, 2H, NH2), 7.3 (d, 2H, phenyl H's ortho to sulfur), 7.75 (d, 2H, phenyl H's ortho to carbonyl), 8.55 (d, 1H, glutamic acid NH), 9.9 (br, 1H, pyrimidine NH), 12.35 (br, 2H, CO2H's).
Reaction SMILES: Cl.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(OCC)(=O)C>C1COCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[CH:19][CH:18]=1
Reactant: BrCc1ccncc1
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(SCc2ccncc2)cc1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
A suspension of 4-bromomethylpyridine hydrochloride (1.59 g, 6.3 mmol) in THF (10 mL) was treated dropwise with a solution of potassium carbonate (3.33 g, 24.0 mmol) in H2O (6 mL) at 0-5° C., and the resulting mixture was stirred at 0-5° C. for 10 min before being treated dropwise with a solution of 4-bromo-benzenethiol (1.14 g, 6.0 mmol) in THF (5.0 mL) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for an additional 20 min. When TLC and LCMS showed that the reaction was complete, the reaction mixture was treated with water (15 mL) and ethyl acetate (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water (2×15 mL) and saturated aqueous NaCl solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5-25% EtOAc-hexane gradient elution) to afford the desired 4-(4-bromo-phenylsulfanylmethyl) pyridine 301 (1.374 g; 82%) as a pale-yellow solid, which was directly used in subsequent reactions.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.C([NH:38][CH2:39][C:40](O)=[O:41])(OC(C)(C)C)=O>>[NH2:38][CH2:39][C:40]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:22]2[S:23][C:9]3[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[N:13][C:12]([C:14]4[CH:19]=[N:18][C:17]([NH2:20])=[N:16][CH:15]=4)=[N:11][C:10]=3[CH:21]=2)[CH2:30][CH2:29]1)=[O:41]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Agent: Cl
Product: NCC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with Boc-glycine via General Procedure B followed by Boc removal with TFA to generate 44 mg of 106 after purification. MS (Q1) 470.2 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.31 (bs, 1H), 10.04 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.75 (t, 1H, J=3.0 Hz), 7.54 (td, 1H, J=3.0 and 9.0 Hz), 7.34 (s, 1H), 7.20-7.15 (m, 2H), 6.80 (d, 1H, J=8.1 Hz), 5.38-5.31 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.49 (dd, 1H, J=11.1 and 16.5 Hz); LCMS: purity: 99%; MS (m/e): 446 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[N:14][CH:15]=[C:8]1[C:7](=[O:23])[NH:6]2)[CH3:2].Cl>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[N:14][CH:15]=[C:8]1[C:7](=[O:23])[NH:6]2)[CH3:2]
Reactant: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(CC)ccc3n12
Agent: Cl
Solvent: CCO
Product: CCc1ccc2c(c1)[nH]c(=O)c1cnc(CCC(=O)O)n12

Procedure:
To a mixture of ethyl 3-(7-ethyl-4-oxo-4,5-dihydroimidazo-[1,5-a]-quinoxalin-1-yl)propanoate as synthesized in above Example 184, 50 mg and ethanol 3 mL, 1N sodium hydroxide solution 1.2 mL was added and heated under reflux for 2 hours. The reaction liquid was allowed to cool off, and to which 1N hydrochloric acid 1.2 mL was added. The precipitated crystals were recovered by filtration, washed with water and dried in flowing air to provide 37 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[C:6]([O:8][CH3:9])[CH:7]=1.[N+:22]([O-])([OH:24])=[O:23].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Cl)ccc1OCc1c(OC)ccc(F)c1F
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F

Procedure:
To a suspension of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)anisole (8.6 g) in acetic anhydride (54 mL) was added 60% nitric acid (2.9 mL) in a dropwise manner under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture was added water (54 mL) in a dropwise manner, and the resulting mixture was stirred under ice-cooling for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and a mixed solvent (n-hexane/ethanol=4/1), and dried under reduced pressure to give the title compound (9.41 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[C:5]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]1([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[CH:9]([N:7]1[CH2:8][CH:4]([CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][C:31]([OH:37])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:32][CH2:33]2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:12])([CH3:11])[CH3:10]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)N1CC(CCCl)C(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)N1CC(CCN2CCC(O)(c3ccccc3)CC2)C(c2ccccc2)(c2ccccc2)C1=O
Product: Cl

Procedure:
A stirred mixture of 26.5 g. (0.078 mole) of 4-(2-chloroethyl)-1-isopropyl-3,3-diphenyl-2-pyrrolidinone, 14 g. (0.078 mole) of 4-phenyl-4-piperidinol and 27 g. of potassium carbonate was refluxed for 18 hrs. The mixture was cooled, filtered and the filtrate was evaporated to an oil. The crude product was dissolved in ether and treated with ethereal hydrogen chloride. After recrystallization from isopropanol the product melted at 130°-132° C. (31.5 g.; 77%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:19]
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCOC(=O)CNCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-aminomethylnaphthalene (2.15 g, 13.6 mmol) and TEA (1.65 g, 16.3 mmol) in CH2Cl2 (50 mL) is treated with ethyl bromoacetate (2.28 g, 13.6 mmol) dropwise over 90 min. The mixture is stirred at RT for 3 h and washed with water. The organic layer is dried over anhydrous MgSO4 and concentrated. The residue is flash chromatographed on silica gel using CH2Cl2→1% MeOH in CH2Cl2 as the eluent to afford N-(1-naphthyl-methyl)-glycine ethyl ester as a yellow oil: [M+1]+=244.
Reaction SMILES: [C:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)#[N:2].[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1(CN)CC1
Temperature: 40 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution in ethanol (127 mL) of the compound (14.0 g) obtained in step (1) above, a Raney nickel catalyst (about 2.8 g) was added. In a hydrogen atmosphere, the mixture was stirred at room temperature for 12 hours and further stirred at 40° C. for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting precipitate was recovered by filtration and washed with ethanol. The filtrate was concentrated to give the titled compound as a red oil (13.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Li].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C[Mg]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH:15]([OH:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: N#CCc1ccc(Cl)cc1
Agent: C[Mg]I
Agent: [Li]C
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2)CC(O)C1
Temperature: -78 °C

Procedure:
(4-Chlorophenyl)acetonitrile (1-1) (14.04 g) was dissolved in freshly distilled tetrahydrofuran (250 mL) and stirred at −78° C. under argon. Methyl lithium (LiBr complex, 1.5 M in diethyl ether, 62 mL, 1 eq) was added dropwise such that the reaction temperature stayed below −66° C. The solution was stirred for one h at −78° C. and turned from yellow to deep red. Epibromohydrin was added dropwise and the solution was stirred for an additional 90 min. Methylmagnesium iodide (3.0 M in diethyl ether, 31 mL) was added and the solution turned light brown as it was slowly warmed to room temperature and stirred overnight. The reaction was quenched with water (75 mL) and acidified to pH 2 with 5 N aqueous hydrochloric acid (ca. 30 mL). Brine was added until the layers separated. The organic layer was collected and the aqueous layer was reextracted with diethyl ether (2×50 mL). The organic layers were combined, dried with magnesium sulfate, filtered and concentrated to give crude 1-(4-chlorophenyl)-3-hydroxycyclobutane-1-carbonitrile (1-2).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH2:2][CH2:3][CH3:4].[NH3:12].C(O)(=O)C.[C:17]1(=O)[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1>CO>[CH2:10]([O:9][C:7]([C:6]1[C:18]2[C:17](=[CH:22][CH:21]=[C:20]([OH:23])[CH:19]=2)[NH:12][C:1]=1[CH2:2][CH2:3][CH3:4])=[O:8])[CH3:11]
Reactant: N
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=C1C=CC(=O)C=C1
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1[nH]c2ccc(O)cc2c1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 6 %

Procedure:
Through a solution of ethyl butyrylacetate (23 g, 0.145 mol) in methanol (200 mL) was bubbled ammonia at 5° C. for 15 minutes and then stirred at room temperature for 24 hours. The reaction mixture was concentrated to about 20 mL. Acetic acid (150 mL) and 1,4-benzoquinone (15.7 g, 0.145 mol) was added to the reaction mixture and it was stirred for 3 hours at room temperature. The suspension that formed was filtered, washed with CH2Cl2 (2×50 mL), and the solid residue was dried in a vacuum oven at 50° C. for 24 hours to give the desired product (2.2 g, 6%). MS: 248.1 (M+1+).