Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[H-].[Li+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>COCCOC>[N:28]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Yield: 42.5 %

Procedure:
To a mixture of 3.63 grams (9.84 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) and 84.75 milligrams (10.7 millimoles) of lithium hydride in 10 milliliters of 1,2-dimethoxyethane was added 1.0 milliliter (10.0 millimoles) of piperidine in 10 milliliters of 1,2-dimethoxyethane. The mixture was heated under reflux for 22 hours, and the resulting heterogeneous mixture filtered to obtain a clear yellow filtrate. The filtrate was concentrated to an orange oil which after evaporation distillation (bath 120° C.; 0.05 torr.) produced 1.18 grams (42.5 percent yield) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine base having infrared and nuclear magnetic resonance spectral characteristics appropriate for said compound. A 286.23 milligram (1.02 millimoles) sample of the free base, 4-(6-piperidinohexyl)-3,5-dioxomorpholine, was dissolved in 1.0 milliliter of 1 N sodium hydroxide (1.0 millimole) and the mixture concentrated to produce 289.63 grams (90 percent yield) of sodium [2-(6-piperidinohexyl)-amino-2-oxoethoxy]acetate product with the following spectral characteristics: IR: (CHCl3l ); 3700-3150 cm-1 (broad); 2935 cm-1 2850 cm-1 (shoulder); 1660, 1610 cm-1 (broad); 1550 cm-1 (shoulder); 1420 cm-1 (broad); 1145 cm-1 ; 1120 cm-1.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[S:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([CH3:40])[CH:21]=[CH:20][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:18][CH:17]=1>>[C:16]1([CH3:40])[CH:17]=[CH:18][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[S:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: S=C1c2ccccc2NC[C@@H]2CCCN12
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@@H]4CCCN4C(=S)c4ccccc43)cc2)cc1
Yield: 59.4 %

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-thione prepared in Reference Example 32 and 4-[[2-(4-tolyl)benzoyl]amino]benzoic acid to thus give the title compound. Yield 59.4%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[C:6]=1Br)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC>>[C:1]([O:4][C:5]1[C:6]2[C:13]([CH3:15])([CH3:14])[CH2:12][O:11][C:7]=2[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)COc1cccc(OC(C)=O)c1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cccc2c1C(C)(C)CO2
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
To a solution of 2-bromo-3-[(2-methyl-2-propen-1-yl)oxy]phenyl acetate (Intermediate 39, 2.324 g) in toluene (20 ml) AIBN (1.606 g, 9.78 mmol) and tributylstannane (4.73 g, 16.30 mmol) were added. The reaction mixture was stirred and heated at 100° C. for 2 hours, then was left at room temperature for 4 hours. The reaction was quenched with water (60 ml) and extracted with ethyl acetate (3 times 50 ml). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 100 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 70/30 as eluent to afford the title compound as a colourless oil (1.290 g).
Reaction SMILES: C(OC([N:8]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1)[CH2:9][C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[ClH:21].[Cl:21][C:20]1[CH:19]=[N+:18]([O-:22])[CH:17]=[C:16]([Cl:23])[C:15]=1[CH2:14][C@@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:37][CH2:38]2)[CH:25]=1)[O:12][C:10](=[O:11])[CH2:9][NH:8][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1
Reactant: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CNCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of (S)-4-(2-(2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)-amino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (258 mg, 0.355 mmol) in DCM (24 ml), HCl 4M in dioxane (1.2 ml, 4.80 mmol) was added drop wise, and the reaction was stirred at RT overnight. The volatiles were evaporated under vacuum and the residue was purified by trituration with diethylether affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzylamino) acetoxy)ethyl)pyridine 1-oxide hydrochloride as a beige solid (0.187 g, 0.282 mmol, 79% yield, MS/ESI+ 626.82 [MH]+, [αD]=−15.57, c=0.56, MeOH).
Reaction SMILES: C(OC(C1C(=O)CCCC1)=O)C.[OH:13][NH:14][C:15]([C@H:17]1[C@@H:23](CC2C=CC=CC=2)[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])=[O:16]>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([S:31]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:17]2[C:15]([NH:14][OH:13])=[O:16])(=[O:32])=[O:33])=[CH:35][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC[C@H](Cc3ccccc3)[C@@H]2C(=O)NO)cc1
Agent: CCOC(=O)C1CCCCC1=O
Product: COc1ccc(S(=O)(=O)N2CCCCCC2C(=O)NO)cc1

Procedure:
1-(4-Methoxybenzenesulfonyl)-azepane-2-hydroxamic acid was synthesized from 6-oxo-cyclohexane carboxylic acid ethyl ester in the same manner as the procedures used for the preparation of cis-3-Benzyl-1-(4-methoxybenzene sulfonyl)-azepane-2-carboxylic acid-hydroxyamide.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:28]([NH:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:30])[CH3:29].CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:28]([NH:31][C:32]1[CH:33]=[C:34]([NH:35][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)[CH:36]=[CH:37][CH:38]=1)(=[O:30])[CH3:29]
Reactant: Cn1cc(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)cn1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3cnn(C)c3)n2)c1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (51 mg, 0.14 mmol) in NMP (0.8 mL) was added 3-acetamidoaniline (24 mg, 0.16 mmol) and pTsOH.H2O (27 mg, 0.14 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (40 mg). MS found for C18H20N8O2 as (M+H)| 381.5. λ=242.8.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:20][NH2:21]>CCO>[NH:20]([C:13]([C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=1)=[O:14])[NH2:21]
Reactant: NN
Reactant: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Solvent: CCO
Solvent: O
Product: CCCCCC(=O)Nc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a suspension of methyl 4-(hexanoylamino)benzoate (583 mg, 2.34 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 321 mg of the title compound (55%) as a white solid in 96.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C(CC)=O)C>[CH2:3]([C:2]1([CH2:11][CH3:10])[NH:12][C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1)[CH3:4]
Reactant: Nc1cccc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCC(=O)CC
Solvent: O
Product: CCC1(CC)Nc2cccc3cccc(c23)N1
Reaction time: 5 h
Yield: 1769.7 %

Procedure:
A mixture of 1.58 g of 1,8-diaminonaphthalene, 10.8 g of diethyl ketone, and 25 mg of p-toluenesulfonic acid monohydrate was heated and stirred for 5 hours in a steam bath and extracted with 100 ml of ethyl acetate and 50 ml of saturated sodium bicarbonate water. The solvent was distilled off, yielding 20 g of 2,2-diethyl-2,3-dihydroperimidine.
Reaction SMILES: [ClH:1].C([O:6][C:7]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]4[CH:27]=[C:28]([C:32]5[N:36]([CH3:37])[C:35]6[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=6[N:33]=5)[CH:29]=[C:30]([CH3:31])[C:25]=4[N:24]=[C:23]3[CH2:42][CH2:43][CH3:44])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8])(C)(C)C.Cl>CC(C)=O>[ClH:1].[ClH:1].[CH3:31][C:30]1[C:25]2[N:24]=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]([CH2:21][C:18]3[CH:17]=[CH:16][C:15]([C:10]4[C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=3)[C:26]=2[CH:27]=[C:28]([C:32]2[N:36]([CH3:37])[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[N:33]=2)[CH:29]=1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 27.5 °C

Procedure:
Tert.Butyl-4′-[4-Methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-n-propyl-1H-benzimidazol-1-yl-methyl]biphenyl-2-carboxylate hydrochloride (50 gms) is suspended in acetone (250 ml) and hydrochloric acid (50 ml) is added. Temperature of the mass is raised, maintained at 50° C.-55° C. for 3 hrs, cooled and maintained at 25-30° C. for 2 hrs. Product is filtered; wet cake is washed with water (2×50 ml) and acetone (50 ml). Dried the wet cake at temperature 60° C.-65° C. till constant weight.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13](Cl)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[C:36]([NH:38][C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH:12]=4)=[O:14])[CH:35]=[CH:34][C:33]=3[CH3:39])[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)c1ccnc(N2CCOCC2)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cccc(CN2CCN(C)CC2)c1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1C(=O)Nc1cccc(CN2CCN(C)CC2)c1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-morpholinopyridine-4-carbonyl chloride was reacted with N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide. The residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 27% yield; Mass Spectrum: M+H+ 529.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH2:18]([CH:20]([C:23]1[C:24]2[N:25]([CH:30]=[C:31]([CH3:33])[N:32]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:21][CH3:22])[CH3:19]>>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:30]3[N:25]4[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH:20]([CH2:18][CH3:19])[CH2:21][CH3:22])[C:24]4=[N:32][C:31]=3[CH3:33])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Yield: 44.8 %

Procedure:
Using a procedure analogous to Example 16B, 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.29 mmol) and 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.064 g, 0.29 mmol) give the title compound (0.054 g, 0.13 mmol, 43%). 1H NMR (CDCl3): δ 0.91 (t, J=7.5 Hz, 6H), 0.92 (t, J=7.0 Hz, 6H), 1.80-1.93 (m, 8H), 2.43 (s, 6H), 2.47 (s, 6H), 3.36-3.44 (m, 2H), 6.68 (s, 2H). ES-MS (m/z): calcd for C26H36N6 (M+H)+: 433.6. found: 433.3.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.F[C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][CH:12]=[CH:13][CH:14]=3)[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1ccnn1
Yield: 44 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 10, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (75.2 mg, 44%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 7.74 (d, 2H), 7.42-7.17 (m, 7H), 7.03-6.83 (m, 6H), 5.28 (d, 1H), 5.12 (d, 1H), 4.73 (d, 1H), 3.71-64 (m, 1H), 3.31-3.22 (m, 1H), 3.006-2.93 (m, 1H), 2.89 (dd, 1H), 2.71-2.64 (m, 1H), 2.52 (dd, 1H), 1.79-1.70 (m, 1H). MS (EI) for C28H27FN5O3 found 500 (MH+).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:30]4[CH:29]=[CH:28][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccc4ccccc4c3)cc(F)cc12

Procedure:
Staring from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 2-naphthylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:49](=[O:50])[C:48]([CH3:51])=[CH:47][N:12]([C@@H:13]2[O:37][C@H:17]([CH2:18][O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@:15]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([OH:16])[CH2:14]2)[C:11]1=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([NH3+])(C)(C)C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:49](=[O:50])[C:48]([CH3:51])=[CH:47][N:12]([C@@H:13]2[O:37][C@H:17]([CH2:18][OH:19])[C@@:15]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([OH:16])[CH2:14]2)[C:11]1=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)n(COCc2ccccc2)c1=O
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](CO)O2)c(=O)n(COCc2ccccc2)c1=O

Procedure:
A solution of 3-benzyloxymethyl-3′-benzyloxymethyl-5′-O-tert-butyldiphenylsilylthymidine (20 g, 28 mmol) in THF (200 ml) was treated with tert-butyl ammonium fluoride 1 M/THF (40 ml, 40 mmol) at room temperature for 16 hrs. The solution was concentrated in vacuo and the resulting oil chromatographed on silica gel (EtOAc/hexane, 7/3→8/2) to afford the product, 10 g (75%). m.p. 83-84° C.; 1H NMR (CDCl3), 1.92 (s, 3H, C5-CH3), 2.20-2.50 (m, 3H, C2′H, C5′OH), 3.73 (dd, 1H, C5′HH), 3.89 (dd, 1H, C5′HH), 4.09 (m, 1H, C4′H), 4.49 (m, 1H, C3′H) 4.62 (s, 2H, OCH2Ph), 4.70 (s, 2H, OCH2Ph), 4.81 (s, 2H, OCH2O), 5.49 (s, 2H, NCH2O), 6.19 (t, 1H, C1′H), 7.26-7.37 (m, 5H, CH═,ArH). Anal. Calcd. for C26H30N2O7: C, 64.94; H, 6.26; N, 5.75. Found: C, 64.71; H, 6.27; N, 5.81.
Reaction SMILES: [F:1][C:2]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:4].[OH-].[Na+]>C1COCC1>[F:1][C:2]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:4]
Reactant: COC(=O)c1ccc(C(F)(F)C(=O)NNC(=O)c2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NNC(=O)C(F)(F)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoate (74 mg, 0.2 mmol) in THF (3 mL) was added sodium hydroxide (0.58 mmol, 0.58 mL of a 1M solution) and the solution was stirred at ambient temperature for 16 hours. The reaction was partitioned between 1M HCl and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give 4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoic acid as a white solid. ESIMS calcd 365.0 (M++H), found 365.0 (M++H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1OCCOC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][N:6]=[C:5]3[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Ic1ccc2ncnc(Nc3ccncc3)c2c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1cccc(-c2ccc3ncnc(Nc4ccncc4)c3c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To an 8 mL screw-cap vial was added 6-iodo-N-(4-pyridyl)quinazolin-4-amine (95 mg, 0.2729 mmol), (3-chlorophenyl)boronic acid, (1.2 equiv., 0.33 mmol, 51.21 mg), 1-4 dioxane (0.8 mL), potassium phosphate tribasic, (2M in H2O, 3 equiv., 0.82 mmol, 0.41 mL), and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.05 equiv.; 0.014 mmol, 10 mg). The reaction was capped and shaken at 60° C. for 1 h. The reaction was then diluted with 4 mL dichloromethane and washed with water. Organic phase was then concentrated. Crude was purified by reverse phase HPLC yielding 31 mg of product. 1H NMR (400 MHz, DMSO) δ 10.22-10.07 (s, 1H), 8.92-8.86 (s, 1H), 8.82-8.75 (s, 1H), 8.56-8.49 (d, J=5.4 Hz, 2H), 8.31-8.25 (m, 1H), 8.05-7.97 (m, 3H), 7.97-7.91 (d, J=8.7 Hz, 1H), 7.90-7.84 (d, J=7.7 Hz, 1H), 7.64-7.57 (t, J=7.8 Hz, 1H), 7.57-7.50 (d, J=8.0 Hz, 1H). LCMS M/Z (M+H)=333.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH2:11]([Si:16](OC)([O:19][CH3:20])[O:17][CH3:18])[CH2:12][CH:13]([CH3:15])[CH3:14].C([Mg]Br)CC(C)C.CO[Si](OC)(OC)OC>O.CCOCC>[CH2:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Si:16]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([O:19][CH3:20])[O:17][CH3:18])[CH3:10]
Reactant: CO[Si](CCC(C)C)(OC)OC
Reactant: CCc1ccccc1Br
Agent: CC(C)CC[Mg]Br
Agent: CO[Si](OC)(OC)OC
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCc1ccccc1[Si](CCC(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A 1000 mL round bottomed flask was charged with magnesium turnings (1.97 g, 81.0 mmol, Aldrich) and ether (500 mL, Aldrich). Bromo-2-ethylbenzene (14.0 mL, 101 mmol, Aldrich) was added over 30 minutes. The reaction stirred for three hours at room temperature and became dark brown in color. The contents were refluxed for one hour. The contents were cooled to 0° C. and isoamyl-trimethoxysilane (15.9 g, 82.8 mmol, previously prepared by reaction between isoamyl magnesiumbromide and tetramethylortho-silicate) was added over 25 minutes. The reaction was stirred at room temperature overnight (18 hours) during which time a white precipitate formed. The contents were poured into water (500 mL), the layers separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered and the solvent removed via rotary evaporation providing 29.6 g crude material. Distillation under reduced pressure (b.p. 109° C., 1.1 mm Hg) produced (2-ethylphenyl)-3-methylbutyl-dimethoxysilane (7.68 g, 28.8 mmol, 35.6% yield); C15H26SiO2 (Mw=266.45); 1H NMR (CDCl3) δ 7.7 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 3.5 (s, 6H), 2.8 (q, 2H), 1.4 (m, 1H), 1.2 (m, 5H), 0.8 (m, 8H); 13C NMR (CDCl3) δ 150.5, 135.9, 131.2, 130.3, 128.0, 124.9, 50.3, 31.5, 30.7, 28.6, 21.9, 16.1, 10.9; IR (capillary film) ν 3054, 2974, 1590, 1467, 1370, 1200, 1118, 1023, 936, 874, 803, MS m/z (relative abundance) 266 (0.02), 195 (100), 163 (59.1), 160 (28.8), 133 (25.5), 105 (11.2), 91 (12.3), 59 (18.4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.O>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:34][CH:33]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(Cl)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (0.4 g, 1.1 mmol), prepared as described in Example 1 in DMF (5 mL) was added K2CO3 (0.46 g, 3.3 mmol) and 4-chlorobenzyl bromide (0.28 g, 1.3 mmol). The reaction mixture was heated at 60° C. for 20 min. After this time, water (50 mL) was added to the reaction mixture and the resultant solid was collected by filtration. The final product (0.32 g, 60%) was obtained by purification using reverse phase preparative HPLC. MS (M+H)=481; 1H NMR (CDCl3): δ 8.18 (1H, s), 7.25-7.40 (10H, m), 7.08 (2H, d, J=10.0 Hz), 5.18 (2H, s).