Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+].[C:14](Cl)(=[O:25])[O:15][CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1>C(Cl)Cl>[Cl:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([Cl:24])[CH:20]=1)[CH2:16][O:15][C:14]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)=[O:25]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)CCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-piperidin-4-yl-propionic acid (1 g, 6.36 mmol) in DCM (20 ml) was added 2M NaOH (9.54 ml, 19.08 mmol) to give a colorless biphasic solution. 3,5-Dichlorobenzyl carbono-chloridate (1.523 g, 6.36 mmol) was added to the reaction mixture and this was stirred at RT for 2 hrs. The mixture was extracted with DCM (2×50 ml), and the organics were dried (MgSO4) and concentrated to give the product as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)=[C:2]=[O:3].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:25]=[C:24]2[C:19]([CH:20]([NH2:26])[CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1>>[CH:9]1[C:10]2[C:5](=[C:4]([NH:1][C:2]([NH:26][CH:20]3[C:19]4[C:24](=[CH:25][C:16]([C:15]([F:28])([F:14])[F:27])=[CH:17][CH:18]=4)[O:23][CH2:22][CH2:21]3)=[O:3])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: NC1CCOc2cc(C(F)(F)F)ccc21
Reactant: O=C=Nc1cccc2cnccc12
Product: O=C(Nc1cccc2cnccc12)NC1CCOc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
3 ml of the 5-isocyanato-isoquinoline solution was added to the product of Example 4D (49 mg, 0.3 mmol) and stirred at ambient temperature overnight, and the precipitate formed was collected by filtration and washed with diethyl ether to give 23 mg of the title compound (23% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.63 (s, 1H), 8.55 (d, J=6.0 Hz, 1H), 8.32 (m, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.60 (m, 2H), 7.30-7.12 (m, 3H), 5.02 (m, 1H), 4.42-4.20 (m, 2H), 2.30-2.00 (m, 2H). MS (ESI) m/e 388 (M+H)+. Calcd. For C20H16N3O2F3.0.2; H2O: C, 62.01; H, 4.16; N, 10.85. Found: C, 61.29; H, 3.94; N, 10.64.
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[CH:4][C:5]2[CH2:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC1(F)OC2C=C(C)C([C:22]3[CH:23]=[CH:24][C:25]([NH:28]C(=O)C4C=CC=CC=4F)=[N:26][CH:27]=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.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>[Cl:11][C:3]1[C:2]([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[CH:10][C:6]2[O:7][CH2:8][CH2:9][C:5]=2[CH:4]=1
Reactant: Cc1cc2c(cc1-c1ccc(NC(=O)c3ccccc3F)nc1)OC(F)(F)O2
Reactant: Clc1cc2c(cc1Br)OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Temperature: 85 °C
Yield: 75.5 %

Procedure:
A mixture of 6-bromo-5-chloro-2,3-dihydrobenzo[b]furan (18) (233 mg, purity ca 60%, ca 0.6 mmol), 2-aminopyridine-5-boronic acid pinacol ester (6) (220 mg, 1 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (36 mg, 10% mol), Pd(PPh3)4 (58 mg) and K3PO4 (212 mg, 1 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 4 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to prep HPLC purification to give 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (19) (111.8 mg, yield: 75.5%, purity>95%) as yellow solid.
Reaction SMILES: Cl.[CH:2]([O:5][C:6](=[O:11])[C@@H:7]([CH2:9][OH:10])[NH2:8])([CH3:4])[CH3:3].[NH:12](C(OCC1C=CC=CC=1)=O)[C@H:13]([C:25](O)=[O:26])[CH2:14][C:15](=[O:24])[O:16]CC1C=CC=CC=1>>[CH:2]([O:5][C:6](=[O:11])[C@@H:7]([CH2:9][OH:10])[NH:8][C:25](=[O:26])[C@H:13]([CH2:14][C:15](=[O:16])[OH:24])[NH2:12])([CH3:4])[CH3:3]
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)OC(=O)[C@H](N)CO
Agent: Cl
Product: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O

Procedure:
This compound was prepared from 1.8 g D-serine isopropyl ester hydrochloride and 3.6 g Z-Asp(OBzl) in a manner similar to Example 11 (A). Yield: 1.7 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Mg].[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O)(=O)C>C1COCC1>[C:25]([O:24][C:22]([N:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Temperature: -75 °C
Yield: 81 %

Procedure:
2-Bromobenzotrifluoride (4.5 g, 20 mmol) and magnesium turnings (0.54 g, 22 mmol) were refluxed under a nitrogen atmosphere in 100 ml THF until the magnesium had dissolved. The resulting solution was cooled to -75° C. and added to 4.6 g (20 mmol) di-t-butyl azodicarboxylate in 100 ml THF at -75° C. The solution was warmed to -40° C., acetic acid (1.5 ml, 25 mmol) was added, and the mixture concentrated to 20 ml. Hexane and water were added, and the hexane solution was evaporated to leave a brown oil which was chromatographed on silica with 10% ether in CHCl3, providing 6.1 g (81% yield) of N,N'-bis(t-butoxycarbonyl)-2-(trifluoromethyl)phenylhydrazine as a brown gum. This material was dissolved in 200 ml isopropanol, and hydrogen chloride gas was passed into the solution resulting in a weight gain of 8 g. The solution was stirred at 50° C. for 30 minutes, then evaporated to dryness. The residue was treated with ether, and the solids collected by filtration and dried in vacuo, providing 2.7 g (79% yield) 2-(trifluoromethyl)phenylhydrazine hydrochloride as a white powder, mp 241°-242° C.
Reaction SMILES: Cl.O.[C:3]([O:10][C:11]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[C:20]1([NH:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N+:30]([O-])=O)[C:21]1=[O:33])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)C.[Fe]>[C:3]([O:10][C:11]1[CH:16]=[C:15]([CH:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][C:12]=1[C:20]1([NH:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH2:30])[C:21]1=[O:33])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCC)C(=O)c2cccc(N)c2C1=O
Yield: 59.2 %

Procedure:
Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-hexanamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate (40 mg, 0.07 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (21 mg, 57%).
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20]C)=O)=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[NH3:22]>CO>[N:1]12[CH2:8][C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([NH2:22])=[O:20])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: COC(=O)c1cccc2nc(C34CCCN(CC3)C4)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(C34CCCN(CC3)C4)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
Methyl 2-(1-azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxylate (80 mg, 0.28 mmol) was added to ammonia in methanol (15 ml) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, the residue solution was concentrated under vacuum. Then the residue was purified by flash column chromatography to give 2-(1-azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxamide (20.6 mg, yield: 27%) 1H-NMR (400 MHz, CD3OD) δ: 1.18 (s, 1H), 1.63-1.67 (m, 1H), 1.82 (s, 1H), 1.94-1.98 (m, 1H), 2.10-2.15 (m, 2H), 2.23-2.28 (m, 1H), 2.38-2.44 (m, 1H), 2.91-2.93 (m, 2H), 3.12-3.18 (m, 1H), 3.20-3.30 (m, 1H), 7.34-7.37 (t, J=8 Hz, 1H), 7.72-7.77 (m, 2H), LC-MS (m/z): 272 (M+1)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH:12]1[CH2:15][CH2:14][CH2:13]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC2)cc1

Procedure:
The title compound was prepared from 4-fluoronitrobenzene and azetidine hydrochloride according to Method AE and was isolated as a yellow solid (69%) after trituration in water, and then in Et2O, δH (DMSO-d6) 8.10-7.99 (2H, m), 6.48-6.35 (2H, m), 4.04 (4H, t, J 7.5 Hz), 2.47-2.31 (2H, m). LCMS (ES+) 178.9 (M+H)+, RT 2.71 minutes (Method 3).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([C:21]([CH3:23])=[O:22])C>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][CH:21]2[CH2:23][O:22]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(O)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCc1ccc(OCC2CO2)cc1

Procedure:
A mixture of 44 g of 4-pentylphenol (Eastman Kodak), 50 ml of epichlolorohydrin, 120 g of potassium carbonate in 250 ml methyl ethyl ketone was refluxed for 12 hr. Residual after removal of solid and solvent was distilled through a Kugelrohr adaptor to give the title compound, bp 180°-195°/0.3 mmHg.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH:49]([C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH:59]([CH3:61])[CH3:60])=[CH:54][CH:53]=1)[CH2:50][CH3:51]>ClCCl>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)[CH:49]([C:52]1[CH:53]=[CH:54][C:55]([CH2:58][CH:59]([CH3:60])[CH3:61])=[CH:56][CH:57]=1)[CH2:50][CH3:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1ccc(CC(C)C)cc1
Reactant: O=C(CCCn1cc(C(=O)c2cccc(NCc3ccccc3)c2)c2ccccc21)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1ccc(CC(C)C)cc1)N(Cc1ccccc1)c1cccc(Cc2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of benzyl 4-[3-(3-benzylaminobenzoyl)indol-1-yl]butyrate (88 mg) and diisopropylethylamine (45 mg) in dichloromethane (3 ml) was added a solution of 1-bromo-1-(4-isobutylphenyl)propane (90 mg) in dichloromethane (1 ml). The mixture was stirred at room temperature for 24 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (5 g) eluting with a mixture of n-hexane and ethyl acetate (4:1) to give benzyl 4-[3-[3-[N-benzyl-N-[1-(4-isobutylphenyl)propyl]amino]benzyl]indol-1-yl]butyrate (30 mg) as an oil.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([CH3:35])[CH:33]=3)[NH:28][CH:27]=2)=[CH:19][N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:24][O:23][C:22]1[C:17]([NH2:7])=[N:18][CH:19]=[C:20]([CH2:25][C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([CH3:35])[CH:33]=3)[NH:28][CH:27]=2)[CH:21]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ncc(C(O)c3c[nH]c4ncc(C)cc34)cc2OC)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncc(C)cc23)cnc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a round bottom flask, {5-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-3-methoxy-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (127, 1 equivalent) is combined with 100 mL of acetonitrile, triethylsilane (18 equivalents), and trifluoroacetic acid (18 equivalents). The reaction is heated at reflux for 24 hours, then concentrated under vacuum. The resulting material is dissolved in 40 mL of trifluoroacetic acid and stirred at room temperature for 18 hours. This is concentrated under vacuum and combined with water and sodium bicarbonate, then extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate, water, brine, then dried with magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[N:6][N:7]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH:8]=1)([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[N:5]=[N:6][N:7]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH:8]=1
Reactant: O=[N+]([O-])c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1
Yield: 92.5 %

Procedure:
A solution of 16 (1.23 g, 0.005 mol) in methanol (25 ml) and 5% palladium-on-carbon catalyst (250 mg) was stirred at room temperature while a solution of 99% hydrazine hydrate in methanol (1:3, v/v) was added dropwise until evolution of nitrogen ceased. The catalyst was removed by filtration through Celite and the solvent was removed. The product was crystallized from ethyl acetate-methanol (3:1) to give 1.0 g (92%) of 18, m.p. 102°-104°. The nmr spectrum indicated the presence of ethyl acetate. After heating at 100° in vacuo overnight 18 had a melting point of 141°-143°: [α]D25 -65.8° (c 1.00, water); nmr (DMSO-d6) δ 5.77 (d, 1, J1',2' 4.0 Hz, 1'--H), 7.34 (s, 1, 5--H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:14][C@@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(CCBr)NC(=O)OCc1ccccc1
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@H](CCOc1ccc(CCCO)cc1)NC(=O)OCc1ccccc1
Yield: 52.7 %

Procedure:
The mixture constituted by 306 mg of 4-hydroxybenzenepropanol, 770 mg of ethyl 4-bromo-2-[[(phenylmethoxy)carbonyl]amino]butanoate and 740 mg of Cs2CO3 in 10 ml of acetonitrile is heated under reflux for 45 minutes, the solid is filtered, washed with dichloromethane then the filtrate is evaporated under reduced pressure until 1.5 g of crude product is obtained which is purified by chromatography on a silica column (Kieselgel 60; 40-63 μm) eluting with a dichloromethane/methanol mixture 95/5. 440 mg of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][C:34]([CH3:63])([O:36][C:37](=[O:62])[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.NC1C=CC(N(CC)CC)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:56]([C:55]2[CH:54]=[C:53]([CH2:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][C:37]([O:36][C:34]([CH3:63])([CH3:35])[CH3:33])=[O:62])[CH:61]=[CH:60][CH:59]=2)=[O:57])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.42 h
Yield: 77.3 %

Procedure:
To a solution of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (1.77 g, 4.0 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (1.70 g, 3.86 mmol) and DIPEA (1.47 g, 11.4 mmol) in DMF (20 ml) was added HATU (1.56 g, 4.10 mmol). The reaction mixture was stirred for 30 minutes, at which time additional 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (0.06 g, 0.14 mmol) was added. After stirring an additional 25 minutes, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (200 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (50% to 100% EtOAc in hexanes) gave the title compound (2.58 g) as an oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc(Br)cc1F
Product: CCSc1ncc(C(=O)c2ccc(OC)c(F)c2)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-bromo-2-fluoroanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(3-fluoro-4-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 308.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].P(=O)(O)(O)O.[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])(=[O:13])[CH3:12]
Reactant: C=CC(=C)C
Reactant: CC(=O)O
Agent: O=P(O)(O)O
Product: CC(=O)OCC=C(C)C

Procedure:
Although the addition of acetic acid to isoprene in the presence of a catalytic amount of phosphoric acid will occur slowly at room temperature to yield prenyl acetate (systematically named as 3-methyl-2-buten-1-yl acetate), gentle heating of the reaction mixture in a pressure vessel at temperatures of approximately 40° C. to 100° C. is preferred if one wishes to conduct the process in several hours.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=5[N:13]([CH3:21])[CH:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:31])=[CH:25][CH:24]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)cc2)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to a solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (70 mg, 0.232 mmol), (4-fluorophenyl)acetic acid (37.5 mg, 0.244 mmol), and HATU (93 mg, 0.244 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.928 mmol). The mixture was stirred at overnight. The reaction was poured into water (100 mL), and an off-white solid was formed. The solid was filtered, washed with water (10 mL), and dried to afford the title compound as an off-white solid. LC-MS (ES) m/z=402.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (t, J=8.34 Hz, 2H), 3.73 (s, 3H), 3.88 (s, 2H), 4.23 (t, J=8.46 Hz, 2H), 7.15-7.20 (m, 2H), 7.21-7.26 (m, 2H), 7.30-7.37 (m, 3H), 8.13 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
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]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:20]([O:24][C:25](=[O:34])[NH:26][C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][N:28]=1)([CH3:23])([CH3:22])[CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[C:20]([O:24][C:25](=[O:34])[NH:26][C:27]1[N:32]=[C:31]([NH:33][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]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH:3]=2)[CH:30]=[CH:29][N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1nccc(N)n1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nccc(Nc2cc(-c3cc(Cl)ccc3F)nc3ncccc23)n1
Yield: 27.7 %

Procedure:
200 mg 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine (cf. EXAMPLE 1) and 143 mg (4-amino-pyrimidin-2-yl)-carbamic acid tert-butyl ester in 8 ml dioxane containing 444 mg Cs2CO3, 13 mg Pd2(dba)3 and 16 mg xantphos were incubated under argon gas at 80° C. for 16 hrs. After evaporation to dryness the crude sample was flashed on SiO2 with a MeOH gradient in DCM. A pooled fraction was dried down and digested with ether to give 88 mg product {4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-pyrimidin-2-yl}-carbamic acid tert-butyl ester as a white powder with Rt˜1.80 min and correct mass found M+H˜467.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([N:1]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@H](N)CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a stirred solution of (S)-(+)-2-aminobutan-1-ol (5 g, 56.18 mmol) in dry acetonitrile (100 ml) was added dry powdered potassium carbonate (31 g, 224.72 mmol) followed by benzyl bromide (19 g, 111.11 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under vaccuo and the residue was taken up in ethyl acetate (100 ml) and water (100 ml). The organic phase was washed again with water, dried (Na2SO4) and concentrated to provide the pure product as slightly yellow oil (14.5 g, 97.3%). δH (250 MHz, CDCl3) 0.98 (3 H, t, J 7.5, CHCH2CH3), 1.38-1.2 (1H, m, CHCHHCH3), 1.94-1.78 (1 H, m, CHHCH3), 2.83-2.71 (1 H, m, CHCHHCH3), 3.22 (1 H, s, b, OH), 3.65-3.4 (2 H, m, CH2OH), 3.47 (2 H, d, J 17.5, 2×CHHPh), 3.94 (2H, d, J 17.5, 2×CHHPh), 7.46-7.26 (10 H, m, 2×C6H5); δC (250 MHz, CDCl3) 139.42 (2×C), 129.1 (2×CH), 128.52 (2×CH), 127.25 (2×CH), 61.97 (CH), 60.67 (CH2), 53.23 (CH2), 17.92 (CH2), 11.83 (CH3); m/z 270.2 (M+H)