Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P([O-])([O-])([O-])=O.CCOCC>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
To Carbobenzyloxy-L-proline (Aldrich, 9.80 g, 39.3 mmol)in THF (100 mL) at 0° C. was added BH3 -THF complex (Aldrich, 1M in THF, 100 mL, 100 mmol). The mixture was stirred at 0° C. for 2 hours, then at ambient temperature for 16 hr. The reaction mixture was poured into pH 7 phosphate buffer solution (500 mL) and ether (600 mL) and mixed well. The layers were separated and the aqueous portion was extracted with ether (500 mL). The combined organic layers were washed with brine (500 mL),dried (Na2SO4) and filtered. The solvents were evaporated in vacuo leaving the crude carbobenzyloxy-L-prolinol as an oil (10.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]=[O:38])[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(=CC)C.Cl([O-])=[O:47].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][C:37]([OH:47])=[O:38])[C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC=O)C(=O)c3ccc(OC)cc3)cc2)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC(=O)O)C(=O)c3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirring solution of 4-((4-methoxy-N-(4-oxobutyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-8 (264 mg, 0.484 mmol) in tert-butanol (12 mL) was added 2-methylbut-2-ene (4.7 ml, 44.4 mmol). A solution of sodium chlorite (400 mg, 4.42 mmol) and sodium dihydrogen phosphate (400 mg, 3.33 mmol) in H2O (2.5 mL) were added and the reaction stirred for 1 h at room temperature. The reaction was quenched with aq. Na2S2O5 (10 mL) and brine (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to provide 150 mg (55%) of 4-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-methoxybenzamido)butanoic acid 88. LCMS-ESI (m/z) calculated for C33H39NO7: 561; found 560 [M−H]−, tR=9.53 min (Method 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[S:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:23][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:13]2[S:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:17]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cnc(-c2cccn2C(=O)OC(C)(C)C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2ccc(Br)n2C(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 19 h
Yield: 60.1 %

Procedure:
Ethyl 2-[1-(t-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-thiazole-5-carboxylate (800 mg, 2.48 mmol) synthesized in Example (5a) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (442 mg, 2.48 mmol) was added with stirring under nitrogen atmosphere, and subsequently stirring was carried out at room temperature for 19 hours. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (598 mg, yield 60%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(OC([N:16]1[CH2:21][CH2:20][C:19]2([CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:24]2[CH2:25][CH2:26][C:19]3([CH2:20][CH2:21][NH:16][CH2:17][CH2:18]3)[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: Oc1ccc(Cl)cc1
Product: Clc1ccc(OC2CCC3(CCNCC3)CC2)cc1

Procedure:
Was prepared according to method A from 4-chlorophenol and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. Mp. 140-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1Nc1cc(Cl)ncn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1Nc1ccncn1
Yield: 93.4 %

Procedure:
10% Palladium-on-carbon (0.02 g) was added to a mixture of 4-[2-methyl-5-(3-morpholinobenzamido)anilino]-6-chloropyrimidine (0.169 g), ammonium formate (0.165 g) and ethanol (5 ml) and the resultant mixture was stirred and heated to reflux for 18 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water and the organic phase was washed with brine, dried over sodium sulphate and evaporated. There was thus obtained the title compound (0.145 g); NMR Spectrum: (DMSOd6) 2.23 (s, 3H), 3.24 (m, 4H), 3.83 (m, 4H), 6.68 (m, 1H), 7.2 (m, 1H), 7.3 (m, 1H), 7.43 (m, 2H), 7.5 (m, 1H), 7.61 (m, 1H), 7.88 (m, 1H), 8.28 (m, 1H), 8.57 (s, 1H), 9.06 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:20])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
6-Amino-9-benzyl-2-methylaminopurine (75 mg, 0.30 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent of the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (73 mg, yield 74%).
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=[N+:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O-:6]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1cc([N+](=O)[O-])ccc1O
Yield: 75.1 %

Procedure:
A mixture of tert-butylhyroxylamine (10.5 g, 120 mmol), 2-hydroxy-5-nitrobenzaldehyde (15 g, 90 mmol) and p-toluenesulfonic acid (1.6 g, 9 mmol) in benzene (375 mL) was refluxed in a flask fitted with a Dean-Stark trap until no more aldehyde was detectable by TLC. The mixture was cooled and the resulting suspension was filtered. The title compound was isolated in 75.1% yield as a pale yellow solid, m.p. 172° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([O:22][CH2:23][CH2:24][C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[CH:19]=[C:18]([O:30][CH:31]([CH3:33])[CH3:32])[CH:17]=2)=[N:12][CH:13]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([O:22][CH2:23][CH2:24][C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[CH:19]=[C:18]([O:30][CH:31]([CH3:32])[CH3:33])[CH:17]=2)=[N:12][CH:13]=1
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(C(C)(C)O[SiH2]C(C)(C)C)cn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CO)cn2)c1
Temperature: 0 °C
Yield: 74.7 %

Procedure:
N-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (1.25 g, 2.37 mmol) was dissolved in THF (12 mL) and cooled to 0° C. Tetrabutylammonium fluoride (1.0 M solution in THF, 3.08 mL, 3.08 mmol) was added dropwise and the mixture was allowed to warm to rt over 24 hours. The reaction mixture was concentrated under reduced pressure and partitioned in EtOAc (30 mL) and water (30 mL). The organic layer was rinsed with water (20 mL), and then a saturated sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated to yellow oil. After chromatography on silica gel with a gradient from 15-100% ethyl acetate-hexanes, N-(5-hydroxymethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (0.73 g, 74.9% yield) was obtained as a colorless oil. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.30 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.75 (d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 5.25 (t, 1H), 4.70 (m, 1H), 4.50 (d, J=3.0 Hz, 2H), 4.25 (t, 2H), 3.05 (t, 2H). 1.25 (s, 6H); LCMS (m/z): 413.1 [C22H24N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:16][CH2:17][CH2:18]OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(NCCOCc2ccccc2)cc1
Reaction time: 24 h
Yield: 33.1 %

Procedure:
p-Chloroaniline (8 g), methanesulfonic acid 2-benzyloxyethyl ester (12.29 g) and sodium hydrogen carbonate (hereinafter, reffered to as sodium bicarbonate) (8.97 g) were dissolved in dioxane (35 ml), suspended and the mixture was heated with stirring for 24 hours. After concentrated under reduced pressure, water and ethyl acetate were added to the mixture and the mixture was separated into layers. The organic layer was washed with water 2 times, and concentrated again under reduced pressure, and the resulting rsidue was subjected to column chromatography on silica gel, and eluted with chloroform/n-hexane [2:1 (v/v)] to give 4-chloro-N-(2-benzyloxyethyl)aniline (4.63 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[N:36](C2N=C3C(N=C(OC4CCNCC4)N3C)=C(N3CCOCC3)N=2)[C:35]2[CH:60]=[CH:61][CH:62]=[CH:63][C:34]=2[N:33]=1)[CH3:31].FC(F)(F)C(O)=O>>[NH:15]1[CH2:16][CH:13]([O:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=[C:2]([N:33]2[C:34]4[CH:63]=[CH:62][CH:61]=[CH:60][C:35]=4[N:36]=[C:32]2[CH2:30][CH3:31])[N:10]=3)[CH2:14]1
Reactant: Cn1c(OC2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CCNCC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CNC3)n(C)c2n1

Procedure:
The compound was prepared from tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yloxy)azetidine-1-carboxylate in a similar manner as that of 4-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-(piperidin-4-yloxy)-9H-purin-6-yl)morpholine, following General Procedures of Buchwald coupling shown in Scheme 3 and Boc-deprotection. The compound was used either as a mixture with unknown equivalent of trifluoroacetic acid or as a free base after treatment with aqueous base. Free base: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.9 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 5.66-5.54 (m, 1H), 4.22 (s, 4H), 4.08-3.99 (m, 2H), 3.94-3.79 (m, 6H), 3.63 (s, 3H), 3.40-3.25 (m, 3H), 1.43 (t, J=7.5 Hz, 3H). LCMS: M+H+=435.2.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH3:30])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OC3CCN(C(C)C)CC3)ccc21

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-methoxyphenylboronic acid. The title compound was obtained in 7% yield as yellow oil. MS (m/e): 512.3 (MH+, 100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9]/[C:10](=[N:25]/[S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(/CO[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Yield: 48.6 %

Procedure:
To a mixture of 58a (11.3 g, 42.1 mmol) and (R)-2-methylpropane-2-sulfinamide (6.60 g, 54.7 mmol) in THF (200 mL) at RT was added Ti(Oi-Pr)4 (29.9 g, 105 mmol). The reaction mixture was heated to reflux under N2 overnight. The mixture was cooled then treated with saturated NH4Cl (5.0 mL), and the insoluble material was filtered. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc gradient (60:1 to 20:1) to afford 7.6 g (49%) of (R,E)-N-(2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (58b) as yellow oil. LCMS (ESI) m/z: 372.2 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37].C[O-].[Na+]>CCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 63.4 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (83 mg, 0.36 mmol) and NaOMe (39 mg, 0.72 mmol) in 2 mL of EtOH was heated at 150° C. for 3 h in a CEM microwave reactor. The solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-40% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 24 mg of the title compound. MS: (+) m/z 421.02 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:27]=[CH2:28])[CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:2]([F:14])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([P:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH:27]=[CH2:28])[CH:18]=2)(=[O:13])[O:10][CH2:11][CH3:12])=[CH:7][CH:8]=1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Reactant: CCO[PH](=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1cc(P(=O)(OCC)c2ccc(C(F)(F)F)cc2)ccc1OC(C)C
Temperature: 70 °C
Yield: 8.6 %

Procedure:
To a degassed solution of ethyl 4-(trifluoromethyl)-phenylphosphinate (1.00 g, 4.20 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (921 mg, 3.81 mmol) in DMF (40 mL) were added the triethylamine (1.1 mL, 7.62 mmol) and tris(dibenzylideneacetone)dipalladium (698 mg, 0.762 mmol). The mixture was warmed at 70° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography using 5 to 100% ethyl acetate in petroleum ether to afford compound BA1 (130 mg) as a dark green oil in 8.6% yield.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[Cl:25])=[CH:22][CH:21]=[CH:20][CH:19]=2>ClCCl>[Cl:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyryl chloride (3.77 mL, 1.3 eq) and triethylamine (5.85 mL, 1.3 eq) were added sequentially to a chilled (0° C.) solution of 3-amino-4-chloroquinoline (5.0 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was warmed to ambient temperature and then allowed to stir overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 6.5 g of N-(4-chloroquinolin-3-yl)butyramide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][NH2:10])[CH2:3][CH2:2]1.[NH2:11][C:12]1[N:13]=[C:14]([CH3:31])[C:15]2[C:21](=S)[NH:20][C@@H:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Br:30])[CH2:18][C:16]=2[N:17]=1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]/[N:10]=[C:21]2\[NH:20][C@@H:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Br:30])[CH2:18][C:16]3[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([CH3:31])[C:15]\2=3)[CH2:3][CH2:2]1
Reactant: NOCCN1CCOCC1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OCCN1CCOCC1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of O-(2-morpholinoethyl)hydroxylamine (600 mg, 4.1 mmol) in anhydrous toluene (6 mL) was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (0.150 g, 0.41 mmol) and mercuric acetate (II) (262 mg, 0.82 mmol). The resultant mixture was heated to 100° C. for 1 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a yellow-green oil, which was purified by preparative HPLC eluting with TFA/ACN/H2O. The fractions were concentrated to provide (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-morpholinoethyl oxime (196 mg, 0.41 mmol). [M+H] calc'd for C20H24BrFN6O2, 480. found, 480.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (276 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (420 mg, 82%).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.C(N(CC)CC)C.[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](Cl)=[O:42])[CH3:39]>O1CCCC1>[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](=[O:42])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)[CH3:39]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 100 °C

Procedure:
A mixture of dehydro-aripiprazole (1.50 g, 3.36 mmol), triethylamine (1.03 mL, 7.39 mmol), diethyl carbamoyl chloride (1.02 mL) were combined in tetrahydrofuran (30 mL). This was then heated to 100° C. for 6 hours by microwave. The reaction was quenched with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatrography on silica eluting with ethyl acetate to 20% tetrahydrofuran/ethyl acetate to give the product. The product was then triturated with heptane to remove aliphatic impurities and then dried to give Compound-334 (1.54 g) as a light brown oil.