Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1.[CH3:23]B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][N:10]=2)[C:15]#[N:16])[CH:5]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1
Reactant: CB(O)O
Reactant: N#Cc1ccnc(Nc2cc(C3CCOCC3)cc(Cl)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Product: Cc1cc(C2CCOCC2)cc(Nc2cc(C#N)ccn2)n1
Temperature: 100 °C
Reaction time: 19 h
Yield: 8.6 %

Procedure:
A vial was charged with 2-[(6-chloro-4-tetrahydropyran-4-yl-2-pyridyl)amino]pyridine-4-carbonitrile (51.1 mg, 0.162 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.5 mg, 10 mol %), methylboronic acid (20.0 mg, 0.325 mmol), and potassium carbonate (68 mg, 0.49 mmol) and purged under nitrogen before the addition of degassed 1,4-dioxane (1.6 mL) and degassed water (0.5 mL). The mixture was stirred at 100° C. for 19 hr and then diluted with CH2Cl2, filtered through Celite and washed with brine. The organics were dried over MgSO4 and concentrated to dryness. The reaction residue thus obtained was purified by RPLC to afford 2-((6-methyl-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile as a white solid (4.1 mg, 9%); ESI-LRMS m/z [M+1]+=295.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[S:20][CH2:19][C:18]1([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH3:29])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[S:20][CH2:19][C:18]1([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH3:29]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
(3RS,4RS)-4-[8-(t-Butyldimethylsilyloxy)-1-octyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (4.5 g, 8.29 mmol) was dissolved in tetrahydrofuran (100 ml), and cooled to 0°. To this solution was added tetrabutylammonium fluoride (16.6 ml, 16.58 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate, which was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography on silica gel, eluting with 30% ethyl acetate in n-hexane to afford 3.3 g of the title compound as a pale yellow oil. (yield: 93.0%)
Reaction SMILES: O[CH2:2][CH2:3][C:4]([CH:6]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:5].ClC([O-])=O>C(Cl)(Cl)Cl>[C:4]([CH:6]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[CH:3]=[CH2:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CCO
Agent: O=C([O-])Cl
Solvent: ClC(Cl)Cl
Product: C=CC(=O)C(CCCCCCC(=O)O)CCCC(O)CCCCC
Reaction time: 24 h

Procedure:
A solution of 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid . 1/3 chloroformate (Example 8, Step G) (3.58 g., 0.01 mole) in chloroform (5 ml.) is applied to a silica gel column (100 g., E. Merck, Darmstadt, 0.05-0.2 mm.). The column is allowed to stand at 25° for 24 hours, then eluted with chloroform-methanol (98:2) to slowly elute the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: CCC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Solvent: CO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-ethylcyclohexyl)-6-methyl-3-piperidinecarboxamide (187 mg, 0.403 mmol), EtOH (5 mL), Hunig's base (0.070 ml, 0.403 mmol), and hydrazine anhydrous (0.076 mL, 2.415 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (50 mg) as a light yellow solid. LC-MS (ES) m/z=477 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.79-1.25 (m, 14H), 1.64 (m, 3H), 1.68-1.88 (m, 5H), 2.22 (m, 1H), 2.90 (m, 1H), 3.41-3.58 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.58 (s, 1H), 7.65-7.84 (m, 2H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].O[C:17]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]=1[O:31][CH3:32].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:32][O:31][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:17]=1[O:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OC)c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
17.7 ml of Tf2O was added to a solution of 16.8 g of ethyl 4-hydroxy-3-(methyloxy)-5-nitrobenzoate and 11.3 ml of pyridine in 500 ml of CHCl3 at 0° C. The mixture was stirred for 30 min, then washed successively with water, HClaq, and saturated NaHCO3aq, dried over Na2SO4, and concentrated. The residual solid was washed with a mixed solvent of CHCl3 and n-hexane to give a 22.0 g of the intended compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5](S(C)(=O)=O)=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].[CH2:34]([NH2:37])[CH:35]=[CH2:36].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:34]([NH:37][C:5]1[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[N:4]=1)[CH:35]=[CH2:36]
Reactant: C=CCN
Reactant: COC(=O)c1ccc(C)c(-n2c(S(C)(=O)=O)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of methyl 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylsulfonyl)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (3.02 g, 6.05 mmol), allyl amine (0.55 mL, 7.26 mmol), and DMAP (0.07 g, 0.61 mmol) in dioxane (8 mL) was stirred at ambient temperature overnight. Observed product and impurity (1:1 ratio). Added ethyl acetate (4 mL), cooled (0° C.) the reaction mixture, filtered the precipitate, and dried in vacuo to give the product as a white solid (1.17 g, 41%). 1H NMR (CD3OD/400 MHz) δ8.08 (m, 1H), 7.82 (s, 1H), 7.57 (m, 2H), 7.00 (t, 2H, J=8.8 Hz), 5.80 (m, 1H), 5.51 (m, 2H), 5.07 (m, 2H), 4.56 (s, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 3.65 (s, 3H). ESHRMS m/z 476.1184 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over one hundred minutes. The solvents were removed under reduced pressure at 40° C. and the residue dissolved in ethyl acetate (approx. 1 L). The solution was washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. To the resulting oil was added hexane (approx. 1 L) and the mixture warmed to 60° C. with swirling. After cooling to room temperature, the solids were collected and washed with 2 L of hexane. The resulting solid was recrystallized from her ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. and M+Li+ =340.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:32]1([CH2:35][C:36]([OH:38])=O)[CH2:34][CH2:33]1.[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1>CN(C=O)C.O>[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][N:58]([C:36](=[O:38])[CH2:35][CH:32]5[CH2:33][CH2:34]5)[CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1
Reactant: O=C(O)CC1CC1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
71 mg of TBTU (0.22 mmol), 0.19 ml of ethyldiisopropylamine and 0.022 ml of cyclopropyl-acetic acid were dissolved in 6 ml DMF and stirred for one minute at rt under argon. Then 100 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.22 mmol) were added and the reaction mixture was stirred for 22 h at rt. The reaction mixture was then diluted with 30 ml water and extracted with ethylacetate (twice). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 130 mg of a light red solid (100%). MS (ISP) 533.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>O1CCOCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)ccc1O
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(Br)ccc2o1
Temperature: 120 °C
Yield: 91 %

Procedure:
A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1,1′-carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120° C. for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1:1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5-bromobenzo[d]oxazol-2(3H)-one in 91% yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) δ11.85 (br s, 1H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M+1), 214.0 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.S(Cl)(Cl)=O.[CH3:18]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:18])=[O:12])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of carboxylic acid 73 (10 g, 57.1 mmol) in MeOH (500 mL) was added dropwise thionyl chloride (21 mL, 285 mmol) at 0° C. The mixture was stirred at room temperature for 2 h and concentrated in vacuo to remove solvent. The residue was diluted with EtOAc and washed with aq. saturated NH4Cl solution, aq. saturated NaHCO3 solution and brine successively. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude titled compound 74 (10.9 g, quantitative) was used without further purification. MH+190.
Reaction SMILES: C(Br)(Br)(Br)Br.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[C:13]([CH2:24]O)=[CH:12]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].BrCC1C(C2C=CC=CC=2C)=NC2C(C=1)=CC=CC=2C.O.[SH:68][C:69]1[N:77]=[CH:76][N:75]=[C:74]2[C:70]=1[NH:71][CH:72]=[N:73]2.Cl>C(Cl)Cl.C1COCC1.[Cl-].[Na+].O>[N:77]1[C:69]([S:68][CH2:24][C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:6])=[C:70]2[C:74]([NH:73][CH:72]=[N:71]2)=[N:75][CH:76]=1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CO
Agent: BrC(Br)(Br)Br
Agent: Cc1ccccc1-c1nc2c(C)cccc2cc1CBr
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CSc1ncnc2[nH]cnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Solid carbontetrabromide (429 mg, 1.29 mmol) was added to a mixture of (8-methyl-2-o-tolylquinolin-3-yl)methanol (227 mg, 0.86 mmol) and triphenylphosphine (339 mg, 1.29 mmol) in CH2Cl2 (5 mL) at 0° C., and the mixture was stirred at 0° C. for 0.5 h. The crude mixture was concentrated under reduced pressure, evaporated onto silica gel, and purified by flash chromatography (Biotage® Si 25+M) eluting with EtOAc/hexane (0% to 10%) to provide an off-white solid; used without further purification, MS (ESI+) m/z=326.0 (M). A 2.0M aqueous solution of sodium hydroxide (0.86 mL, 1.72 mmol) was added to a mixture of 3-(bromomethyl)-8-methyl-2-o-tolylquinoline (140 mg, 0.43 mmol) and 6-mercaptopurine monohydrate (146 mg, 0.86 mmol) in THF (1.6 mL), and the biphasic mixture was heated under reflux for 5 h. The reaction mixture was cooled to 0° C., neutralized by the addition of 1N aqueous HCl, diluted with brine (10 mL), and extracted with THF (3×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in THF/DMSO, evaporated onto silica gel, and purified by flash chromatography (Biotage® Si 25+M) eluting with acetone/hexane (20% to 50%). The resulting off-white solid was recrystallized from THF/MeOH to provide a white solid [PI3δ IC50=889 nM]. MS (ESI+) m/z=398.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:28](=[O:29])[O:30][CH3:31])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 3 h

Procedure:
To a solution of 9.24 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 7.9 ml of N,N-diisopropylethylamine followed by 3.5 ml of methyl chloroformate. This mixture was stirred for 3 hours, then the solid was collected and washed with 100 ml of dichloromethane. The solid was heated with dichloromethane-hexane and filtered, giving 8.25 g of the desired product as crystals, mp 150°-153° C. (dec.).
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>[OH-].[Na+].C1COCC1>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:1][CH:2]([CH:6]2[CH2:11][CH2:10][C:9]([F:12])([F:13])[CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: NC(C(=O)O)C1CCC(F)(F)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
The amino(4,4-difluorocyclohexyl)acetic acid (2.68g, 10.973 mmol) was dissolved in 2N NaOH (20 mL). The solution was cooled to 0° C., 5-chlorothiophene-2-sulfonyl chloride (3.25g, 12.42 mmol) was added (5 min) dropwise as a solution in THF (10 mL). The solution was allowed to warm up to 25° C. overnight. After 19 h, THF was removed in vacuo and the mixture was acidified to a pH of about 1 to about 2 with 2N HCl (20 mL). The aqueous layer was washed with EtOAc (4×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to produce {[(5-chlorothien-2-yl)sulfonyl]amino}(4,4-difluorocyclohexyl)acetic acid as a crude oil (3.8 g, 98.2%).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCC(OCc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 1.6 g of a 50% aqueous sodium hydroxide solution, 10 ml of methylene chloride, 2 g (0.008 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 2.32 g (0.012 mol) of 4-fluorobenzyl bromide and 0.15 g (4×10-4 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50° C. After dilution of the reaction medium with 20 ml of water and 30 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral, dried (MgSO4) and evaporated in vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 2.23 g of a product which is purified by dissolving it in 11 ml of dimethylformamide (DMF) and reprecipitating it by the dropwise addition of 11 ml of water, whilst stirring. After washing with water and drying in vacuo, 1-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)-piperidine, m.p. 120° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:49][CH2:50][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]([B:36]2[O:44][CH:43]3[C:38]([CH3:48])([CH:39]4[CH2:45][CH:41]([CH2:42]3)[C:40]4([CH3:47])[CH3:46])[O:37]2)[CH2:20][C:21]2[C:22]([O:34][CH3:35])=[C:23]([CH:31]=[CH:32][CH:33]=2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH2:68]=[O:69]>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([CH2:49][CH2:50][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]([CH2:68][OH:69])[C:16]([NH:18][C@H:19]([B:36]2[O:44][CH:43]3[C:38]([CH3:48])([CH:39]4[CH2:45][CH:41]([CH2:42]3)[C:40]4([CH3:47])[CH3:46])[O:37]2)[CH2:20][C:21]2[C:22]([O:34][CH3:35])=[C:23]([CH:31]=[CH:32][CH:33]=2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](N(CCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C[C@H](NC(=O)C(CO)[C@H]2CC[C@H](N(CCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-((2R)-2-(2-(trans-4-(tert-butoxycarbonyl(2-(tert-butoxycarbonyl(methyl)amino)ethyl)amino)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (110 mg) in THF (5 mL) was added LDA (2 M in benzene, 160 μL) at −76° C. The reaction mixture was stirred at same temperature for 30 min before formaldehyde (20 mg) was added. The reaction mixture was allowed to warm up to RT and stirred for 4 hr. Brine was added and extracted with EtOAc. The organic phase was dried and concentrated to afford the crude product which was used to next step without further purification.
Reaction SMILES: CC1C=C(N2CCN(CC[O:14]C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[C:27]([C:29]1[CH:52]=[CH:51][C:32]([CH2:33][N:34]2[CH2:38][CH2:37][N:36]([C:39]3[S:43][C:42]([C:44]([O:46]CC)=[O:45])=[C:41]([CH3:49])[CH:40]=3)[C:35]2=[O:50])=[CH:31][CH:30]=1)#[N:28]>>[C:27]([C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:34]2[CH2:38][CH2:37][N:36]([C:39]3[S:43][C:42]([C:44]([OH:46])=[O:45])=[C:41]([CH3:49])[CH:40]=3)[C:35]2=[O:50])=[CH:51][CH:52]=1)(=[O:14])[NH2:28]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C#N)cc3)C2=O)cc1C
Reactant: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Product: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)O
Yield: 77 %

Procedure:
Following the procedure as described in Example 54, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)-thiophene-2-carboxylate with ethyl 5-(3-(4-cyanobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 77% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (br s, 1H), 7.87 (d, J=7.9 Hz, 2H), 7.36 (d, J=7.9 Hz, 2H), 6.30 (s, 1H), 4.45 (s, 2H), 3.90-3.80 (m, 2H), 3.54-3.42 (m, 4H), 2.40 (s, 3H); MS (ES+) m/z 382.3 (M+23).