Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@H](CCl)COc1ccccc1Br
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-bromophenyl(2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][C:11]([CH3:23])([O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[C:12]#[CH:13]>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]([CH3:23])([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1)[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: COc1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccccc1C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 48 h
Yield: 34 %

Procedure:
2.34 g of 2-iodoanisole were added at room temperature to a solution of 9 mg of palladium(II) chloride, 26 mg of triphenylphosphine and 19 mg of copper(I) iodide in 25 ml of diethylamine. This mixture was treated with 1.85 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile and the resulting mixture was stirred for 48 hours. The mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 0.99 g of 4-[1,1-dimethyl-3-(2-methoxyphenyl)-2-propynyloxy]benzonitrile in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:12]=2)[CH:7]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C[I:45]>>[F:1][C:2]1[CH:3]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][I:45])[N:12]=2)[CH:7]=1
Reactant: OCCCc1coc(-c2cc(F)cc(C(F)(F)F)c2)n1
Reactant: CI
Agent: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Product: Fc1cc(-c2nc(CCCI)co2)cc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 33.6 %

Procedure:
To 3-{2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}propan-1-ol (250.3 mg, 0.865 mmol) was added a mixture of triphenyl phosphate (295.4 mg, 0.952 mmol, 1.1 equiv.) and methyl iodide (184.2 mg, 1.298 mmol, 1.5 equiv.). The mixture was heated at 130° C., while adding a further amount of methyl iodide (184.2 mg, 1.298 mmol, 1.5 equiv.). The reaction mixture was heated for a total of 2 hours, and then purified by column-chromatography (SiO2=25 g, hexane/EtOAc=7:1) followed by preparative TLC (SiO2=6 plates, hexane/EtOAc=15:1) to give 2-[5-fluoro-3-(trifluoromethyl)phenyl]-4-(3-iodopropyl)-1,3-oxazole (116.1 mg, 0.291 mmol, 34%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[C:30](=[CH2:41])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([C:30](=[CH2:41])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: C=C(Br)C(=O)OCc1ccccc1
Reactant: COCCOCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OCc1ccccc1)c1ccc(COCCOC)c(F)c1
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
A suspension of 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 16.129 mmol), Cs2CO3 (15.7 g, 48.38 mmol) in DMF (50 mL) was deoxygenated by purging Argon for 30 min at RT. Pd(dppf)Cl2 (657 mg, 0.806 mmol) was added and purging was continued. After 10 min, benzyl 2-bromoacrylate (4.6 g, 19.35 mmol) was added and stirred at 100° C. for 1 h until complete consumption of 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, as evidenced by TLC analysis. The reaction mixture was diluted with ethyl acetate (200 mL), filtered through a celite pad, washed with ethyl acetate (2×25 mL). The filtrate was washed with water (2×100 mL), brine (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by CC using 10% ethyl acetate in PE as eluent to afford benzyl 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)acrylate (1.4 g, 25%) as pale brown oil (TLC solvent system: 30% EtOAc-PE; Rf: 0.4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:44])(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:44])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Trifluoro-methanesulfonic acid 3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (13.33 g, 30.33 mmol) was azeotroped with THF (2×50 mL) then dissolved in anhydrous THF (150 mL) with benzophenone imine (6.3 mL, 17.61 mmol), cesium carbonate (14.23 g, 43.67 mmol) and BlNAP (racemic, 1.89 g, 3.03 mmol). The reaction vessel was degassed (evac./N2 purge 3×) before charging with palladium (11) acetate (410 mg, 1.82 mmol). The reaction was warmed to 80° C. for 18 h, at which point it was judged incomplete by APCl MS. After cooling additional BlNAP (racemic, 1.89 g, 3.03 mmol) and palladium (11) acetate (410 mg, 1.82 mmol) were introduced and the reaction was warmed to 80° C. for 60 h. at which point it was judged complete by APCl MS. The reaction was cooled and filtered through Celite, rinsed with THF and concentrated. The resulting oil was dissolved in CH2Cl2 (200 mL), washed with water (100 mL) and saturated aqueous NaCl solution (100 mL), dried through a cotton plug and concentrated to give the crude product. To this was added fresh THF (150 mL) followed by 2N HCl (150 mL) and this stirred solution was warmed to 65° C. for 60 min then at room temperature for 18 h. The reaction mixture was treated with hexanes (150 mL). The resulting orange solid is filtered. (On occasion an orange gum separates and is separated by decantation or filtration.) The biphasic filtrate was separated and the hexane layer discarded. The aqueous layer was extracted with Et2O (150 mL) and the Et2O layer discarded. The aqueous layer was then neutralized with 25% aqueous NaOH solution to achieve pH 9 and the product was extracted with CH2Cl2 (5×40 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4 and concentrated to give the crude product. Flash chromatography provided the title compound as a thick yellow oil (3.36 g, 36%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 2H), 7.36 (m, 2H), 7.26 (m, 2H), 7.07 (t, J=7.9 Hz, 1H), 6.71 (dd, J=7.9, 1.6 Hz, 1H). 6.64 (m, 1H), 6.50 (dd, J=7.9, 2.0 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 1H), 3.15 (m, 2H), 2.80 (m, 1H), 2.17 (br d, J=14.2 Hz, 2H), 2.00 (m, 3H), 1.79 (br d, J=12.5 Hz, 1H), 1.72 (m, 1H), 1.64 (m, 1H), 1.38 (m, 1H); APCl MS m/z 307.1 (M+1)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=3)[OH:35])=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.ClCCl.C(#N)C>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:35])[C:36]3[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a 20 L temperature controlled reactor charge [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-bromophenyl)-hydroxy-methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1492.5 g; 65% purity; 1.506 moles), then acetonitrile (4.87 L), and then dichloromethane (4.87 L). Cool the mixture to 0° C. Add triethylsilane (3.77 moles; 437.83 g) over 5 minutes. Set the reactor jacket to −5° C. When the reaction mixture temperature is −2° C., start addition of boron trifluoride etherate (3.77 moles; 534.4 g). Note: at the start, this addition results in a significant exotherm (temperature increases to ˜8° C. during the first ˜10 ml of addition). Once the initial exothermic event has taken place, add the remainder of the boron trifluoride etherate at a rate to maintain the temperature between 5° C. and 7° C. When the addition is complete stir the reaction mixture at 5° C. for 50 minutes. Charge a 50 L glass flask equipped with a bottom outlet valve with ice (6 kg), and then water (˜15 C; 3.74 Kg). Add sodium bicarbonate (11.16 moles; 937.55 g) and stir the mixture for 5 minutes. Pump the reaction mixture into the sodium bicarbonate mixture over about 5 minutes. A little effervescence is seen, but no tendency to foam. Add ethyl acetate (17.04 L) and stir the mixture for 10 minutes. Stop the stiffing and allow the mixture to stand for 30 minutes. Separate the layers, wash the organic phase with brine (4.87 L), and concentrate under reduced pressure. Split the mixture into two approximately equal portions and purify each by passage through a 4.5 Kg pad of silica eluting with dichloromethane. Concentrate the appropriate fractions to give the title compound (990 g, about 70% purity (as determined by quantative NMR; 73% yield from [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-(4-bromobenzoyl)-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate): mass spectrum (m/z): 630.2/632.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH:17]1[CH2:22]CN(C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrC[C@@H]1CCC[N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][C@@H:17]1[CH2:18][CH2:19][CH2:59][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(C[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl (3R)-3-(bromomethyl)-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[C:33]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: OB(O)c1cccc2[nH]ccc12
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (88 mg) was reacted with 1H-indol-4-ylboronic acid via General Procedure A to produce 22.8 mg of 109 following reverse phase HPLC purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[CH:11]=[N:15]/[OH:16])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: NO
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2cc(/C=N/O)ccc21
Reaction time: 2 h

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (9.0 g, 47.4 mmol) and NH2OH.HCl (3.92 g, 56.9 mmol) in THF (100 mL) and H2O (25 mL) at rt was added NaOAc (5.83 g, 71.1 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][CH:8]([C:19]([NH:21][C@@H:22]([C:24]([O:26]C)=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])=[O:6])[CH3:3]>C(Cl)(Cl)Cl>[CH3:28][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:19]([NH:21][C@@H:22]([C:24]([OH:26])=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])=[O:6])[CH3:3]
Reactant: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)O

Procedure:
The title compound was prepared by the methods of Example 9 using diastereomer F of the title compound of Example 6. [α]D -21.7 (CHCl3)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[OH-].[K+].[CH2:18](I)[CH3:19]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8](=[O:13])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:14]=1
Reactant: CCI
Reactant: Cc1cc2c(cc1Br)NC(=O)C(C)(C)O2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Compound 1B (1.0 g, 3.7 mmol) was dissolved in 25 mL of DMSO and added to a prestirred 2.0 M solution of potassium hydroxide (415 mg, 7.4 mmol) in DMSO. Next, ethyl iodide (0.6 mL, 7.4 mmol) was added and the reaction stirred at room temperature overnight. The reaction was quenched with 75 mL of water and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and excess solvent removed to yield 1.04 g (95%) of desired product. MS (electrospray): mass calculated for C13H16BrNO2, 297.04; m/z found 298, [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:53][C:54]([F:60])([F:59])[CH2:55][C:56](O)=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([C:56](=[O:57])[CH2:55][C:54]([F:60])([F:59])[F:53])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)CC(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 58.8 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 50.0 mg, 0.116 mmol) and HATU (52.8, 0.139 mmol) in dry DMF (0.50 mL) was added 3,3,3-trifluoropropanoic acid (19.3 mg, 0.150 mmol) and the mixture was stirred at ambient temperature for 2 minutes. DIEA (80.6 μL, 0.463 mmol) was added and the resulting homogeneous solution was stirred at ambient temperature for 18 hours. The reaction mixture was added to H2O (5.0 mL) and extracted with EtOAc. The combined extracts were washed with H2O, saturated aqueous NaHCO3 and dried over MgSO4. The solution was eluted through a silica gel column eluting with EtOAc then with 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated to give the title compound (32 mg, 59% yield) as a white solid. MS (apci) m/z=470.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12]OCCOCCO)=[O:9])(=[O:3])[CH3:2].[Cl-].C(OC1C(=CC=CC=1)C(O)=O)(=O)C.C(O)C[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][OH:50].C(OC(C)C)(C)C>>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][OH:50])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Reactant: OCCCCCCCCCCO
Agent: CC(=O)Oc1ccccc1C(=O)O
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Product: CC(=O)c1ccc(C(=O)OCCCCCCCCCCO)c(O)c1C(C)=O

Procedure:
The compound (IV) was prepared according to the procedure described in Example 1 for the synthesis of (XIX), starting from 5 g of the chloride of acetylsalicylic acid, 3.5 ml of TEA and 2.17 g of 1.10-decandiol. The product was purified by chromatography utilizing an eluent mix constituted by ethylether/hexane 7:3 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and a solid residue was obtained which, trirurated with isopropyl ether, produced 1.37 g of 1.10-decandiol bis-acetylsalicylate (IV) with m.p.=75° C.
Reaction SMILES: C(C(CC)CNCC1SC([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([C:21]([NH2:23])=O)[CH:20]=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.C1(CN)CCCCC1.[BH3-]C#N.[Na+]>>[CH:19]1([CH2:21][NH:23][CH2:37][C:39]2[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=2)[CH2:20][CH2:12][CH2:13][CH2:14][CH2:18]1
Reactant: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: NCC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: OB(O)c1ccc(CNCC2CCCCC2)s1

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give 4.7 mg of the title compound (6%).
Reaction SMILES: Cl.[CH2:2]([C:10]1[NH:11][NH:12][C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(O)=O.[Na+]>>[CH2:2]([C:10]1[NH:11][N:12]([C:20](=[O:22])[CH3:21])[C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC1=Nc2cnccc2NN1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCCC1=Nc2cnccc2N(C(C)=O)N1
Yield: 75 %

Procedure:
3-Octyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride is reacted with acetic anhydride as described in Example 1, and the resulting salt is treated with a solution of sodium hydrocarbonate to obtain 3-octyl-1-acetyl-1,2-dihydropyrido[3,4-e]-as-triazine with a yield of 75%. This compound is reacted with an equimolar amount of fumaric acid in ethanol to obtain the hydrogen fumarate melting at 285°-287° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[CH3:36].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[C@@H:4]([CH3:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](C)C1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f65) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.