Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:14])[CH:5]1[CH2:15][C:16]([O:18]C)=O)(=[O:3])[CH3:2].BrC1C=CC=C2C=1C=C[N:25]=C2.C([Si](OC(OC)=C)(C)C)(C)(C)C.Cl>C(Cl)Cl>[Br:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:25][C:16](=[O:18])[CH:15]=[C:5]12
Reactant: Brc1cccc2cnccc12
Reactant: COC(=O)CC1c2cccc(Br)c2C=CN1C(C)=O
Agent: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
methyl 2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate. To a stirred solution of 5-bromoisoquinoline (100 g, 481 mmol) in DCM (1900 mL) acetyl chloride (35.9 mL, 505 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to −78° C. (yellow suspension) and then a solution of tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (95 g, 505 mmol) in DCM (500 mL) was added in one portion. The resulting yellow solution was stirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2N aqueous HCl (400 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (1000 mL), charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (147 g) which was used without further purification. UPLC-MS: MS 324.0/326.0 (M+H+); UPLC rt 1.03 min.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]([CH3:18])[CH3:17].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]([CH3:18])[CH3:17]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1nc2ccccc2n1CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc2ccccc2n1CCCCCBr
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Part C. A solution of the alcohol prepared in Part B above (4.18 g, 17.0 mmol) and carbon tetrabromide (6.75 g, 20.3 mmol) in methylene chloride (40 mL) was cooled to 0° C., and a solution of triphenylphosphine (5.34 g, 20.4 mmol) in methylene chloride (40 mL) was added dropwise. The mixture was stirred for 20 hours, then evaporated. The residue was separated by flash chromatography (1:2 ethyl acetate-hexane) to afford the product, 1-(5-bromopentyl)-2-(1-methylethyl)-1H-benzimidazole, as an oil (4.80 g, 15.5 mmol, 92%. 1H NMR (CDCl3): 7.79-7.72 (1H, m) ; 7.32-7.21 (3H, m); 4.14 (2H, t, J=7.5 Hz); 3.39 (2H, t, J=6.6 Hz); 3.18 (1H, heptet, J=7.0 Hz); 1.94-1.78 (4H, m); 1.63-1.50 (2H, m); 1.45 (6H, d, J=7.0 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[NH:13][CH:12]=[N:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:27])=CC=1>C1COCC1.O>[C:1]1([CH:7]([C:9]2[NH:13][C:12](=[S:27])[NH:11][CH:10]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)c1cnc[nH]1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1)c1c[nH]c(=S)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(1-phenyl-ethyl)-1H-imidazole (Intermediate C2) (0.20 g, 1.16 mmol) in THF (6 mL) and water (6 mL) was treated with NaHCO3 (0.98 g) at rt for 10 sm. Phenyl chlorothionoformate (0.40 mL, ˜3.0 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (8 mL) and treated with NEt3 (1 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give 4-(1-phenyl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 4)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[F:15][CH2:16][C:17](=[O:20])[CH2:18][F:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][F:19])[CH2:16][F:15]
Reactant: O=C(CF)CF
Reactant: Cc1ccc(I)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(CF)CF)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 2-bromo-1-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (25 mL) at 0° C. was slowly added i-PrMgCl (24 mL, 24 mmol). After being stirred for 1 h at 0° C., the reaction mixture was cooled to −78° C. Then a solution of 1,3-difluoropropan-2-one (0.85 g, 9.04 mmol) in dry THF (25 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with HCl (2 N) and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, eluting with PE:EA (5:1) to give 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, yield 55%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1 H), 7.46 (s, 1 H), 7.21 (d, 1 H), 6.21 (s, 1 H), 4.97-4.94 (m, 1 H), 4.85-4.82 (m, 2 H), 4.74-4.71 (m, 1 H), 2.26 (s, 3 H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([OH:15])(C)C.C1(=O)OC(=O)C2=CC=CC=C12>C(O)(C)C>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:15])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)O
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
Phthalamic acids have also been prepared by addition of a solution of secondary fatty amines in isopropanol at about 78° C. to a phthalic anhydride/isopropanol slurry in a 1:1 phthalic anhydride/amine molar ratio with subsequent vacuum stripping of the solvent. This method utilizes isopropanol as the solvent for the reaction. Isopropanol, a secondary alcohol, reacts with phthalic anhydride to yield the isopropyl mono ester of phthalic acid. At 78° C., as much as 40% of the product may be an ester.
Reaction SMILES: [CH3:1][Si:2]([NH:5][Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].C([Li:14])CCC.CCCCCC>CCOCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[N-:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Li+:14]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]
Temperature: 0 °C

Procedure:
An oven-dried 5 ml Schlenk flask was evacuated, purged with argon, and charged with 0.9 mol (0.689 g, 4.27 mmol) of bis(trimethylsilyl)amine followed by 5 ml of dry ether. The solution was cooled to 0° C. with an ice bath. To this solution was added n-butyllithium in hexane (2.4 ml of 1.6M, 3.84 mmol) dropwise. A white suspension was obtained. The ice bath was removed and the mixture was refluxed for 0.5 hours. After cooling to room temperature, the solvents were pumped off under vacuum to give a white crystalline solid of lithium hexamethyldisilazide (LiHMDS). To the solid was added 40 ml of dry toluene to obtain a clear colorless solution.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:16][CH2:15][N:14]([C:12]([NH:11][CH:2]3[CH:3]4[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][CH:1]3[CH2:8]5)[CH2:4]4)=[O:13])[CH2:19][CH2:18]2)[CH2:20]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a solution N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (50 mg, 0.108 mmol) and DIEA (27.86 g, 0.22 mmol) in dry CH2Cl2 (2-mL) at 0° C. under nitrogen was added dropwise a solution of acetyl chloride (9.28 mg, 0.12 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred overnight at rt and evaporated to give a residue, which was purified by preparative HPLC to provide a white solid 1-acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (5.2 mg, 12%). 1H NMR (400 MHz, CD3OD): δ=1.61 (s, 1H), 1.653 (d, 2H), 1.72 (s, 1H), 1.88 (m, 10H), 2.015 (d, 5H), 2.286 (s, 3H), 3.027 (t, 2H), 3.867 (s, 1H), 4.088 (d, 4H), 7.044 (t, 1H), 7.191 (t, 2H), 8.082 (d, 1H); LC-MS (4 min) tR=1.59 min, m/z=408(M++1).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].F[C:10]1[C:15]([I:16])=[CH:14][CH:13]=[CH:12][N:11]=1.CCOC(C)=O.CCCCCC>C1COCC1>[I:16][C:15]1[C:10]([CH2:7][C:6]#[N:8])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC#N
Reactant: Fc1ncccc1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCc1ncccc1I
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 33.5 %

Procedure:
To a solution of n-butyllithium (11 mL, 27 mmol) in dry THF (150 mL) at −78° C., was added dry ACN (2 mL, 29 mmol). The resulting mixture was stirred at −78° C. for 45 minutes to generate a suspension of lithionitrile. 2-Fluoro-3-iodopyridine (5 g, 22 mmol) was added as a solution in 10 mL of THF, and the yellow mixture was allowed to warm slowly to room temperature. By the time that the temperature reached −19° C., the reaction had turned dark green. After 35 minutes (reaction temperature=−7° C.), TLC (0-30% EtOAc/hexane) showed a new lower spot and a trace of starting material. LCMS showed the desired mass ((M+H)+=245). The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed 3 times with saturated NH4Cl and brine, and then dried over MgSO4 and concentrated in vacuo to give a dark solid. The resulting product was purified by silica flash chromatography (0-50% EtOAc/hexane and then 10% MeOH/DCM) to give the title compound as a dark yellow solid (1.8 g, 33%). MS (m/z)=245 (M+H)+. Calculated for C7H5IN2 244.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (21 g) in 100 mL of ethyl acetate cooled to 0° C. was added 100 mL of saturated sodium carbonate and benzyl chloroformate (17 g). The solution was stirred for 3 h, then separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as an oil:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71].C([BH3-])#N.[Na+].Cl>O1CCOCC1.O.O>[C:70]([CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:72])=[O:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
50 mg (0.054 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 16) were dissolved in 8 ml of dioxane/water, and 70 ml (0.108 mmol) of a 15% solution of 4-oxobutanoic acid in water were added. The reaction mixture was subsequently stirred at 100° C. for 1 h. After cooling to RT, 3.7 mg (0.059 mmol) of sodium cyanoborohydride were added and the mixture was adjusted to a pH of 3 by adding about 300 μl of 0.1 N hydrochloric acid. The reaction mixture was then stirred at 100° C. for a further 2 h. After cooling, another 70 ml (0.108 mmol) of the 15% 4-oxobutanoic acid solution were added and the reaction mixture was again stirred at 100° C. for 1 h. Then a further 3.7 mg (0.059 mmol) of sodium cyanoborohydride were added and about 300 μl of 0.1 N hydrochloric acid were subsequently used to adjust the pH back to 3. The reaction mixture was then stirred at 100° C. for another 2 h. In the event of conversion still being incomplete, this procedure was repeated for a third time. The reaction mixture was finally concentrated and the residue was purified by means of preparative HPLC. In this way, 32 mg (65% of theory) of the title compound were obtained in the form of a colourless foam.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.Cl>C1COCC1>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:29]4[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=4)[CH:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (38 mg, 0.072 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% methanol/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (18.1 mg, 59%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.12 (s, 1H), 8.47 (s, 1H), 8.32-8.26 (m, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=11.5 Hz, 1H), 4.57-4.53 (m, 1H), 2.74 (s, 3H), 2.51 (d, J=12.3 Hz, 2H), 2.26 (d, J=12.3 Hz, 2H), 1.87 (q, J=12.5 Hz, 2H), 1.71-1.62 (m, 2H). ESI MS m/z 428 [C23H23ClFN3O2+H]+; HPLC>99% (AUC), tR=9.43 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23](O)[CH:22]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24]([C:27](=[O:29])[CH2:28][C:2]3([O:1]2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(F)cc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.5 g, 37.8 mmol) in pyrrolidine (4.5 mL, 54.1 mmol) and anhydrous methanol (10.2 mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (5.8 g, 37.6 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1 N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsing with hexanes to remove tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate (8.6 g), which was collected as light yellow solid; ESI-MS m/z calc. 386.2, found 387.2 (M+1)+; Retention time: 2.59 minutes (3 min run). The filtrate was concentrated and the residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give tert-butyl 7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g, 21%) as a light yellow solid; ESI-MS m/z calc. 335.2, found 336.2 (M+1)+; Retention time: 2.49 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d, J=12.1 Hz, 2H), 3.21 (t, J=12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J=12.8 Hz, 2H), 1.62 (td, J=14.1, 4.8 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (34 mg, 0.12 mmol) and 4-(4-BOC-piperazino)phenylboronic acid (46 mg, 0.15 mmol), the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacteic acid buffer) followed by neutralization to isolate tert-butyl 4-(4-(3-methyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)piperazine-1-carboxylate 3B.15.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[C:25]1(OB(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:3]1
Reactant: OB(O)Oc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(Oc3ccccc3)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A suspension of 0.200 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate, 0.0906 g of phenylboric acid, 0.113 g of copper(II) acetate, 0.309 g of triethylamine, 0.700 g of 3 angstrom molecular sieves (powder) and 6 ml of dichloromethane is stirred vigorously at room temperature for 28 hours. The reaction mixture is clarified by filtration and concentrated by evaporation. The title compound is obtained as a yellowish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.44 (1:1 EtOAc-heptane); Rt=5.03.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([SH:37](=[O:39])=[O:38])=[CH:33][CH:32]=1.[CH:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)CCCCC>[N:1]#[N:2].[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([OH:4])(=[O:39])=[O:38])=[CH:33][CH:32]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([OH:4])(=[O:39])=[O:38])=[CH:33][CH:32]=1.[CH2:45]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH2:46][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: Cc1ccc([SH](=O)=O)cc1
Reactant: c1ccccc1
Agent: N#N
Solvent: CCCCCCO
Product: CCCCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydride in 10 ml of n-hexyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 3 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 50 ml of ethyl ether and 50 ml of petroleum ether were added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine n-hexyl ester di(p-toluenesulfonate) in 95% yield; mp. 190°-193° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[CH:19][N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:18])[N:7]3[CH:19]=[CH:20][S:21][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:3])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.037 g, 0.12 mmol), 6-bromo-9H-purine (0.048 g, 0.24 mmol), and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H14F2N7OS (M+H)+: m/z=426.1. Found: 426.0. 1H NMR (DMSO-d6, 400 MHz) δ 7.99 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.53 (1H, d, J=4.8 Hz), 7.24 (1H, m), 7.16 (2H, m), 6.88 (1H, br s), 5.41 (2H, br s), 5.05 (1H, m), 1.27 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.