Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32]I)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(OCCCI)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCOc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 150 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and 1-chloro-4-(3-iodopropoxy)benzene and conditions outlined in procedure V. M.p.=130-132° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92-7.87 (m, 1H), 7.82-7.74 (m, 2H), 7.6-7.52 (m, 1H), 7.36-7.18 (m, 2H), 7.0-6.92 (m, 2H), 4.1-3.95 (m, 2H), 3.07 (s, 2H), 2.83-2.72 (m, 2H), 2.55-2.48 (m, 2H), 2.4-2.25 (m, 2H), 2.05-1.75 (m, 6H); LCMS: 470 [M+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[C:8]#[CH:9].C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](=[O:39])(=[O:38])[N:35]([CH3:37])[CH3:36])[CH:29]=1>C(Cl)(Cl)Cl>[CH2:12]([O:11][C:7]([C:8]1[CH:9]=[N:27][N:28]2[CH:29]=[C:30]([S:34](=[O:38])(=[O:39])[N:35]([CH3:37])[CH3:36])[CH:31]=[CH:32][C:33]=12)=[O:10])[CH3:13]
Reactant: C#CC(=O)OCC
Reactant: CN(C)S(=O)(=O)c1ccc[n+](N)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn2cc(S(=O)(=O)N(C)C)ccc12

Procedure:
Potassium carbonate and ethyl propiolate are added to a stirred suspension of 1-Amino-3-dimethylsulfamoyl-pyridinium mesitylenesulfonate in chloroform at room temperature. For more details, see literature: Yasumitsu Tamura, Yoshio Sumida, Yasuyoshi Miki and Masazumi Ikeda, J. Chem. Soc. Perkin 1, 1974, 406-409
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC#N>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCNCc1nc2ccccc2[nH]1
Yield: 43.6 %

Procedure:
2-Chloromethylbenzimidazole (19.81 g, 118.9 mmol) was added as a solid to a mechanically stirred and cooled (1.2° C. internal temperature) solution of (4-amino-butyl)-carbamic acid tert-butyl ester (56.0 g, 297.3 mmol) and DIPEA (51.8 mL, 297.3 mmol) in CH3CN (3 L) under N2. After 4.5 h at low temperature the cooling bath was removed and the mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (1.5 L) and washed with brine (1 L). The aqueous layer was extracted with CH2Cl2 (2×500 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford a yellow foamy solid. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH (98:1:1) to CH2Cl2/MeOH/NH4OH (80:10:10)) afforded product containing mixed fractions. Repurification of these fractions by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH (98:3:3)) afforded the title compound as a yellow solid (16.5 g, 44%). 1H NMR (CDCl3) δ 1.50 (s, 9H), 1.60-1.64 (m, 4H), 2.70-2.74 (m, 2H), 3.10-3.18 (m, 2H), 4.13 (s, 2H), 4.86 (s, 1H), 7.19-7.25 (m, 2H), 7.50-7.95 (m, 2H), 10.4 (bs, 1H); 13C NMR (CDCl3) δ 26.1, 27.3, 28.1, 39.7, 41.2, 47.2, 47.7, 48.3, 49.4, 78.9, 121.7, 153.9, 155.9; ES-MS m/z 319 (M+H). Anal Calcd. For C17H26N4O2.0.2(H2O): C, 63.41; H, 8.26; N, 17.40. Found: C, 63.51; H, 8.19; N, 17.33.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[C:26]([CH2:28][C:29]([OH:31])=[O:30])#[N:27]>>[C:26]([CH2:28][C:29]([O:31][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:30])#[N:27]
Reactant: N#CCC(=O)O
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: N#CCC(=O)OC1(N=O)CCCCC1

Procedure:
1-Nitrosocyclohexyl 2-cyanoacetate was prepared from cyclohexanone oxime, lead tetraacetate and cyanoacetic acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 3.62 (2H, s), 2.01-2.21 (2H, m), 1.70-1.97 (5H, m), 1.41-1.69 (3H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])CCC.OC(C(O)(C)C)(C)C.[B:25]([O:34][CH:35]([CH3:37])[CH3:36])([O:30][CH:31]([CH3:33])[CH3:32])OC(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:25]2[O:30][C:31]([CH3:32])([CH3:33])[C:35]([CH3:36])([CH3:37])[O:34]2)=[CH:10][CH:9]=[N:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cnn(C2CCCCO2)c1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a 500 ml flask was added 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 14.1.A and 100 ml of THF. The solution was cooled to −78° C. at which time butyllithium (52 ml, 83 mmole, 1.6M in hexanes) and pinacol (9.8 g, 83 mmole) were added. The reaction was stirred for 5 minutes at −78 C and then triisopropyl borate (19 g, 103 mmole) was added. The reaction was slowly warmed to room temperature over 90 minutes and then stirred at room temperature for an additional 16 hours at which time the reaction was quenched with NH4Cl aq. (pH ˜7-8), extracted with EtOAc, and purified by silica gel chromatography to give 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14.1.B (7.2 g, 38% yield).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cn1c(CBr)nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cn1c(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1-methyl-1H-benzoimidazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (20%) as a colorless solid: mp>240° C.; 1H NMR (300 MHz, CDCl3) δ7.58-7.53 (m, 2H), 7.30-7.14 (m, 5H), 7.06-6.99 (m, 1H), 6.60 (s, 1H), 6.51 (s, 1H), 5.28 (ABq, 2H), 4.81 (d, J=9.3 Hz, 1H), 4.71 (d, J=9.3 Hz, 1H), 4.22-4.10 (m, 4H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ176.6, 154.5, 149.1, 144.1, 142.3, 141.7, 137.8, 136.1, 131.9, 128.5, 123.3, 123.0, 122.1, 121.5, 121.4, 118.6, 112.0, 110.1, 109.7, 98.5, 79.3, 64.1, 63.6, 57.3, 37.1, 29.8; MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[C:7]([C:17](=O)[CH3:18])[C:6]=2[CH:20]=1.[NH2:21][OH:22].Cl>CCO.N1C(=O)CC[C@H]1C(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[C:7]([C:17](=[N:21][OH:22])[CH3:18])[C:6]=2[CH:20]=1
Reactant: NO
Reactant: CC(=O)c1c(-c2ccc(O)cc2)oc2ccc(O)cc12
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCO
Product: CC(=NO)c1c(-c2ccc(O)cc2)oc2ccc(O)cc12
Yield: 6.5 %

Procedure:
Ketone 110 (1.9 g, 7.1 mmol) was dissolved in a solution of EtOH/Pyr (50 mL/10 mL) and treated with NH2OH—HCl (0.5 g, 7.2 mmol) and heated at reflux until all of the starting material was consumed by TLC analysis. The reaction was worked up by concentrating down and partitioning the residue between EtOAc and 2 N HCl aq, washing the EtOAc layer with saturated NaHCO3 aq, brine and drying over MgSO4. The solution was then filtered, concentrated and chromatographed on silica gel (1:4 EtOAc/hexanes) and the product obtained triturated with CH2Cl2 to yield 0.131 g of the pure oxime. Stereochemistry of the oxime was tentatively defined as cis since no NOE effect between the oxime hydroxyl proton and the adjacent methyl group could be observed: Mp=217° C.; 1H NMR (DMSO-d6) δ 11.27 (s, 1 H), 9.94 (br s, 1 H), 9.23 (br s, 1 H), 7.51 (d, 2 H, J=8.8 Hz), 7.36 (d, 1 H, J=8.3 Hz), 7.03 (d, 1 H, J=2.4 Hz), 6.88 (d, 2 H, J=8.8 Hz), 6.74 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 1.99 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH2:28][OH:29])=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH:28]=[O:29])=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(CO)ccc3c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C=O)ccc3c12
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Step 1 A solution of 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 31-4, 0.54 g, 1.155 mmol) in THF (38.5 mL) was treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1 H)-one (Dess-Martin periodinane, 0.784 g, 1.848 mmol) at rt and the mixture was stirred for 2 h. The mixture was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was triturated with methanol and the solid was collected by filtration and dried to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-formyl-9H-carbazole-1-carboxamide as an orange solid (458 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 11.98 (1 H, s), 10.16 (1 H, s), 10.03 (1 H, s), 8.23-8.32 (2 H, m), 8.05-8.14 (3 H, m), 7.60 (1 H, br. s.), 7.49-7.55 (1 H, m), 7.39-7.49 (2 H, m), 7.32-7.39 (2 H, m), 7.21-7.27 (1 H, m), 7.09 (2 H, t, J=8.1 Hz), 1.88 (3 H, s). Mass spectrum m/z 466.3 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([N:14]([C:27]2[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[CH:17]=2)[C@@H:8]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])([CH3:3])[CH3:2].[CH3:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[CH:17]=2)[C:27]2[N:32]=[CH:31][C:30]([C:45]3[CH:44]=[N:43][N:42]([CH3:41])[CH:46]=3)=[CH:29][N:28]=2)[C@@H:8]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(Br)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CC[C@@H]1C[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Temperature: 90 °C
Reaction time: 17 h
Yield: 50.5 %

Procedure:
(2S,3S,5R)-2-Benzyl-3-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)-amino]-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.042 mmol; 27 mg), tetrakis(triphenylphosphine) palladium (0.0042 mmol; 4.9 mg), 1-methylpyrazol-4-boronic acid pinacol ester (0.063 mmol; 13 mg) and sodium carbonate (0.084 mmol; 8.9 mg) are dissolved in 1,2-dimethoxyethane (0.8 mL) and water (0.08 mL) at room temperature. The mixture is stirred at 90° C. for 17 hours, and then cooled to ambient temperature. To the mixture is added brine and the solution is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-Benzyl-3-{(3-chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (13.6 mg, 51%); ESI-MS m/z: 641 [M+1]+, Retention time 2.62 min (condition A).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH:37]4CCN(C)CC4)[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:44][CH3:45]>N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:44][CH3:45])[CH:17]=3)[C:29]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 5 h
Yield: 68.4 %

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (48 mg, 0.231 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (101 mg, 0.231 mmol) in pyridine (1.0 mL). After 5 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide (83 mg, 59%). 1H NMR (CDCl3-d) δ 1.68 (m, 2H), 1.82 (m, 4H), 2.01 (m, 4H), 2.29 (s, 3H), 2.44 (m, 3H), 2.93 (m, 2H), 3.30 (m, 2H), 4.03 (s, 3H), 4.77 (m, 1H), 5.60 s, 2H), 7.33 (m, 2H), 1.79 d, J=8.19 Hz, 2H), 8.04 (d, J=8.04 Hz, 2H), 8.37 (s, 1H), 8.66 (m, 2H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+ =609.4, Rt=2.50 min.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1(C2C=CC(OC)=C(C=2)[CH:30]=[O:31])CC1)#N>>[C:1]1([C:7]#[C:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:13]=2)[CH:30]=[O:31])([CH3:11])[CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1
Product: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1C=O

Procedure:
This compound was prepared from Compound 67 in the same manner of Compound 2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][C:18]1=[O:23].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:24][CH2:25][C:26]([N:15]([CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][C:18]1=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1NCN1C(=O)CSC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N(CN1C(=O)CSC1=O)C(=O)CCl
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.9 %

Procedure:
A suspension of 7 g of anhydrous potassium carbonate, 7.3 g of N-(2-methoxyphenylaminomethyl)-2,4-thiazolidinedione, and 5.3 g of chloroacetyl chloride in 50 ml of chloroform was cooled in an ice bath and stirred at ambient temperature for 48 hrs. The resulting precipitate was filtered, washed with water and recrystallized from nitromethane-ethanol to give 5.6 g of 2-chloro-N-(2,4-dioxothiazolidin-3-ylmethyl)-N-(2-methoxyphenyl)acetamide; mp 188°-191° C; M+ = 328.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:4][CH2:3]1.[Br:22]Br>N1C=CC=CC=1>[Br:22][C:10]1[S:9][C:7]2[NH:8][C:2](=[O:1])[CH2:3][N:4]=[C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[C:6]=2[CH:11]=1
Reactant: COC(=O)c1ccc(C2=NCC(=O)Nc3sccc32)cc1
Reactant: BrBr
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C2=NCC(=O)Nc3sc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
In a 20 mL dram screw-cap vial with septum was dissolved compound 493 (0.140 g, 0.466 mmol) in pyridine (3 mL) to give an orange solution. The mixture was cooled to 0° C. and bromine (0.029 mL, 0.559 mmol) was added dropwise. The reaction mixture was left to stir at 0° C. for 1 hour. The mixture was quenched with saturated thiosulfate solution and extracted with ethyl acetate. The organic layer was washed several times with water, then brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in ether and filtered to afford title compound 494 (101 mg, 57%) as a tan solid. MS (m/z): 379.33 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][N:16]=[C:17]=[O:18])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:25])[NH2:24].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:25])[NH:24][C:17]([NH:16][CH2:15][C:14]1[CH:19]=[CH:20][CH:21]=[C:12]([C:10](=[N:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:11])[CH:13]=1)=[O:18]
Reactant: CN(C)N
Reactant: CC(=NOCc1ccccc1)c1cccc(CN=C=O)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=NOCc1ccccc1)c1cccc(CNC(=O)NN(C)C)c1
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of 2.75 g of crude 3-(1-(benzyloxyimino)ethyl)benzylisocyanate in 13 ml of dry toluene was added dropwise a solution of 0.53 g (8.74 mmol) of N,N-dimethylhydrazine in 5 ml of dry toluene with ice-cooling. The mixture was removed from an ice bath and stirred for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 0.55 g (1.62 mmol) of 1,1-dimethyl-4-{3-(1-(benzyloxyimino)ethyl)benzyl}-semicarbazide.
Reaction SMILES: [CH2:1]([N:3]1[C:11]([CH2:12]O)=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]1[CH3:29])=[N:7][C:8]=2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:2].O1CCCC1.P(Br)(Br)[Br:36]>>[Br:36][CH2:12][C:11]1[N:3]([CH2:1][CH3:2])[C:4]2[C:9]([N:10]=1)=[C:8]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[N:7]=[C:6]([N:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]1[CH3:29])[N:5]=2
Reactant: CCn1c(CO)nc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc21
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: CCn1c(CBr)nc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc21
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of (9-ethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol (3 g, 7.65 mmol) in tetrahydrofuran (150 mL, 1800 mmol) was added phosphorus tribromide (1.44 mL, 15.3 mmol;) dropwise. The mixture was stirred for 2 hrs until LC/MS showed the reaction was complete. The reaction was quenched with MeOH and extracted with Ethyl acetate and water. The organic layer was collected, dried with Magnesium sulfate, filtered and concentrated to give a crude orange oil. The oil was purified by flash chromatography to give 2.6 g of 4-(8-(bromomethyl)-9-ethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine as an orange solid, of which 50 mg was reacted with 2-(piperidin-4-yl)propan-2-ol via Gen Procedure E to give 34.6 mg 236 following reverse phase purification. MS (Q1) 519.3 (M)+
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][C:27]([C:31]#[N:32])=[C:28]([CH3:30])[N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[S:26][C:27]([C:31]#[N:32])=[C:28]([CH3:30])[N:29]=1)=[CH:14][CH:13]=2
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)sc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Tert-butyl[6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.21 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carbonitrile hydrochloride (0.11 g, 91.7%) as crystals.
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([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]([C:29](=[O:50])[NH:30][C@@H:31]3[CH2:35][CH2:34][C@H:33]([CH2:36][N:37]4[CH2:42][CH2:41][CH:40]([CH2:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH2:39][CH2:38]4)[CH2:32]3)([CH3:28])[C@@H:15]2[CH2:24][C:25]([CH3:27])=[CH2:26])[C:6]1([CH3:54])[CH3:53])(=O)C.[CH2:55]1COCC1.[OH-].[Na+]>CO>[CH2:43]([CH:40]1[CH2:39][CH2:38][N:37]([CH2:36][C@H:33]2[CH2:34][CH2:35][C@@H:31]([NH:30][C:29]([C@:14]34[CH2:28][CH2:55][C@@H:24]([C:25]([CH3:27])=[CH2:26])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:51])([CH2:12][CH2:13]4)[C@@:10]4([CH3:52])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:53])([CH3:54])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:50])[CH2:32]2)[CH2:42][CH2:41]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: C=C(C)C[C@@H]1[C@H]2CC[C@@H]3[C@@]4(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]2(C)CC[C@]1(C)C(=O)N[C@@H]1CC[C@H](CN2CCC(Cc3ccccc3)CC2)C1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)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

Procedure:
(2S,4aR,4bR,6aR,7R,8S,10aR,10bR,12aR)-8-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentylcarbamoyl)-1,1,4a,8,10a,10b-hexamethyl-7-(2-methylallyl)octadecahydrochrysen-2-yl acetate (Example 31, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 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 (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); MASS: 711 (100%).