Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[CH:5]=1)([CH3:3])[CH3:2]>[OH-].[Na+]>[CH:1]([C:4]1[O:8][C:7]([CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)C)oc1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1oc(C(C)C)cc1C(=O)O

Procedure:
Saponification of 0.5 g of the ester was accomplished by refluxing 4 hours in 10 ml of 25% aqueous sodium hydroxide. Acidification precipitated the crude acid, which was recrystallized from water-ethanol to give 5isopropyl-2-methyl-3-furoic acid as white needles, mp 88.5° C.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:19])[C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:19][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:9]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)=[N:10][C:11]=1[CH3:12]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ncccn2)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ncccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Dimethyl sulfoxide (2.5 ml) was added to 5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (167 mg), and cesium carbonate (243 mg), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (54 mg, yield 55%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:31]([C:33]1[C:34](=[C:44]([C:47]#[N:48])[C:45]#[N:46])[O:35][C:36]([CH3:43])([C:39]([F:42])([F:41])[F:40])[C:37]=1[CH3:38])#[N:32]>C(O)C>[CH2:27]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16](=[CH:22][CH:23]=[CH:38][C:37]3[C:36]([CH3:43])([C:39]([F:42])([F:40])[F:41])[O:35][C:34](=[C:44]([C:45]#[N:46])[C:47]#[N:48])[C:33]=3[C:31]#[N:32])[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=O)CC(C)(C)C2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 70.9 %

Procedure:
In 6 ml of ethanol were dissolved 200 mg (0.49 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 136 mg (0.54 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 3.5 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 224 mg of a dark brown crystal (yield: 71.2%; mp: 196-201° C.)
Reaction SMILES: CO.C(N)CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3[C:20](=[CH:21]C=CC=3)[C:19]2=[O:28])[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH3:21])[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Solvent: Cc1ccccc1
Solvent: CCCCN
Solvent: CO
Product: CCC(=O)NCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.6 %

Procedure:
2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of pyridine were then added to the residue. 0.31 ml of propionic anhydride was added dropwise to the resulting mixture, and then the mixture was stirred at room temperature for 2 hours and 30 minutes. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was thereafter subjected to silica gel column chromatography, using 2:1, 3:1 and 1:0 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using 1:4, 3:7, 2:3 and 1:1 by volume mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 125 mg of the title compound as a yellow oil having an Rf value of 0.45 (silica gel thin layer chromatography; using ethyl acetate as the developing solvent).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl.CCOC(C)=O>[OH:12][C:11]1[C:2]([O:1][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1=COCCC1
Reactant: O=c1cc(-c2ccccc2)c2ccc(O)c(O)c2o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(O)c2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To 7,8-dihydroxy-4-phenyl-2H-chromen-2-one (500 mg, 2 mmol) and 3,4-dihydro-2H-pyran in 4 mL THF and 4 mL DCM was added pyridinium paratoluene sulfonate (PPTS, 8 mg). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with NaHCO3 (sat. 30 mL) and water (50 mL) and dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed (hexane/EtOAc) to afford 8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one as a yellow solid (180 mg, 26%). MS (ESI) m/z 339 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:21](F)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[O:35]([CH3:37])[K].CO.[Al]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:21]([O:35][CH3:37])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Reactant: CO[K]
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1N1CCOCC1
Yield: 67.2 %

Procedure:
A mixture of 4-(6-Fluoro-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (28.9 mg, 69.5 μmol), as prepared in Example 94a, DMSO (50 μL), and 10M KOMe/MeOH (140 μL, 140 μmol) was stirred in a sealed vial at 100° C. (aluminum block) for 13 hr. The crude reaction was then diluted with toluene and directly loaded onto a silica flash column (1:2 hexanes/EtOAc eluent) to provide the title compound (20.0 mg, 67%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.36 (s, 1H), 7.25 (s, 1H), 4.05 (s, 3H), 3.51 (m, 1H). Irradiation of the diagnostic methine proton at δ 3.51 generates an nOe to the quinazoline C5 proton at δ 7.25, but not to the quinazoline C8 proton at δ 7.36. Irradiation of the methoxy protons at δ 4.05 generates an nOe to the C5 proton at δ 7.25, but not to the C8 proton at δ 7.36. This indicates methoxy substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 428.2, found 429.3 (MH)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([C:25]1[C:26]([Cl:35])=[N:27][C:28]3[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:35][C:26]1[C:25]([C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O)ccc21

Procedure:
A solution of tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy }-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (1-7, 2.50 g, 4.91 mmol, 1 equiv) and triethylamine trihydrofluoride (3.60 mL, 22.1 mmol, 4.50 equiv) in acetonitrile (100 mL) was stirred at 23° C. for 20 hours. The reaction mixture was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate (1-8) as a tan colored foam (2.1 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J=9.0 Hz), 8.17 (s, 1H), 8.07 (d, 1H, J=8.4 Hz), 7.86 (d, 1H, J=8.1 Hz), 7.77 (br t, 1H, J=8.4 Hz), 7.61 (br t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=2.6 Hz), 6.93 (dd, 1H, J=8.8, 2.6 Hz), 6.55 (s, 1H), 1.26 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][C:23]#[N:24])[C:16](=O)[C:15]12[O:30][CH2:29][CH2:28][CH2:27][O:26]1)(=[O:11])=[O:10].N.C1COCC1.[H][H]>[Ni].CCO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][N:24]=[C:16]3[C:15]3([O:26][CH2:27][CH2:28][CH2:29][O:30]3)[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 135 °C
Yield: 14.5 %

Procedure:
A mixture of 3-[5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′ (2′H)-yl]propanenitrile (4.48 g, 10.3 mmol), and wet Raney nickel (4.1 g) in 2M EtOH.NH3 (100 mL) and THF (100 mL) was hydrogenated in a Parr Hydrogenation Bottle (2L) at 45 lb/in2 hydrogen for 24 hours. The Raney nickel was removed by filtration through Sulka Floc. The filtrate was poured into a steel pressure vessel and heated to 135° C. for 51 hours. The reaction was cooled and the solvents were removed. The residue was taken up in CH2Cl2 and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (Biotage KP silica gel, and step gradient of CH2Cl2/CH3OH/NH4OH (98.5/1.0/0.5-98/01.5/0.5)) to give the title compound as a white solid (0.63 g, 14.5% yield). Anal: Calc'd. for C20H27N3O5S: C, 56.99; H, 6.46; N, 9.97; Found: C, 56.80, H, 6.45, N, 9.87; NMR (400 MHz, DMSO-d6): consistent. MS: (ES+) m/z 422 [M+H]. Opt. Rotation: 94.1(calculated) at 25° C. in CH3OH (1% concentration), wavelength 589; m.p. 129-130°.
Reaction SMILES: C(OC(NC1C=C(C2C(C3C=CC=CC=3[F:35])=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C.C(OC([NH:43][C:44]1[CH:49]=[C:48]([C:50]2[C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[N:52][N:53]([C:55]3[CH:56]=[CH:57][C:58]4[N:59]([CH:61]=[N:62][N:63]=4)[N:60]=3)[CH:54]=2)[CH:47]=[CH:46][N:45]=1)=O)(C)(C)C>>[NH2:43][C:44]1[CH:49]=[C:48]([C:50]2[C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([F:35])[CH:65]=3)=[N:52][N:53]([C:55]3[CH:56]=[CH:57][C:58]4[N:59]([CH:61]=[N:62][N:63]=4)[N:60]=3)[CH:54]=2)[CH:47]=[CH:46][N:45]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2F)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2cccc(F)c2)ccn1
Yield: 86 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 4.00 g (8.47 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(2-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 42-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 2.71 g of the title compound as a pale beige powder. (Yield: 86%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH3:11][O:12][C:13](=[O:34])[CH:14]=[CH:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:10]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)C=Cc1cc(Br)ccc1F
Temperature: 95 °C
Yield: 100 %

Procedure:
A solution of 5-Bromo-2-fluoro-benzaldehyde (1.0 g, 4.9 mmol) in anhydrous acetonitrile (20.0 mL) was added methyl(triphenylphosphoranylidene)acetate (3.3 g, 9.0 mmol) and heated to 95° C. for 12 h. The mixture was cooled, filtered and concentrated under reduced pressure. Silica gel chromatography (5% Ethyl acetate/petroleum ether) gave the title compound as a white solid (1.27 g, 99%) which was used directly in the next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:39](Cl)(=[O:50])[O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[N+:47]([C:44]1[CH:43]=[CH:42][C:41]([O:40][C:39](=[O:50])[NH:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=2)[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:46][CH:45]=1)([O-:49])=[O:48]
Reactant: NCC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NCC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a solution of 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propan-1-amine (1.37 g, 3.00 mmol), prepared as described in Example 10 (Procedure 13, 14, 15, and 16), in CH2Cl2 (35 mL) was added K2CO3 (2.1 g, 15 mmol) followed by 4-nitrophenyl carbonochloridate (806 mg, 4.0 mmol) and the reaction mixture was stirred at rt for 5 h. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with 1N Na2CO3 (6×50 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 0 to 40% EtOAc/hexane to yield [3-phenyl-2,2-bis-(3-trifluoromethoxy-phenyl)-propyl]-carbamic acid 4-nitro-phenyl ester (1.50 g, 81% yield) as a clear, colorless oil. LCMS: RT=2.30 min [M+H] 620.94 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 3.42 (s, 2 H), 3.92 (d, J=6.15 Hz, 2 H), 4.72 (t, J=5.71 Hz, 1 H), 6.60 (d, J=7.03 Hz, 2 H), 7.05-7.26 (m, 9 H), 7.37 (t, J=8.13 Hz, 2 H), 8.23 (d, J=9.23 Hz, 2 H).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cc1c(Br)ccc2c(Cl)ccnc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(SCc2ccccc2)ccc2c(Cl)ccnc12
Temperature: 110 °C
Yield: 99.2 %

Procedure:
To a vial charged with 7-bromo-4-chloro-8-methylquinoline (0.950 g, 3.70 mmol) was added Dioxane (14.81 ml), DIEA (1.294 ml, 7.41 mmol), xantphos (0.429 g, 0.741 mmol), Pd2(dba)3 (0.339 g, 0.370 mmol) and benzyl mercaptan (0.438 ml, 3.70 mmol). The vessel was sealed and heated to 110° C. for 3 hr affording complete conversion according to LC-MS. The mixture was filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product as a yellow oil as a mixture of mono and bis substituted product according to MS as one LC peak, 7-(benzylthio)-4-chloro-8-methylquinoline (1.100 g, 3.67 mmol, 99% yield). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)[N:14]=1)=[NH:8].[ClH:33]>O1CCOCC1>[ClH:33].[CH3:32][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[N:14]=1)=[NH:8]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2C(=O)OC(C)(C)C)cs1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Reaction time: 3 h

Procedure:
To 490 mg (1.06 mmol) tert-butyl 2-(2-{[[(2,6-dimethoxybenzyl)amino](imino)methyl]amino}-1,3-thiazole-4-yl)pyrrolidine-1-carboxylate from Example 120 in 20 ml dioxane were added 5 ml 4N HCl in dioxane at room temperature and the mixture was stirred for 3 hours. Chromatography on RP-silica gel of the crude product obtained following concentration (Chromabond column, acetonitrile/water+0.1% glacial acetic acid; 0-100%) yielded 240 mg of the target product as a light colored solid; ESI-MS [M+H+]=362.15.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][NH:12][C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1.[CH2:15]([O:22][C@H:23]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:25][C@@H:24]1Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][N:12]([C@@H:24]3[O:25][C@H:26]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:23]3[O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1
Reactant: CSc1nc(Cl)c2cc[nH]c2n1
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.1 g sodium hydride, 25.9 g of 4-chloro-2-methylmercapto-7H-pyrrolo[2,3-d]pyrimidine, and 250 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 0.5 hour, cooled, and added to 62.8 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride. The solution is stirred at ambient temperature for 15 hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate and water. Chromatography of the dried (MgSO4) layer over silica gel with 4:1 toluene-ethyl acetate provides 76 g of yellow, syrupy 4-chloro-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.O>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(Br)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(N1CCCC1)n2Cc1ccccc1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
Compound 35 (500 mg, 1.05 mmol) obtained in Example 35 was dissolved in N,N-dimethylformamide (15 mL), to the solution were added potassium carbonate (430 mg, 3.11 mmol, 3.0 equivalents) and pyrrolidine (260 μL, 3.11 mmol, 3.0 equivalents), and then the mixture was stirred with heating at 100° C. for 3.5 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 97:3), and to the residue were added acetone and diethyl ether. The deposited crystals were collected by filtration to obtain the title compound (467 mg, 95%) as white crystals.