Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]2[CH:4]=[CH:3][C:2]([C:34]3[N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:37]=[CH:36][CH:35]=3)=[CH:7][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.127 g, 0.32 mmoL), 1-N-BOC-pyrrole-2-boronic acid (0.21 g, 1.0 mmoL), tetrakis(triphenylphosphine)palladium (0) (0.033 g, 0.029 mmoL), 2 M Na2CO3 (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirred reaction mixture was heated at reflux overnight under a nitrogen atmosphere. The oil bath was removed and the reaction mixture was allowed to cool at RT. The reaction mixture was transferred to a separatory funnel and partitioned between H2O and EtOAc. The organic phase was separated, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give an orange-brown oil. The crude product was purified by flash chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 80:20) to give 111 mg (72%) of compound 18 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 12 H), 1.24 (m, 11 H), 1.92 (s, 2 H), 1.94 (s, 2 H), 6.19 (m, 1 H), 6.23 (m, 1 H), 6.65 (d, J=8.5 Hz, 2 H), 6.92 (d, J=8.4 Hz, 2 H), 7.09 (d, J=8.1 Hz, 2 H), 7.21 (d, J=8.0 Hz, 2 H), 7.31 (m, 1 H), 9.27 (s, 1 H). LCMS (ESI): m/z 508 (M+Na)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=O)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=[S:21])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NCCCC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCCC(N)=S
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 149.2 %

Procedure:
A suspension of 4-methanesulfonylamino-butyramide (0.50 g, 2.8 mmol) and Lawesson's reagent (0.56 g, 1.4 mmol) in THF (50 mL) was stirred at room temperature for 45 minutes. During this time all of the solid dissolved. The solution was concentrated and purified by flash chromatography (79:1 EtOAc:MeOH) to afford the title compound (0.41 g); 1H NMR (400 MHz, CDCl3) δ 3.29 (s, 3H), 3.07-3.11 (m, 2H), 2.91 (s, 3H), 2.62-2.66 (m, 2H), 1.93-1.99 (m, 2H); MS 197 (M++1).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]1([CH2:18][CH2:19][CH:20]2[C:24]3[CH:25]=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][C:23]=3[O:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C(Cl)Cl>[C:12]1([CH2:18][CH2:19][CH:20]2[C:24]3[CH:25]=[C:26]([CH:29]=[O:30])[CH:27]=[CH:28][C:23]=3[O:22][CH2:21]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccc2c(c1)C(CCc1ccccc1)CO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)C(CCc1ccccc1)CO2
Reaction time: 12 h
Yield: 6.1 %

Procedure:
To a suspension of PCC (3.69 g, 17.10 mmol) in methylene chloride (20 ml), a solution of 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl-methanol (3.32 g, 13.16 mmol) in methylene chloride (100 ml) was added at room temperature. After stirring for 12 h, diethyl ether (300 ml) was added and the black solid precipitated was filtered and washed with diethyl ether several times. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5-9/1) affording 0.202 g of the title compound (67% yield).
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CO>[OH:23][C:20]1[CH2:21][S:1][C@@H:2]2[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:24])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (70 mg) prepared by the method of 4.-III(2) in a mixture of methylene chloride (2 ml) and methanol (2 ml) is stirred for 3 hours at room temperature. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-hyroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (42 mg), identical with the product of Example 4(3). Yield: 70%.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([CH3:13])([CH3:12])[CH:8]([CH3:11])[C:9](=O)[C:4]=2[CH:3]=1.[BH4-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:11])=[CH:9][C:4]=2[CH:3]=1
Reactant: CC1C(=O)c2cc(Br)ccc2OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1=Cc2cc(Br)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo[b]pyran (407 g) (see Preparation 3) was dissolved in ethanol (1500 ml), cooled in an ice bath and sodium borohydride (61.4 g) was added portionwise over 20 minutes. The mixture was stirred at room temperature for 3 hours, the solvent removed under reduced pressure, the residue dissolved in diethyl ether and the mixture washed first with water and then with brine. The organic layer was dried (anhydrous magnesium sulphate) and the solvent removed to yield the crude alcohol. This was dissolved in toluene (1000 ml), para-toluenesulphonic acid (40 g) added and the mixture heated under reflux (with removal of water) for 2 hours. The solvent volume was reduced to approximately 500 ml and the solution was washed with aqueous sodium carbonate solution and then brine. The organic phase was dried (anhydrous magnesium sulphate) and the solvent removed under reduced pressure to yield 6-bromo-2,2,3-trimethyl-2H-benzo[b]pyran (350 g) as an orange oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[NH:26][C:25]2[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1>CC(O)C.O>[CH3:32][O:31][C:27]1[C:25]2[NH:26][C:22]([NH:18][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:8]4[C:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=3)=[N:23][C:24]=2[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc2nc(Cl)[nH]c12
Reactant: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cccc2nc(Nc3ccc(Oc4ncccc4C4CCOCC4)cc3)[nH]c12
Temperature: 170 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.1130 g, 0.418 mmol) and 2-chloro-7-methoxy-1H-benzo[d]imidazole (0.092 g, 0.502 mmol) in IPA. The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 170° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 7-methoxy-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([O:15]C(C)(C)C)=[O:14])(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)O
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of Intermediate 4A (0.048 g, 0.171 mmol) in 50% TFA/DCM (2 mL) was stirred at rt. After 1 h, the reaction was concentrated to give Intermediate 4 (0.038 g, 100%) as a yellow solid. The material was carried onto the next step without further purification. MS (ESI) m/z: 225.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=O.[BH4-].[Na+]>>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: CC(C)(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)CCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 68.2 %

Procedure:
Using a method similar to Example 201, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol), 3,3-dimethylbutyraldehyde (75 mg, 0.750 mmol), and NaBH4 (38 mg, 1.00 mmol) gives the title compound (130 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.55 (s, 1H), 8.14 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H), 5.76 (br. s, 2H), 3.03 (m, 1H), 2.92-2.80 (m, 2H), 2.71-2.55 (m, 3H), 2.49-2.41 (m, 1H), 1.85-1.65 (m, 4H), 1.42 (t, 2H), 0.90 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:22])=[N:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:29]([C:27]3[S:28][C:24]([CH3:23])=[CH:25][CH:26]=3)(=[O:31])=[O:30])=[N:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1F
Solvent: c1ccncc1
Product: COc1ccc(Cn2nc(NS(=O)(=O)c3ccc(C)s3)c3c(OC)cccc32)cc1F
Reaction time: 3 h

Procedure:
A solution of 1-{[3-fluoro-4-(methyloxy)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 80) (130 mg, 0.8 mmol) in pyridine (2 mL) was added to 5-methyl-2-thiophenesulfonyl chloride (0.24 mmol). The reaction mixture was shaken briefly and allowed to stand for 3 h at 21° C. prior to concentration by blowdown. The residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier (Method C). The solvent was evaporated in vacuo to give the title compound (76 mg) LCMS (System A) RT=1.11 min, ES+ve m/z 462 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[CH:17]1([C:20]2[N:21]([NH2:30])[C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=3)[CH2:19][CH2:18]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH:17]1([C:20]2[N:21]([NH:30][C:8]([C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:11]4[N:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[N:5][CH:6]=3)=[O:10])[C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=3)[CH2:19][CH2:18]1
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: Nn1c(C2CC2)cc2cc(F)ccc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1c(C2CC2)cc2cc(F)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
A solution of 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (184 mg, 0.85 mmol) and 2-cyclopropyl-5-fluoro-indol-1-ylamine (135 mg, 0.71 mmol) in DMF (3 mL) is stirred at 40° C. for 1 h. The mixture is treated with DMTMM (235 mg, 0.71 mmol) and stirred at 40° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (2-cyclopropyl-5-fluoro-indol-1-yl)-amide (35 mg, 13%). MS: 389 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 11.93 (s, NH, 1H), 9.31 (s, 1H), 9.06 (d, 2H), 7.70 (m, 1H), 7.42 (m, 1H), 7.26 (m, 1H), 6.97 (m, 1H), 6.16 (s, 1H), 2.79 (s, 3H), 1.97 (m, 1H), 1.01 (m, 2H), 0.74 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:70]1([C@@H:76]([NH2:78])[CH3:77])[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:78][C@H:76]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH3:77])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@@H](C)c3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [(1S)-1-phenylethyl]amine (12.9 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 45%). LC-MS m/z 625 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[C:12]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+]>C(O)C.C(Cl)Cl.[Cl-].[Na+].O>[C:12]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[NH:19][C:20]([S:22][CH2:2][C:3]3[C:8]4[O:9][CH2:10][O:11][C:7]=4[CH:6]=[CH:5][N:4]=3)=[N:21][C:17]=2[CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc2[nH]c(S)nc2cc1C
Reactant: ClCc1nccc2c1OCO2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2nc(SCc3nccc4c3OCO4)[nH]c2cc1C

Procedure:
2-Chloromethyl-3,4-methylenedioxypyridine (90 mg, 0.52 mmol) and 5-acetyl-6-methyl-2-mercaptobenzimidazole (214 mg, 1.04 mmol) were dissolved in ethanol (15 ml). The pH value of the solution was adjusted to 9 (0.2M NaOH) whereupon the solution was refluxed for 10 min. After concentration of the reaction mixture at reduced pressure the residue was taken up in methylene chloride (10 ml) and brine (2 ml). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica (ethyl acetate). Yield: 140 mg (79%) of the title compound. Mp: 141°-143° C. (uncorr.)
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@H:32]4[CH2:36][C@@H:35]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH:34]=[CH:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:31][C@H:32]4[CH2:36][C@@H:35]([CH2:37][N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)[CH:34]=[CH:33]4)=[O:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C=C[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C=C[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1S,4R)-4-(morpholinomethyl)cyclopent-2-enylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 21, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m, 9H); 1.25-1.39 (m, 11H); 1.43-1.88 (m, 24H); 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, 1H); 4.74 (s, 1H); 5.52-5.55 (m, 1H); 5.69-5.70 (m, 1H); 5.72-5.91 (m, 1H); ES Mass: 620 (100%), [M+1] 621; HPLC: 96.98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22]Cl)=[CH:7]2.[H-].[Na+].[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:21])[F:20])[C:8]([CH2:22][N:29]1[C:30]3=[N:31][CH:32]=[N:33][C:34]([NH2:36])=[C:35]3[C:27]([I:26])=[N:28]1)=[CH:7]2
Reactant: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F

Procedure:
Prepared according to Procedure I using 8-chloro-3-(chloromethyl)-2-(2-trifluoromethylphenyl)quinoline (0.356 g, 1.0 mmol), NaH (0.044 g 60% in oil, 1.1 mmol, 1.1 eq) and 3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.287 g, 1.1 mmol, 1.1 eq) in 5 mL DMF. 1-((8-Chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3Kδ IC50=7 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (1 H, s), 8.08 (1 H, d, J=8.2 Hz), 7.96-8.03 (2 H, m), 7.74-7.84 (1 H, m), 7.56-7.70 (3 H, m), 7.26-7.37 (1 H, m), 5.47 (2 H, s) Mass Spectrum (ESI) m/e=580.9 and 583.0 (M+1)
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[S:5][C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[C:10]([F:11])[C:2]=2[F:1])=[N:6][C:23]=1[CH3:25])=[O:19])[CH3:22]
Reactant: NC(=S)c1ccc(C(F)(F)F)c(F)c1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)c(F)c2F)nc1C
Yield: 41.7 %

Procedure:
A solution of 2,3-difluoro-4-trifluoromethyl-thiobenzamide (1.15 g, 4.8 mmol) and ethyl 2-chloro-acetoacetate (0.67 ml, 4.8 mmol) in ethanol (70 ml) was heated at reflux temperature for 14 hours. The solvent was removed under reduced pressure and the residue partitioned between ice water and ethyl acetate. The layers were separated and the aqueous phase extracted two more times with ethyl acetate. The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 700 mg (2 mmol, 42%) of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])=[O:18])=[CH:15][C:10]=3[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[N:3]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])=[O:18])=[CH:15][C:10]=3[NH:9][N:8]=2)=[N:3]1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1ccn(C)n1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(-c3ccn(C)n3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 55 %

Procedure:
A solution of crude (R)-1-(3-(1-methyl-1H-pyrazol-3-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (36 mg, 0.060 mmol) in DCM (1 mL) was treated with TFA (0.2 mL) and triethylsilane (0.02 mL, 0.125 mmol). The mixture was stirred at room temperature for 5.5 h, evaporated in vacuo and purified on reversed phase HPLC to afford (R)-1-(3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (15.7 mg, 0.033 mmol, 55%) as a white solid. MS ESI calcd. For C19H20N7O [M+H]+ 362, found 362. 1H NMR (600 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.16 (s, 1H), 9.12 (s, 1H), 7.84-7.79 (m, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.57 (s, 1H), 7.35-7.27 (m, 4H), 7.21 (ddd, J=8.7, 5.8, 2.6 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 4.97-4.71 (m, 1H), 3.93 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).