Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>>[CH2:1]([CH:8]1[N:12]([CH3:29])[C:11](=[O:13])[N:10]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(Cc3ccccc3)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)C(Cc3ccccc3)N(C)C2=O)cn1
Yield: 95 %

Procedure:
Prepared as in example 10-5 from 5-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-2) and iodomethane. Yield: 95%. 1H NMR (CDCl3, 400 MHz): δ 2.04 (s, 3H), 2.15 (s, 3H), 2.96 (s, 3H), 3.24-3.23 (m, 2H, J=4.0 Hz), 4.23-4.21 (m, 1H), 5.00 (s, 2H), 7.24-7.23 (m, 5H, J=4.0 Hz), 7.70 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:52](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH3:52])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCl
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 120 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 3 ml DMF were added 39 mg EDC, 25 mg DMAP and 34 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 47 mg MS (ES+): m/e=724.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[N:25]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:32]#[C:31][C@:29]([C:26]4[N:25]=[C:24]([CH3:23])[O:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: CC(C)(O)c1nn(-c2nc(N)ncc2Cl)c2cc(I)ccc12
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(C)(C)O)nn(-c4nc(N)ncc4Cl)c3c2)no1
Temperature: 35 °C

Procedure:
To a solution of 2-[1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (150 mg, 0.35 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (40.3 mg, 0.02 mmol), copper(I) iodide (6.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (106 mg, 0.70 mmol). The reaction was warmed to 35° C. for 1.5 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (heptane/EtOAc gradient) to furnish the title compound as a dark red solid: 1H NMR (500 MHz, DMSO-d6) delta 1.69 (6H, s), 1.93 (3H, s), 2.69 (3H, s), 5.65 (1H, s), 6.85 (1H, s), 7.34 (2H, br. s.), 7.39 (1H, dd, J=8.35, 1.10 Hz), 8.21 (1H, d, J=8.35 Hz), 8.26 (1H, s), 8.51 (1H, s); LC-MS: m/z=+454.05/456.05 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]2[N:9]=[C:10]([NH:13][C:14]3[C:19]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:17]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:16][N:15]=3)[S:11][CH:12]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(Cl)Cl.CO.Cl>O1CCOCC1>[CH3:1][CH:2]1[CH:7]([C:8]2[N:9]=[C:10]([NH:13][C:14]3[C:19]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:17]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:16][N:15]=3)[S:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1c1csc(Nc2ncc(Sc3ccccn3)cc2Oc2ccccc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC1CNCCC1c1csc(Nc2ncc(Sc3ccccn3)cc2Oc2ccccc2)n1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A 25 mL flask was charged with tert-butyl 3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (0.296 g, 0.514 mmol), CH2Cl2 (3 mL) and MeOH (3 mL). 4N HCl in dioxane (6 mL) was added and the reaction was stirred for 1 hour and then concentrated. The crude material was dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford N-(4-(3-methylpiperidin-4-yl)thiazol-2-yl)-3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine (0.202 g, 82% yield)
Reaction SMILES: [Cl:1]C1C=C(N2CCN(C[CH2:15][CH2:16][N:17]3[C:21](=[O:22])[N:20]=[C:19](CC)[NH:18]3)CC2)C=CC=1.[O:25](CCBr)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].ClC1C=C(N2CCN(CCCN3C(=O)N(CCOC4C=CC=CC=4)C(CC)=N3)CC2)C=CC=1.Cl>C(O)C.C(#N)C>[ClH:1].[O:25]([CH2:15][CH2:16][N:17]1[C:21](=[O:22])[NH:20][CH:19]=[N:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCc1nc(=O)n(CCCN2CCN(c3cccc(Cl)c3)CC2)[nH]1
Reactant: BrCCOc1ccccc1
Agent: CCc1nn(CCCN2CCN(c3cccc(Cl)c3)CC2)c(=O)n1CCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC#N
Product: O=c1[nH]cnn1CCOc1ccccc1
Yield: 53 %

Procedure:
A mixture of 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3(2H)-one (15 g., 0.043 mole), phenoxyethyl bromide (8.62 g., 0.043 mole) and potassium carbonate (11.9 g., 0.086 mole) and a trace of potassium iodide in 100 ml. of acetonitrile is refluxed for a 64 hr. period. The reaction mixture is filtered, the filtrate concentrated under reduced pressure and residual material taken up in ether and filtered. Concentration of the ethereal filtrate affords 18.35 g. (91%) of the free base product 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one. The free base is converted to the hydrochloride in ethanol employing ethanolic hydrogenchloride and crystallized from ethanol to afford a 53% yield of analytically pure 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl-2H-1,2,4-triazol- 3(4H)-one hydrochloride, m.p. 175°-177° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]2[C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][S:13](=[O:26])(=[O:25])[CH2:12]2)[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:7]1[N:6]=[CH:5][C:4]([NH:10][C@H:11]2[C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][S:13](=[O:26])(=[O:25])[CH2:12]2)=[CH:3][C:2]=1[NH:36][C:31]1[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=[C:33]([CH3:35])[N:32]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS(=O)(=O)C[C@H]1Nc1cnc(C#N)c(Br)c1
Reactant: COc1cc(C)nc(N)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COc1cc(C)nc(Nc2cc(N[C@@H]3CS(=O)(=O)CC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)c1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl rel-{(3S,4S)-3-[(5-bromo-6-cyanopyridin-3-yl)amino]-1,1-dioxidotetrahydro-2H-thiopyran-4-yl}carbamate (Enantiomer 1 from previous step) (50 mg, 0.11 mmol), 4-methoxy-6-methylpyridin-2-amine (16 mg, 0.11 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), cesium carbonate (91 mg, 0.28 mmol), and Xanthpos (13 mg, 0.022 mmol) was purged with argon for 5 minutes. 1,4-Dioxane (1.0 ml) was added, and the reaction mixture was purged with argon for 5 minutes, and then heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through CELITE, and concentrated under reduced pressure to afford tert-butyl rel-[(3S,4S)-3-({6-cyano-5-[(4-methoxy-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamate, which was used directly in the next step without purification. MS ESI calc'd. for C23H31N6O5S [M+H]+ 503. found 503.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:14][C:15](=O)[CH2:16][CH:17]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:19]2([CH2:24][CH2:23][N:22]([C:25]([NH:27][CH:28]3[CH:35]4CC5C[CH:33]([CH2:37][CH:29]3C5)[CH2:34]4)=[O:26])[CH2:21][CH2:20]2)[CH2:18]1.N1C=CC=CC=1>O1CCOCC1.O>[C:15]([CH2:16][CH:17]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:19]2([CH2:24][CH2:23][N:22]([C:25]([NH:27][CH:28]3[CH2:35][CH2:34][CH2:33][CH2:37][CH2:29]3)=[O:26])[CH2:21][CH2:20]2)[CH2:18]1)#[N:14]
Reactant: NC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: N#CCC1CC2(CCN(C(=O)NC3CCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
A solution of trifluoroacetic anhydride (39 mg, 0.18 mmol) in dioxane (2 mL) was added dropwise to a stirred, ice-cooled solution of (±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (60 mg, 0.14 mmol) and pyridine (63 mg, 0.28 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative TLC to afford (±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (10 mg, 18%). LC-MS Method 5 tR=1.508 min, m/z=404.2; 1H NMR (CDCl3) δ=1.60-1.73 (m, 5H), 1.77-1.82 (m, 5H), 1.85-1.94 (m, 2H), 2.07-2.14 (m, 1H), 2.51-2.62 (m, 3H), 2.71-2.83 (m, 114), 2.98-3.10 (m, 2H), 3.46-3.55 (m, 1H), 3.82-3.94 (m, 3H), 7.10-7.15 (m, 1H), 7.20-7.28 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 44.9 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 120 mg (0.35 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 123 mg (0.39 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 100 mg of a dark brown crystal (yield: 44.4%; mp: 156-160° C.)
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:40]4[CH:41]=[C:36]([CH:37]=[CH:38][CH:39]=4)[C:34]([O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:35])=[C:3]([C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)c1
Temperature: 80 °C

Procedure:
To a stirred solution of compound 18b (51 mg, 0.12 mmol), (3-(tert-butoxycarbonyl)phenyl)boronic acid (39 mg, 0.18 mmol), and cesium carbonate (0.12 g, 0.36 mmol) in degassed 1,4-dioxane (4 mL) and water (0.5 mL) under Argon was added dichloro(diphenylphosphinoferrocene)palladium (II) (4.3 mg, 0.0059 mmol). The resulting mixture was heated at 80° C. for 2 h, allowed to cool to rt, and treated with EtOAc (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel (20-100% EtOAc/heptane) to give compound 18c as a brown oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H29N5O3: 532.2 (M+H). found: 532.5.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[C:14]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][CH3:71])=[CH:66][CH:65]=2)=[CH:15][C:16]([C@@:20]2([CH2:59][C:60]([CH3:62])=[CH2:61])[C@H:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:23]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[O:21]2)=[C:17]([OH:19])[CH:18]=1>>[Cl:12][C:13]1[C:14]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][CH3:71])=[CH:66][CH:65]=2)=[CH:15][C:16]([C@@:20]2([CH:59]=[C:60]([CH3:62])[CH3:61])[C@H:25]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@@H:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:23]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[O:21]2)=[C:17]([OH:19])[CH:18]=1
Reactant: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCc1ccc(Cc2cc([C@]3(C=C(C)C)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 65 °C
Yield: 75.4 %

Procedure:
A mixture of p-toluenesulfonic acid (0.136 mg, 0.789 mmol) and 25 (0.65 g, 0.789 mmol) was heated at 65° C. for 7 hours. The reaction mixture was cooled to ambient temperature, after which it was partitioned between 10% NaHCO3 and EtOAc. The organic layer was dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column chromatography eluting with 5% EtOAc in petroleum ether to give 26 (490 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 7.20-7.34 (m, 18H), 7.03-7.10 (m, 2H), 6.92-7.00 (m, 7H), 6.85 (s, 1H), 5.59 (s, 1H), 4.77-4.89 (m, 3H), 4.63 (d, J=12.0 Hz, 1H), 4.36-4.44 (m, 3H), 4.00 (d, J=15.6 Hz, 1H), 3.95 (dd, J=5.1, 10.2 Hz, 1H), 3.65-3.80 (m, 6H), 3.52 (dd, J=2.1, 10.5 Hz, 1H), 2.56 (q, J=7.8 Hz, 2H), 1.70 (s, 3H), 1.42 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). LC/MS m/z 846 (M+Na).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([OH:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.Cl[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>CCCCCC.CCOCC>[CH:16]1[C:17]2[CH2:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH:11]([O:18][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C(=O)CCl
Reactant: OC1c2ccccc2CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)C(=O)COC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
Washed sodium hydride (2.6 g, 64.6 mmol, 60 weight % in oil) two times with hexane under a nitrogen atmosphere. Added 50 mL of dry ether, and then added dibenzosuberol (13.6 g, 64.6 mmol) dissolved in 30 mL of dry ether followed by 2-chloro-N,N-dimethylacetamide (7.8 g, 64.6 mmol) dissolved in 20 mL of dry ether. Stirred at room temperature for 16 hours. Added water, and separated layers. Evaporated the organic solution, and triturated the residue with carbon tetrachloride and hexane. Filtered the white solid to give 13.79 g (72% yield) of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-oxy-N,N-dimethylacetamide.
Reaction SMILES: [OH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH:23]4[CH2:24][CH2:25][CH:18]3[CH:19]3[N:26]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[CH:22]4[CH2:21][CH2:20]3)=[O:16])=[CH:11][CH:10]=2)[N:4]1C(OC(C)(C)C)=O.O>Cl.O1CCOCC1>[C:41]1([C@H:2]([C@H:3]2[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH:18]5[CH2:25][CH2:24][CH:23]4[CH:22]4[N:26]([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH:19]5[CH2:20][CH2:21]4)=[O:16])=[CH:11][CH:10]=3)[NH:4]2)[OH:1])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3C4CCC3C3CCC4N3Cc3ccccn3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)N1C2CCC1C1CCC2N1Cc1ccccn1

Procedure:
The title compound from Step C above (30 mg, 0.06 mmol was dissolved in 4 M HCl in dioxane plus 10% water (v/v) (2 mL) and stirred at RT for 2 h. The mixture was concentrated under reduced pressure and dried under high vacuum to give the title compound. ESI-MS calculated for both is C33H36N4O2: Exact Mass: 522.32. Found 523.30.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[CH:13]3[CH2:14][C:15]([CH3:18])=[CH:16][CH2:17][CH:12]3[C:11]([CH3:20])([CH3:19])[O:10][C:9]=2[CH:21]=1.[CH3:28][Mg]Br.CBr.[Mg]>C(OCC)C>[OH:1][C:2]([CH3:28])([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[CH:13]3[CH2:14][C:15]([CH3:18])=[CH:16][CH2:17][CH:12]3[C:11]([CH3:19])([CH3:20])[O:10][C:9]=2[CH:21]=1
Reactant: C[Mg]Br
Reactant: CCCCCC(=O)C=Cc1cc(O)c2c(c1)OC(C)(C)C1CC=C(C)CC21
Agent: CBr
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC(C)(O)C=Cc1cc(O)c2c(c1)OC(C)(C)C1CC=C(C)CC21

Procedure:
A solution of 1.0 g (0.0028 mole) of 3-(3-oxo-1-octenyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol in diethyl ether was added dropwise to a solution of methyl magnesium bromide in ether prepared by bubbling methyl bromide into 0.78 g (0.032 mole) of magnesium. After the addition was complete, the mixture was refluxed for 3 hours and then decomposed by the careful addition of a mixture of methanol/diethyl ethr followed by dilute acid. The ethereal layer was separated and washed consecutively with water, 5% sodium bicarbonate and again water. It was dried and evaporated to leave 0.95 g of a gum which was chromatographed on magnesium silicate and eluted with graded mixtures of ether/petroleum ether. This furnished 0.28 g of 3-(3-hydroxy-3-methyl-1-octenyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol as a resinous material. The infrared and nuclear magnetic resonance spectra were consistent with the structure of the desired hydroxy compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.0241 mL, 0.297 mmol) at room temperature followed by acetyl chloride (0.0106 mL, 0.149 mmol) and stirred at the same temperature for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 19 as described in general methods) to yield N-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)acetamide (45.0 mg, 67.9%) as a white solid. LCMS (Condition 4): retention time 2.44 min, [M+1]=446.2. HPLC (Condition 28): retention time=6.44 min, purity 97.94%. 1H NMR (400 MHz, DMSO-d6) δ 2.13 (s, 3 H), 4.51 (d, J=4.8 Hz, 2 H), 5.06 (dd, J=4.8 Hz, J=5.2 Hz, 1 H), 7.02-7.04 (m, 2 H), 7.23-7.29 (m, 3 H), 7.42-7.52 (m, 5 H), 7.68 (dd, J=1.6 Hz, J=7.2 Hz, 1 H), 7.85-7.93 (m, 2 H), 8.36 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.52 (d, J=2.0 Hz, 1 H), 8.84 (d, J=2.0 Hz, 1 H), 10.37 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31](B(O)O)=[C:30]([O:38][CH3:39])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:17]([F:26])=[C:18]([F:25])[C:19]([F:24])=[C:20]([F:23])[C:21]=4[F:22])(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: COc1cc(Cl)c(F)cc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
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: [K+]
Product: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 50 °C
Yield: 85.3 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 1.7 g, 4.15 mmol), (4-chloro-5-fluoro-2-methoxyphenyl)boronic acid (INTERMEDIATE FFFFF; 1.272 g, 6.22 mmol), potassium carbonate (1.720 g, 12.45 mmol), and Pd(PPh3)4 (0.479 g, 0.415 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (15.56 ml) and water (5.19 ml) were added. The flask was fitted with a reflux condenser and heated in a 50° C. heating bath for 1 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give perfluorophenyl 1-(4-chloro-5-fluoro-2-methoxyphenyl)isoquinoline-6-sulfonate (1.89 g, 3.54 mmol, 85% yield) as a white foam. m/z (ESI) 534.0 (M+H)+.