Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23]3)[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2.[H-].[Na+].[CH3:38]I.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C@@H:22]3[CH2:26][CH2:25][C:24](=[O:27])[N:23]3[CH3:38])[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(CC3CCC(=O)N3)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1CN[C@H]1CCCN(C[C@@H]3CCC(=O)N3C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
To 6-Methoxy-1-methyl-7-{[1-(5-oxo-pyrrolidin-2-ylmethyl)-(2S,3S)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one (194 mg, 0.408 mmol) in 5 mL of THF at room temperature was added 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil and stirred for 20 minutes. Methyl iodide (0.028 mL, 0.448 mmol) was then added and stirred for 1 hour 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil was added and stirred overnight. A small amount of water was added and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed twice with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (95:5 ethyl acetate/methanol) as the eluent gave 25 mg (13%) of the title compound, a pale yellow oil. Rf=0.07 (9:1 ethyl acetate/methanol). MS (M+H)+=491.2; 1H NMR (400 MHz, CDCl3): δ 1.42–1.60 (m, 3H), 1.84–1.88 (dd, J=13.4 Hz, 4.8 Hz, 1H), 2.01–2.14 (m, 5H), 2.17–2.24 (m, 2H), 2.54–2.57 (t, J=7.3 Hz, 3H), 2.67–2.73 (m, 1H), 2.76–2.78 (t, J=7.3 Hz, 2H), 2.88 (s, 3H), 3.13 (s, 3H), 3.21–3.24 (d, J=10.9 Hz, 1H), 3.32–3.33 (d, J=3.0 Hz, 1H), 3.36–3.40 (d, J=14.3 Hz, 1H), 3.56 (s, 3H), 3.61–3.68 (m, 2H), 6.49 (s, 1H), 6.65 (s, 1H), 7.18–7.34 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.4, 23.9, 25.5, 27.5, 29.6, 31.8, 45.4, 54.2, 55.5, 56.3, 58.0, 59.9, 72.7, 109.9, 116.0, 127.1, 128.1, 129.0, 133.6, 140.9, 152.8, 170.0, 175.0. The dihydrochloride salt was prepared by the addition of 2 M HCl In ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].S(Cl)SCl.S(Cl)(Cl)(=O)=O.[Cl:14]C1C=CC(C(Cl)(Cl)Cl)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]([Cl:36])([Cl:35])[Cl:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:14][C:29]1[CH:30]=[C:31]([Cl:32])[C:26]([Cl:25])=[CH:27][C:28]=1[C:33]([Cl:36])([Cl:34])[Cl:35]
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1Cl
Agent: ClSSCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(=O)(Cl)Cl
Product: Clc1cc(Cl)c(C(Cl)(Cl)Cl)cc1Cl
Yield: 47 %

Procedure:
A solution of 4.6 g (34 mmol) of aluminum chloride and 4.6 g (34 mmol) of disulphur dichloride in 344 g (2.55 mol) of sulphuryl chloride was added dropwise to a mixture of 57.5 g (250 mmol) of p-chlorobenzotrichloride and 115 g (850 mmol) of sulphuryl chloride at 40° C. The reaction mixture was further processed in the manner described in Example 5, that is to say that, after the working up, unreacted p-chlorobenzotrichloride and 3,4-dichlorobenzotrichloride were separated off by distillation and fed to renewed chlorination with sulphuryl chloride under the conditions given here. By distillation of the combined sump fractions, 2,4,5-trichlorobenzotrichloride was obtained in a yield of 47% of theory.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:27])[NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19]1)[CH2:9][CH2:10][N:11]1[N:15]=[CH:14][CH:13]=[N:12]1)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[NH2:7][CH:8]([CH2:9][CH2:10][N:11]1[N:15]=[CH:14][CH:13]=[N:12]1)[C:16]([NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:27]
Reactant: CC(C)(C)OC(=O)NC(CCn1nccn1)C(=O)NC1(c2ncccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(CCn1nccn1)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the [1-(1-pyrimidin-2-yl-cyclopropyl-carbamoyl)-3-1,2,3-triazol-2-yl-propyl]-carbamic acid tert-butyl ester (143 mg, 0.37 mmol) in CH2Cl2 (5 mL) was added TFA (0.14 mL, 1.85 mmol) and the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and 106 mg of crude 2-amino-N-(1-pyrimidin-2-yl-cyclopropyl)-4-1,2,3-triazol-2-yl-butyramide trifluoroacetate. The title compound was used in subsequent reactions without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][C:27]1([CH3:48])[O:32][CH2:31][CH:30]([C:33]2[CH:34]=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:26][C:27]1([CH3:48])[O:32][CH2:31][CH:30]([C:33]2[CH:38]=[C:37]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=3)[CH:36]=[N:35][CH:34]=2)[CH2:29][O:28]1
Reactant: CC1(C)OCC(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CO1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)CO1
Temperature: 90 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (80 mg, 0.23 mmol) in 1,4-dioxane (6 mL) and H2O (0.5 mL) under nitrogen was added 3-(2,2-dimethyl-1,3-dioxan-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.35 mmol), and potassium carbonate (96 mg, 7.0 mmol). The mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (12 mg, 0.015 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 90° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography using 20% EtOAc in hexanes to provide 2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (45 mg, 39%). LCMS Method T: retention time 1.75 min; [M+1]=504.2.
Reaction SMILES: C([NH:4][C:5]1[N:10]([O:11]C(=O)C)[C:9](=[NH:15])[N:8]=[C:7](Cl)[CH:6]=1)(=O)C.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[NH2:4][C:5]1[N:10]([OH:11])[C:9](=[NH:15])[N:8]=[C:7]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1
Reactant: CC(=O)Nc1cc(Cl)nc(=N)n1OC(C)=O
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Reaction time: 1 h
Yield: 80 %

Procedure:
After adding 0.49 g (2 mmoles) of 6-acetamido-1-acetoxy-4-chloro-1,2-dihydro-2-iminopyrimidine to a solution containing 10 ml of chloroform and 2 ml of piperidine, the mixture is refluxed for 30 minutes, then evaporated under reduced pressure. The residue is dissolved in the mixture of 10 ml of ethanol and 3 ml of 1N aqueous sodium hydroxide solution. The reaction mixture is left to stand at room temperature for one hour and then again evaporated under reduced pressure. After taking up the residue in 10 ml of water, the crystals are filtered, washed with water and dried to give 0.34 g (80% yield) of the aimed compound which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:13](=O)[CH2:14][CH3:15].C([BH3-])#N.[Na+]>CO>[CH3:12][N:8]1[C:7]2[C:2]([NH:1][CH2:13][CH2:14][CH3:15])=[CH:3][CH:4]=[CH:5][C:6]=2[NH:10][C:9]1=[O:11]
Reactant: CCC=O
Reactant: Cn1c(=O)[nH]c2cccc(N)c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNc1cccc2[nH]c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.4 %

Procedure:
To 0.87 g (5.3 mmol) of 7-amino-1-methyl-1,3-dihydro-2H-benzoimidazol-2-one in 50 mL of methanol was added 1.94 mL (26.7 mmol) of propionaldehyde and 1.0 g (16 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 5 h and concentrated in vacuo. The crude solid was partitioned between water and ethyl acetate, the biphasic mixture was filtered to remove particulates and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with a 50% ethyl acetate/hexanes mixture to give 0.69 g (63%) of the title compound as a cream colored powder.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]4[C:34](=[O:35])[C:33](=[O:36])[C:32]=4OC(C)C)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(O)(=O)C>CO>[C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]4[C:34](=[O:35])[C:33](=[O:36])[C:32]=4[N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: COC(=O)[C@H](Cc1ccc(Nc2nc(-c3ccccc3)cc3ccccc23)cc1)Nc1c(OC(C)C)c(=O)c1=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(Nc2nc(-c3ccccc3)cc3ccccc23)cc1)Nc1c(N2CCOCC2)c(=O)c1=O

Procedure:
A solution of methyl (S)-3-[4-(3-phenyl-1-isoquinolinylamino)phenyl]-2-(2-isopropoxy-3,4-dioxocyclobut-1-enylamino)propanoate (20 mg, 0.08 mmol) [prepared in a similar manner to the compound of Example 1]in MeOH (0.2 ml) was treated with morpholine (0.011 ml, 0.12 mmol) and the resulting mixture heated at 60° for 24 h. The mixture was concentrated to dryness then redissolved in anhydrous THF (1.0 ml) and treated with polystyrene methylisocyanate resin (Argonaut Technologies, 120 mg, 2.0 mmol/g, 0.24 mmol) at room temperature for 24 h. The resulting mixture was filtered, and the resin was washed with MeOH(1.0 ml). The combined filtrate was evaporated to dryness then redissolved in THF (0.2 ml) and treated with an aqueous solution of lithium hydroxide monohydrate (0.2 ml of a solution of 100 mg in 4.0 ml water, 0.12 mmol) at room temperature for 24 h. The reaction mixture was quenched with glacial acetic acid (0.007 ml, 0.12 mmol), then evaporated to dryness to give the crude product which was purified by preparative HPLC to afford the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([NH:32][C:33]([NH2:35])=[O:34])[C:30]#[CH:31]>CO>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][NH:32][C:33]([NH2:35])=[O:34])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCNC(N)=O
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: CO
Product: Cc1ccc(-n2cc(CNC(N)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.15 mmol) and prop-2-ynyl-urea (0.30 mmol). The crude product was purified by flash chromatography using EtOAc as the eluent to afford a solid. Trituration in MeOH gave the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(CC(=O)[O-])c1-c1ccccc1
Reactant: CCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-6-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated under reduced pressure and crystallized to give ethyl 2-amino-6-biphenylacetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:23]([CH2:30][CH3:31])[CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:20])[NH:13][C:14]([CH3:19])=[CH:15][C:16]=1[CH2:17][OH:18])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.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>[CH2:30]([N:23]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:4]1[C:5]([CH3:22])=[C:6]([C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:20])[NH:13][C:14]([CH3:19])=[CH:15][C:16]=2[CH2:17][OH:18])=[O:8])[CH:21]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=1)[CH3:31]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(CO)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(CO)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
To a stirred solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (250 mg, 0.5 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (230 mg, 7.6 mmol) in dioxane (5 mL), aqueous 2M Na2CO3 solution (0.9 mL, 1.8 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (57 mg, 0.05 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (60 mg, 25%). LCMS: 589.35 (M+1)+; HPLC: 95.58% (@ 254 nm) (Rt; 3.524; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.22 (t, 1H), 7.57 (d, 2H, J=7.6 Hz), 7.38 (d, 2H, J=5.6 Hz), 7.36 (s, 1H), 7.21 (s, 1H), 6.16 (s, 1H), 5.28 (m, 1H), 4.52 (d, 2H, J=4.8 Hz), 4.25 (d, 2H, J=3.6 Hz), 3.81-3.83 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.01-3.09 (m, 3H), 2.36 (m, 4H), 2.23 (s, 3H), 2.15 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 1.23 (m, 2H), 0.82 (t, 3H, J=6.4 Hz).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[BH4-].[Na+].Cl>C1COCC1.C(O)C>[CH3:16][N:12]1[C:11]2[CH2:10][CH2:9][N:8]3[CH:4]([C:15]=2[CH:14]=[CH:13]1)[CH2:3][CH2:2][C:1]3=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: Cn1cccc1CCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc2c1CCN1C(=O)CCC21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A mixture of 110.9 g (1.098 mole) of succinic anhydride and 985 ml of THF was cooled to 10° C. and a solution of 140.53 g (1.098 mole) of 2-(2-aminoethyl)-1-methylpyrrole in 1400 ml of THF was added dropwise over a period of thirty minutes while stirring under an atmosphere of argon, the temperature being maintained at 10 to 15° C. After the addition was complete, stirring was continued an additional one hour and then the solvent removed in vacuo to give a dark-brown, oily residue. The residue was stirred and heated at 175° in an oil bath for three hours under an atmosphere of argon. The residue was distilled on a Kugelrohr apparatus, collecting the product imide at 170° C./0.06 mm, which crystallized to yield an off white solid, mp 116°-121° C. A small sample of the intermediate imide was recrystallized from ethanol to yield a white solid, mp 120°-122° C. A solution of 100 g (0.485 mole) of the above-obtained crude imide was added to 3-1 of 90% aqueous ethanol and the mixture cooled in an ice bath to about 3° C. Sodium borohydride (68.42 g; 1.81 moles) was added and about 25 ml of 2N hydrochloric acid was added dropwise with stirring over a five hour period by means of a metering pump while maintaining a temperature of 0° to 3° C. After the addition was complete (pH=8-9), the reaction was acidified with 1-1 of 2N hydrochloric acid over a period of 1.5 hours while maintaining a temperature of less than 10° C. Stirring (under nitrogen) was continued overnight as the temperature was allowed to gradually warm to ambient, during which time the mixture became a clear, colorless solution. The solvent was partially removed in vacuo using low heat to a final volume of about 800 mls, diluted with 800 mls of water and extracted three times with 300 ml portions of methylene chloride. The combined extracts were washed with 300 ml of water, 300 ml of brine, and dried over anhydrous potassium carbonate. The solvent was removed in vacuo to give 31.07 g of a crude tan solid. The crude solid was recrystallized from about 100 ml of hot EtOAc to give 23.76 g of nearly pure 4,5,7,8,9,9a-hexahydro-3-methyl-3H-pyrrolo[2,3-g]indolizin-7-one, an off-white solid, mp 122°-125° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:3]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C=O)C>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CNC
Reactant: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2cc(N(C)C)nc(N)n2)cc1
Temperature: 170 °C
Yield: 38.5 %

Procedure:
A mixture of 6-chloro-N4-(4-methylphenyl)-2,4-pyrimidinediamine (1.5 g, 6.4 mmol), and N,N-dimethylamine hydrochloride (0.56 g, 7 mmol) and triethylamine (1.4 g, 14 mmol) in DMF (2 mL), was heated at 170° C. for 16 h. The product was filtered out and the organic layer was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (0.6 g, 40%).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18](OCC)=[O:19])=[C:7]2[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].[H-].[Na+].C(O)(=O)C>O1CCCC1>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18](=[O:19])[CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:7]2[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12

Procedure:
To a stirred mixture of ethyl 5-tert-butyl-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline-3-carboxylate (1.6 g, 5 mmol) and pinacolone (1.25 ml, 10 mmol) in dry tetrahydrofuran (THF) (30 ml) was added sodium hydride (200 mg, 80% in mineral oil, 6.9 mmol). The mixture was brought to reflux for 2 h, then cooled to room temperature and neutralized with acetic acid. After evaporation of the solvent the residue was partitioned between sat. aqueous NaHCO3 (10 ml) and methylene chloride (30 ml). The organic phase was dried over Na2SO4 and evaporated to give the title compound as yellow crystals. M.p. 190°-191 ° C. (Compound 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Br[C:16]1[CH:17]=[N:18][C:19]([C:22]([O:24]C)=[O:23])=[N:20][CH:21]=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[CH:17]=[N:18][C:19]([C:22]([OH:24])=[O:23])=[N:20][CH:21]=1)[CH:6]=[CH:5]2
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Reactant: COC(=O)c1ncc(Br)cn1
Product: O=C(O)c1ncc(-c2ccc3cc(O)ccc3c2)cn1

Procedure:
Followed the two step procedure described for Example 7 starting from 6-hydroxynaphthalen-2-yl boronic acid and methyl 5-bromopyrimidine-2-carboxylate. 1H-NMR (DMSO-d6 500 MHz): 9.39 (s, 2H), 8.38 (s, 1H), 7.87-7.91 (t, J=8.5, 12.0 Hz, 3H), 7.17-7.20 (t, J=5.5, 10.5 Hz, 2H). MS (ESI): m/z=267.0 [M+1]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]1[C:24]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:33])[N:22]=[C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:20]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:19]1[C:24]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:33])[N:22]=[C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:20]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCc2ccccc2C1
Temperature: 100 °C
Yield: 93.4 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (0.190 mL, 1.5 mmol) and triethylamine (0.277 mL; 2 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL) and heated in a sealed tube to 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.194 g (93%) of the title compound.