Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 85 °C
Yield: 64 %

Procedure:
A mixture of tert-butyl (1R,2S)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (60 mg, 0.109 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.164 mmol) and bis(triphenylphosphine)palladium chloride (15 mg, 0.022 mmol) in DME (1 mL) was placed in a vial. The vial was purged with nitrogen and aqueous sodium carbonate (2 N, 0.219 mL, 0.437 mmol) was added. The vial was sealed and the reaction mixture heated in an oil bath at 85° C. for 3 h. The reaction mixture was filtered through a pad of Celite, which was rinsed with MeOH and DCM. The solvent was removed in vacuo and the residue was diluted with DMSO and MeOH (1/1). The resulting mixture was filtered to recover a white precipitate (31.3 mg). The mother liquor was purified via preparative HPLC. The fractions were collected and dried in vacuo to recover an additional white solid (10.2 mg). The two crops were combined to give the title compound as a white solid (41.5 mg, 64%). [M+H] calc'd for C31H39FN6O5, 595. found, 595.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(CN)CO
Solvent: C1CCOC1
Product: CC(C)(CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
50.0 g of N-(benzyloxycarbonyloxy)succinimide (200 mmol) was added to a solution of 13.8 g of 3-amino-2,2-dimethylpropanol (134 mmol) in tetrahydrofuran (140 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/ethyl acetate=9/1-3/1) to obtain 29.52 g of the title compound (yield: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[C-:11]#[N:12].[K+]>O1CCOCC1.O.CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: N#CCc1cc(F)cc(Br)c1

Procedure:
To a solution of 3-bromo-5-fluorobenzyl bromide (3.2 g, 0.0112 mole) in 1,4-dioxane (20 mL) was added a solution of KCN (0.82 g, 0.013 mole) in H2O (5 mL) and EtOH (5 mL), refluxed for 2 hours, and extracted with ether, washed with brine, dried over MgSO4, and concentrated. Column chromatography was performed using hexane/ethyl acetate (19:1). 3-Bromo-5-fluorophenylacetonitrile was obtained was a colorless oil: 1H NMR (DMSO-d6) δ4.15 (s, 2H), 7.29 (d, 1H, J=9.37 Hz), 7.47 (s, 1H), 7.55 (d, 1H, J=8.45 Hz); MS(EI) M+m/z 213; Anal. Calc. For C8H5BrFN: C, 44.89; H, 2.35; N, 6.54. Found: C, 44.88; H, 2.32; N, 6.46.
Reaction SMILES: [C:1](=[O:18])([O:12][CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)OC1C=CC([N+]([O-])=O)=CC=1.Cl.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]3[CH:42]=[C:41]4[C:36]([CH2:37][CH2:38][NH:39][CH2:40]4)=[CH:35][CH:34]=3)[N:30]=[C:29]([NH2:43])[N:28]=2)[CH2:23][CH2:22]1>>[NH2:43][C:29]1[N:30]=[C:31]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][N:39]([C:1]([O:12][CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)=[O:18])[CH2:40]3)=[CH:35][CH:34]=2)[CH:32]=[C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]2)[N:28]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCOC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 2 starting from 4-nitrophenyl tetrahydrofuran-3-yl carbonate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=439.4.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[N:9][C:10]=2O)[N:5]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:4]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:9]=[C:8]([CH3:13])[N:7]=[C:6]2[N:5]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[N:4]=[C:3]([S:2][CH3:1])[C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(O)c12
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A mixture of 3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol (3.700 g, 9.85 mmol) and phosphorous oxychloride (18.115 g, 11 ml) was heated at reflux for 4 hours. The mixture was cooled and poured over ice-water and stirred for 10 minutes. Precipitate formed and was filtered to give a brown solid. The brown solid was pumped in vacuo to give 3.718 g (96% yield). 1H NMR (CDCl3): 2.65(s,3H),2.7(s,3H), 7.5(s,2H)ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].CC(C)([O-])C.[K+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(O)(C)(C)C>[CH:22]1([C:2]2([CH3:1])[CH2:10][C:9]3[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=3)[C:3]2=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Reactant: BrC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 1 h

Procedure:
A solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (7.35 g., 0.03 mole) in tert.-butyl alcohol (100 ml.) is refluxed in an inert atmosphere and treated with potassium tert.-butoxide (4.48 G., 0.04 mole). After one-half hour at reflux cyclopentyl bromide (9.9 g., 0.06 mole) is added and refluxing is continued for 1 hour. The reaction is poured into water (1 l.) affording 2-cyclopentyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone which melts at 109°-111° C.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([F:4])=[CH:6][CH:7]=1)[CH3:3]
Reactant: CCI
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1ccc(F)cc1
Reaction time: 18.5 h

Procedure:
Iodoethane (3.6 ml) was added to a mixture of 4-fluoroaniline (4.26 ml) and potassium carbonate (6.9 g) in dry DMF (100 ml). After 18.5 h at 23°, the resulting suspension was poured into water (400 ml) and extracted with EA (400 ml). The organic extract was washed with water (200 ml) then saturated brine (200 ml), dried and evaporated. The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent to give the title compound (3.667 g) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3ccncc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M61) (0.27 g, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (133 mg, 64%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[ClH:27].C(O)(=[O:30])C>>[ClH:27].[NH2:12][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1)[CH2:9][C@@H:10]([CH3:20])[C:11]([OH:19])=[O:30]
Reactant: CC(=O)O
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O

Procedure:
5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one of example 6 were mixed with a mixture of acetic acid and concentrated hydrochloric acid (50 ml ratio 1:1) and stirred under reflux for about 20 hours. The solution was then concentrated under vacuum and the residue crystallised from acetic acid/ethyl acetate to yield 4.7 g of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride (3-a, R1=R2=R3=H). 1H-NMR (DMSO): 1.10 (3H, s, CH3); 1.58 (1H, m, 3-CHH); 1.88 (1H, m, CHH); 2.64 (1H, m, 4-CH); 2.88 (1H, dd, 5-CHH); 3.01 (1H, dd, 5-CHH); 3.45 (1H, m, 2-CH); 7.38 (3H, m, aromatic); 7.47 (2H, m, aromatic); 7.66 (4H, m, aromatic); 8.07 (2H, s, NH); 12.25 (1H, s, CO2H). m/z: 284 (MH+, 100%); 267 (25); 249 (47); 221 (13); 193 (24).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CC#N>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]([OH:9])([CH3:8])[CH3:7])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(O)C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Yield: 50.9 %

Procedure:
2-Pyrrolidin-2-yl-propan-2-ol (100 mg, 0.78 mmol) is dissolved in CH3CN (5 mL) to which K2CO3 (300 mg, 2.17 mmol) and p-nitrobenzylbromide (250 mg, 1.16 mmol) were added. The resulting mixture is stirred until MS suggested no starting alcohol is present. The suspension is filtered to remove the potassium salts and the acetonitrile is removed under vacuum. The residue is purified to afford the product (105 mg, 51%). 1H NMR (300 MHz, CDCl3) 8.18 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 4.25 (1H, d, J=15 Hz), 3.72 (1H, d, J=15 Hz), 2.90-2.95 (1H, m), 2.76-2.80 (1H, m), 2.28-2.38 (2H, m), 1.71-1.91 (4H, m), 1.24 (3H, s), 1.20 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:7][CH:6]=3)[C:9]([CH3:33])=[N:10][C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.0 g) and methyl 2-bromopropanoate (2.50 g) in N,N-dimethylformamide (20 mL) was added cesium carbonate (3.0 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.12 g, 89%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[C:9]1([C:15](=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C(=Cc1cccnc1)c1ccccc1
Yield: 30.2 %

Procedure:
To a mixture of 4.3 g of 3-pyridinecarbaldehyde, 5.4 g of phenylacetic acid, and 11.4 ml of acetic anhydride, 5.6 g of triethylamine is added with stirring, and the mixture is stirred at 100° C. for 4 hours. The reaction mixture is alkalified with 10% aqueous sodium bicarbonate solution. The aqueous solution is warmed and filtered. The filtrate is adjusted to pH 4.5 with 10% hydrochloric acid, and the resulting precipitate is collected and recrystallized from ethanol to give 2.7 g of the title compound, m.p. 190°-192° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[CH2:17]Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([Br:27])=[C:25]([CH3:28])[CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20]=[C:21]2[C:26]([Br:27])=[C:25]([CH3:28])[CH:24]=[CH:23][N:22]2[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(N)c1Br
Reactant: O=C(CBr)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: Cc1ccn2cc([C@@H]3CCCN3C(=O)OCc3ccccc3)nc2c1Br
Yield: 47.2 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (0.400 g, 1.23 mmol) and 2-amino-3-bromo-4-methylpyridine (0.2344 g, 1.25 mmol), produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (12 g SiO2, 0-50% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.239 g, 0.58 mmol, 47%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)=[O:26]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)CBr)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution containing the product from Example 1B (1.5 g, 6.1 mmol) and AlCl3 (2.4 g. 18 mmol) in 10 mL of dichloromethane at 0° C. was added bromoactyl bromide (0.55 mL, 6.2 mmol). The mixture was stirred at room temperature for 30 min. to one hour. Upon completion of the reaction as monitored by thin layer chromatography, the reaction mixture was poured into ice-cold water (100 mL), and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure, and the resulting oil was purified by flash chromatography (ethyl acetate/hexane. 1/8) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (m, 2H), 1.19 (t, J=7.06 Hz, 3H), 1.50 (m, 2H), 1.70-1.85 (m, 5H), 2.22 (d, J=6.75 Hz, 2H), 2.56 (m, 1H), 4.07 (q, J=7.06 Hz, 3H), 4.88 (s, 2H), 7.41 (d, J=8.28 Hz, 2H), 8.92 (d, J=8.28 Hz, 2H); MS (ESI) m/z 367.1 [M+H]+.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CN(C)[C:18](=[O:21])[CH:19]=[CH2:20].[S:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[S:23]1[CH:27]=[CH:26][C:25]2[C:18](=[O:21])[CH2:19][CH2:20][C:24]1=2
Reactant: C=CC(=O)N(C)C
Reactant: c1ccsc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: ClCCCl
Product: O=C1CCc2sccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Over a period of 10 minutes a solution of triflic anhydride (84.7 g, 0.30 mol) in DCE (300 mL) was added to a cold solution of N,N-dimethylacrylamide (29.8 g, 0.30 mol) in DCE (2700 mL). The mixture was stirred for 15 minutes at 0° C. A solution of thiophene (25.3 g, 0.30 mol) was added and the mixture was refluxed for seven hours. A solution of potassium carbonate (150 g in 200 mL of water) was added. The mixture was extracted two times with DCM dried over sodium sulphate and evaporated under reduced pressure. The compound was purified by silica gel chromatography with ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:10][CH:11]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCN(Cc1ccccc1F)C(=O)Cc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(Cc1ccccc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
N-Ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide (0.381 g, 1.327 mmol) and methyl 2-(bromomethyl)benzoate (0.334 g, 1.460 mmol) were dissolved in acetonitrile (10 ml) and potassium carbonate (0.367 g, 2.654 mmol) was added. The mixture was stirred at 65° C. for three hours. When N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide was consumed, PS-trisamine (0.3 eqv) was added and the solution was stirred overnight at room temperature. The polymer was filtered off and acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of water, dried (MgSO4) and the solvent was removed by evaporation to give 0.545 g of methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (yield 94.3%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]3[C:15](=O)[NH:16][C:17](=[O:31])[N:18]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>O1CCCC1>[CH:1]1[C:13]2[CH:12]([C:14]3[C:15](=[S:42])[NH:16][C:17](=[O:31])[N:18]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4-c4ccccc43)c(=O)[nH]c2=O)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4-c4ccccc43)c(=S)[nH]c2=O)c1

Procedure:
A mixture of the product from step (iv) (0.3 g) and Lawesson's reagent (0.286 g) in tetrahydrofuran (8 ml) was heated at reflux for 6 hours then cooled and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 30-40% ethyl acetate in isohexane.
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:15]([Cl:25])[CH:14]=1)[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH2:21]([O:20][C:16]1[C:15]([Cl:25])=[CH:14][C:13]([CH2:12][N:9]([OH:8])[CH:10]=[O:11])=[CH:18][C:17]=1[Cl:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1c(Cl)cc(CN(C=O)OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CO
Product: CCCCOc1c(Cl)cc(CN(O)C=O)cc1Cl
Reaction time: 0.83 h
Yield: 41 %

Procedure:
To a solution of the crude N-benzyloxy-N-(4-butoxy-3,5-dichlorobenzyl)formamide in 5 ml of methanol was added 100 mg of 10% palladium on carbon. This was stirred under a hydrogen atmosphere for 50 min. Filtration and removal of volatiles in vacuo then purification by preparative HPLC afforded the title compound (71 mg, 41%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 8.36, 8.20* (s, 1H); 7.37*, 7.33 (s, 2H); 4.64, 4.61* (s, 2H); 4.01 (t, j=6.4 Hz, 2H), 1.80 (quint, j=7.6 Hz, 2H), 1.57 (sext, j=7.6 Hz, 2H), 1.00 (t, j=7.2 Hz, 3H). M+1=292.*: minor rotamer
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[CH3:19][C:20]1([CH3:35])[C:24]2=[N:25][CH:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:28]=[C:23]2[NH:22][CH2:21]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:19][C:20]1([CH3:35])[C:24]2=[N:25][CH:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:28]=[C:23]2[N:22]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:3]=2[CH3:18])[CH2:21]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine (40 mg, 0.156 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo-[3,2-b]pyridin-6-yl)morpholine (36.5 mg, 0.156 mmol), XPhos precatalyst (11.5 mg, 0.015 mmol) and sodium tert-butoxide (30 mg, 0.313 mmol) in toluene (4 mL) for 2 h at 110° C. Purification by reverse phase HPLC (10 to 50% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo-[3,2-b]pyridin-1-yl)-3-methyl-2-(2-pyridinyl)-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (1H, dd, J=4.1, 2.0 Hz), 8.71 (1H, ddd, J=4.8, 1.9, 1.0 Hz), 8.14-8.21 (2H, m), 7.92 (1H, td, J=7.7, 1.8 Hz), 7.62 (1H, d, J=2.3 Hz), 7.37-7.48 (2H, m), 5.82 (1H, d, J=2.3 Hz), 3.86-3.91 (1H, m), 3.69-3.82 (5H, m), 2.93-3.04 (4H, m), 2.50 (3H, s), 1.58 (3H, s), 1.53 (3H, s). Mass Spectrum (ESI) m/e=453.2 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6](=[O:9])[CH2:7][CH3:8])[CH2:2]1.[CH3:10][O-:11].[Na+]>C(OCC)=O>[CH3:8][CH:7]([C:6](=[O:9])[CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[CH:10]=[O:11]
Reactant: C[O-]
Reactant: CCC(=O)C1CCOC1
Agent: [Na+]
Solvent: CCOC=O
Product: CC(C=O)C(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Into a 100-mL round-bottom flask, was placed 1-(tetrahydrofuran-3-yl)propan-1-one (compound 263.2, 2.5 g, 19.5 mmol), sodium methoxide (1.4 g, 25.9 mmol) and ethyl formate (20 mL). The mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1:20 to 1:5) as eluent to obtain the title compound as a yellow solid (2.0 g, 66%).