Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16]([C:18]1[C:19]([Cl:27])=[N:20][CH:21]=[C:22]([C:24](O)=[O:25])[CH:23]=1)=[O:17])[CH3:14].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16](=[O:17])[C:18]1[CH:23]=[C:22]([C:24](=[O:25])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH:21]=[N:20][C:19]=1[Cl:27])[CH3:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc(C(=O)O)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reaction time: 2 h

Procedure:
4-Trifluoromethoxyaniline (1.79 mL, 13.3 mmol) was added to a stirred solution of 2-chloropyridine-3,5-dicarboxylic acid ethyl ester (Stage 72.6, 3.20 g, 14 mmol), 1-hydroxybenzotriazole (3.20 g, 20.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.94 g, 15.3 mmol) in DMF (50 mL). The mixture was stirred for 2 h and then treated with EtOAc, washed with a sat. aq. solution of NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 50% EtOAc) and recrystallized from n-hexane/EtOAc to afford the title compound as a colorless crystalline solid. m.p. 135-137° C., HPLC (Condition 4) tR=6.59 min, UPLC-MS (Condition 8) tR=1.24 min, m/z=389.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.35 (t, J=7.23 Hz, 3H), 4.39 (q, J=7.04 Hz, 2H), 7.39 (d, J=8.60 Hz, 2H), 7.76-7.92 (m, 2H), 8.69 (d, J=2.35 Hz, 1H), 9.08 (d, J=2.35 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C@@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C@@H:11]1[N:16]([CH3:36])[CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2C(F)(F)F)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Combine 10-((S)-3-[2-(2-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (365.7 mg, 0.78 mmol), formaldehyde (69.4 μL, 0.85 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (247.0 mg, 1.17 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 304.3 mg (81%) of the title compound as a tan foam: mp 68°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:63]=[CH:62][C:25]([C:26]([N:28]([CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]=[C:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[CH:43][CH:42]=4)[O:38][N:37]=3)=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([NH:21][C:22]1[CH:63]=[CH:62][C:25]([C:26]([N:28]([CH2:54][C:55]([OH:57])=[O:56])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]=[C:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[CH:43][CH:42]=4)[O:38][N:37]=3)=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1)=[O:14]
Reactant: COc1ccc(F)c(CC(=O)O)c1F
Reactant: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)no3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c1F
Reaction time: 2 h
Yield: 57 %

Procedure:
Prepared using General Procedures 7 and 8: To a stirred suspension of 2-(2,6-difluoro-3-methoxyphenyl)acetic acid in DCM (1.5 mL) and DMF (10 μL) was added oxalyl chloride (9.71 μL, 0.111 mmol). After 1 h a solution of tert-butyl 2-(4-amino-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-59 (50 mg, 0.074 mmol) and TEA (25.8 μL, 0.185 mmol) in DCM (1 mL) was added. After 18 h TFA (1 mL) was added and reaction stirred for 2 h. The solvent was removed from the reaction mixture and the residue purified by preparative HPLC to afford 30 mg (57%) of 2-(4-(2-(2,6-difluoro-3-methoxyphenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 441. LCMS-ESI (m/z) calculated for C46H32F2N4O6: 702; found 703 [M+H]+, tR=8.75 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 10.26 (s, 1H), 8.31-8.22 (m, 2H), 8.12-8.06 (m, 2H), 8.02-7.92 (m, 2H), 7.74-7.69 (m, 2H), 7.69-7.56 (m, 2H), 7.54-7.45 (m, 1H), 7.42-7.29 (m, 4H), 7.23-7.09 (m, 2H), 6.80-6.66 (m, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 4.04 (s, 1H), 3.97 (s, 1H), 2.92-2.81 (m, 5H), 2.38(s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 10 h
Yield: 40.9 %

Procedure:
After suspending 7-benzyloxy-6-cyano-4-chloroquinoline (23 g, 78.03 mmol) in N-methylpyrrolidone (15.8 ml), there were added 5-hydroxyindole (12.5 g, 83.64 mmol) and diisopropylethylamine (15.8 ml) and the mixture was heated and stirred at 150° C. for 10 hours. After allowing it to cool to room temperature, water and tetrahydrofuran were added and the crystals were thoroughly dissolved. After extraction with tetrahydrofuran, washing with saturated brine, drying over anhydrous magnesium sulfate and distilling off of the solvent, the residue was adsorbed onto silica gel. Purification was performed by silica gel column chromatography (hexane/tetrahydrofuran system), and then concentrated hydrochloric acid (0.2 ml) was added at room temperature and the mixture was stirred for 17 hours. The solvent was distilled off under reduced pressure, saturated sodium bicarnobate water was added, and then extraction was performed with a tetrahydrofuran and ethyl acetate mixed solvent, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were suspended in ethyl acetate and diluted with diethyl ether and hexane. The crystals were filtered out, washed with diethyl ether/hexane and dried by aspiration to obtain the title compound (12.5 g, 31.93 mmol, 40.92%) as light yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([N+:22]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H]>[Pd].COCCO>[NH2:22][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:7]([C:6]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:4]([NH2:1])[CH:5]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1)c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cc(C(=O)c2ccc(Oc3ccccc3)c(N)c2)ccc1Oc1ccccc1
Yield: 86.6 %

Procedure:
To a reaction apparatus equipped with a thermometer, reflux condenser and stirrer, 60 g (0.131 mol) of 3,3'-dinitro-4,4'-diphenoxybenzophenone, 150 g of methyl cellosolve and 3.0 g of 5%-Pd/C (50% moisture content) were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 45 g (86 % yield) of 3,3'-diamino-4,4'-diphenoxybenzophenone as light yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23](COCC[Si](C)(C)C)[C:22]([CH3:32])=[C:21]([C:33]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:32])=[C:21]([C:33]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 4-{[(4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidin-7-yl)carbonyl]amino}piperidine-1-carboxylate from example D.d1 (3.74 g; 5.5 mmol), tetrabutylammonium fluoride trihydrate (5.21 g; 16.5 mmol) and ethane-1,2-diamine (0.50 g; 8.25 mmol) in tetrahydrofurane (40 mL) is heated to gentle reflux until the starting material is completely consumed according to LC-MS. The crude is purified by column chromatography on silica gel (ethyl acetate/cyclohexane—1:1 to 2:1) to yield the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]([C:12]1([CH3:15])[CH2:14][CH2:13]1)#[CH:11]>CCN(CC)CC.[Cu]I.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>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:11]#[C:10][C:12]2([CH3:15])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: C#CC1(C)CC1
Reactant: Nc1cnc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C#Cc2cc(Cl)ncc2N)CC1
Yield: 51.8 %

Procedure:
To a solution of 6-chloro-4-iodopyridin-3-amine (7.0 g, 28 mmol) in Et3N (100 mL) was added 1-ethynyl-1-methyl-cyclopropane (11.0 g, 137 mmol), CuI (0.53 g, 2.8 mmol) and Pd(PPh3)2Cl2 (1.9 g, 2.8 mmol) under N2 atmosphere. The mixture was refluxed overnight and quenched with H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% EtOAc in Petroleum ether as eluant) to afford 6-chloro-4-((1-methylcyclopropyl)ethynyl)pyridin-3-amine (3.0 g, 53%). 1H-NMR (CDCl3, 300 MHz) δ 7.84 (s, 1H), 7.08 (s, 1H), 4.11 (br s, 2H), 1.37 (s, 3H), 1.03 (t, J=2.4, 2 H) 0.76 (t, J=2.4, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[N:10]=[CH:11][O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Br[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[CH:18][CH:17]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[N:10]=[C:11]([C:16]4[N:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[CH:18][CH:17]=4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc(Br)nc1)NC(=O)OC(C)(C)C
Reactant: c1nc2ccc(OCC3CC3)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN1CCCC1=O
Product: C[C@@H](COc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1)NC(=O)OC(C)(C)C
Temperature: 125 °C
Reaction time: 15 h
Yield: 34.4 %

Procedure:
A mixture of 6-(cyclopropylmethoxy)-1,3-benzoxazole (500 mg), tert-butyl {(1S)-2-[(6-bromopyridin-3-yl)oxy]-1-methylethyl}carbamate (1.31 g), palladium(II) acetate (29 mg), butyldi(1-adamantyl)phosphine (93 mg), tripotassium phosphate (1.12 g) and N-methylpyrrolidone (12 mL) was stirred under an argon atmosphere at 125° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. The filtrate was diluted with ethyl acetate and water, and the organic layer was separated. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (400 mg).
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([O-:4])(=[O:3])=[O:2].[Na+].C(N(CC)CC)C.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.S([O-])(O)(=O)=O.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([I+:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=2)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl.C(C(C)=O)C(C)C>[C:16]12([C:26]([O:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:3])=[O:2])=[O:27])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2.[C:51]([C:48]1[CH:49]=[CH:50][C:45]([I+:44][C:41]2[CH:40]=[CH:39][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:43][CH:42]=2)=[CH:46][CH:47]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: O=S(=O)([O-])CCO
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(OCCS(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 95 %

Procedure:
In water, 5.1 g (0.035 mole) of sodium isethionate and 6.4 g (0.053 mole) of benzyltrimethylammonium chloride were mixed and dissolved. The solution was concentrated by removing water in vacuum. The concentrate was dispersed in 55 g of acetonitrile. To the dispersion, 5.2 g (0.052 mole) of triethylamine and 0.42 g (0.0035 mole) of 4-(dimethylamino)pyridine were added, and under ice cooling, 20.6 g (0.052 mole) of 50% adamantane-1-carbonyl chloride in dichloromethane was then added dropwise. The reaction mixture was stirred at room temperature over night. Water was added to quench the reaction, from which acetonitrile was distilled off in vacuum. An amount (0.0088 mole) of bis(4-tert-butylphenyl)iodonium hydrogensulfate prepared in Synthesis Example 1-6 and 50 g of methyl isobutyl ketone were added to the residue, followed by stirring at room temperature for 1 hour. The organic layer was taken out, washed with water, and concentrated in vacuum. Diisopropyl ether was added to the concentrate for recrystallization. The crystals were collected and dried, obtaining the target compound, bis(4-tert-butylphenyl)iodonium 2-(adamantane-1-carbonyloxy)ethanesulfonate. White crystals, 5.7 g, yield 95%. The compound, designated PAG-6, has the following structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20](C4C=CC(N5CCN(C)CC5)=CC=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClCCl.[CH3:38][C:39]([OH:56])([CH3:55])[CH2:40][N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.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].O1CCOCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:44]4[CH:43]=[N:42][N:41]([CH2:40][C:39]([CH3:55])([OH:56])[CH3:38])[CH:45]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)cc3n2)cc(OC)c1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(CC(C)(C)O)c4)cc3n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 5, 15.0 mg, 29.8 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complexed with dichloromethane (1:1) (1.30 mg, 1.59 μmol), 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (8.5 mg, 31.8 μmol), and potassium phosphate (13.5 mg, 63.7 μmol) in water (0.2 mL)/1,4-dioxane (0.4 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residues were dissolved in methanol (1.0 mL). Potassium carbonate (8.3 mg, 59.7 μmol) was added and the reaction mixture was warmed up to 60° C. After 1 hour, the reaction mixture was cooled to ambient temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.0 mg) as its TFA salt. LCMS calculated for C23H28N5O3 (M+H)+: m/z=422.2. Found: 422.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([O:32][CH3:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]5[CH2:24][CH2:23][O:22][CH2:21]5)=[O:18])[CH2:13][CH2:12]4)=[N:7][C:6]=23)[C:29]([O:32][CH3:33])=[N:30][CH:31]=1
Reactant: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: COc1ncc(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(F)cc1-c1cnn2ccc(N3CCN(C(=O)O[C@@H]4CCOC4)CC3)nc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
(R)-tetrahydrofuran-3-yl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol), 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (127 mg, 0.5 mmol), triethylamine (211 uL, 1.5 mmol), Pd(OAc)2 (1 mg, 0.0025 mmol), and x-Phos (5 mg, 0.005 mmol) were taken up in 4 mL dioxane and 1 mL water under nitrogen and stirred at 85° C. for 2 hours. Reaction then cooled to room temperature, filtered through celite plug with acetonitrile and DCM. Reduced in vacuo and purified on Shimadzu neutral phase prep, lyopholized to get 30 mg product. 1H NMR (400 MHz, DMSO-d6) d 8.80 (d, J=7.83 Hz, 1H), 8.72 (dd, J=3.03, 10.36 Hz, 1H), 8.56 (s, 1H), 7.94 (d, J=3.03 Hz, 1H), 6.86 (d, J=7.83 Hz, 1H), 5.18 (d, J=1.77 Hz, 1H), 4.00 (s, 3H), 3.71-3.83 (m, 8H), 3.32 (s, 2H), 2.08 (s, 1H), 2.13 (s, 1H), 1.89-2.00 (m, 1H) LRMS (ESI) m/z 443 [(M+H)]+, calc'd for C21H23FN6O4: 442.45.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1C[O:25]CC1.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:25])=[N:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(Br)cn1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-bromopyridin-2-yl)-2-methylpropanenitrile (2.0 g, 8.9 mmol) in dichloromethane (20 mL) under nitrogen was added 1 N solution of DIBAL-H in THF (12.4 mL, 12.4 mmol) dropwise at −30° C. The resulting solution was stirred at ambient temperature for 3 hours before the addition of 2 N hydrochloric acid aqueous solution (10 mL) at 0° C. After stirred at ambient temperature for 10 minutes, the solution was basified with saturated aqueous sodium bicarbonate solution to pH 8-9, and then extracted with ethyl acetate (3×20 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 2-4% ethyl acetate in hexane to afford the title compound as a yellow oil. MS ESI: [M+H]+ m/z 228, 230; 1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H), 8.66 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 1.47 (s, 6H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1cccs1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1cccs1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-thiophenecarbonyl)hydrazine (1 g) was dissolved in 10 ml toluene and treated with 50% aqueous sodium hydroxide (1.0 g) and water (2 ml) followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-thiophenecarbonyl)-N'-benzoylhydrazine, was removed by filtration and washed with water. m.p. >190° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.CN(C=O)C>[CH3:1][CH:2]([CH3:7])[CH2:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: c1ccccc1
Reactant: CC(C)CC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
A mixture of 3-methylbutanoic acid (20.4 g, 0.2 mol), thionyl chloride (35.7 g, 0.3 mol) and DMF (0.5 ml) was heated at reflux for 2 h. The mixture was carefully concentrated in vacuo to give the crude acid chloride. A suspension of anhydrous aluminium chloride (15.4 g, 115 mmol) in dichloromethane (100 ml) was cooled to 0° C. and a solution of the above acid chloride in dichloromethane (50 ml) was added dropwise. The mixture was stirred for 15 min and a solution of benzene (17.9 g, 0.23 mol) in dichloromethane (50 ml) was added dropwise and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was poured into cold 0.05N hydrochloric acid (300 ml) and the resulting mixture extracted with dichloromethane (3×100 ml). The combined organic phases were washed with 1 hydrochloric acid (300 ml), water (300 ml) and saturated sodium hydrogen-carbonate solution (300 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 21.6 g of 3-methylbutyrophenone.