Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]1[NH:29][C:28](=[O:30])[C:27]2[C:22](=[C:23](Br)[CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH2:2][CH3:3].[C:32]1([CH2:38][CH2:39][CH:40]=[CH:41][CH3:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]1[NH:29][C:28](=[O:30])[C:27]2[C:22](=[C:23]([C:40](=[CH:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:41][CH3:42])[CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH2:2][CH3:3]
Reactant: CC=CCCc1ccccc1
Reactant: CCCOc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1nc2c(Br)cccc2c(=O)[nH]1
Product: CCCOc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1nc2c(C(=CCc3ccccc3)CC)cccc2c(=O)[nH]1
Yield: 39 %

Procedure:
The title compounds are prepared analogously to the method of Example 1, starting with 2-(2-n-propoxy-5-morpholinosulfonylphenyl)-8-bromoquinazolin-4(3H)-one and 5-phenyl-2-pentene, respectively.
Reaction SMILES: [CH3:1][C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:7][C:6](=[O:8])[N:5]([C@H:9]([C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH3:10])[CH2:4][CH2:3]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:7][C:6](=[O:8])[N:5]([C@H:9]([C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][C:16]([OH:18])=[O:17])[CH3:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)COc1cccc([C@H](C)N2CCC(C)(c3ccccc3)OC2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1cccc(OCC(=O)O)c1)N1CCC(C)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate (0.0587 g, 0.148 mmol) and lithium hydroxide monohydrate (0.4275 g, 10.2 mmol) in THF (10 mL) and H2O (10 mL) was vigorously stirred at rt for 2 d. The mixture was treated with 1 N HCl (30 mL), extracted with EtOAc (3×), dried over Na2SO4. After the solvents were evaporated, the crude product was directly used in the next step without further purification. LC-MS tR=1.48 min in 3 min chromatography, m/z 370 (MH+).
Reaction SMILES: [Li+].[Cl-].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:12]=[CH2:11]
Reactant: Brc1cncc(Br)c1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Li+]
Product: C=CCc1cncc(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with i-PrMgCl.LiCl (1 mL, 1.05 M in THF, 1.05 mmole), the reaction mixture was cooled to −15° C. and 3,5-dibromopyridine (236.9 mg, 1 mmole) was then added at one portion. The temperature than increased till −10° C. and the Br/Mg-exchange was complete after 15 min (checked by GC analysis of reaction aliquots, conversion more than 98%), allyl bromide (140.6 mg, 1 mmole) was added. The reaction mixture was stirred for 1 h at −10° C. and was then quenched with sat. NH4Cl solution (2 mL). The aqueous phase was extracted with ether (3×4 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (dichloromethane) yielding the 3-allyl-5-bromopyridine (2ca) as a colourless oil (184.2 mg, 93%). 1H-NMR (CDCl3, 200 MHz): δ=8.48 (d, J=2.2 Hz, 1H); 8.32 (d, J=1.6 Hz, 1H); 7.61 (dd, J=2.2 Hz, J=1.6 Hz, 1H); 5.89-5.68 (m, 1H); 5.08-5.01 (m, 1H); 3.32 (brd, J=6.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16]C(C)(C)[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:41])[CH:23]2[CH2:26][CH:25]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)=[O:29])[CH2:24]2)[O:12]1>C(O)(C(F)(F)F)=O.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:12][C@H:13]([CH2:21][N:22]([CH3:41])[CH:23]2[CH2:26][CH:25]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:33][CH:32]=3)=[O:29])[CH2:24]2)[C@@H:14]([OH:18])[C@H:15]1[OH:16]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(NC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A solution of 1-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)-3-(4-(tert-butyl)phenyl)urea (125 mg, 0.23 mmol) in TFA (0.90 mL) and 0.10 mL of water were stirred for 1 hour at room temperature. The reaction was concentrated to dryness, dissolved in MeOH (5 mL) and K2CO3 (60 mg) in 0.5 mL of water was added dropwise. The reaction was stirred at rt for 0.5 h and concentrated to obtain the residue which was purified by prep-TLC (DCM:MeOH:NH4OH=300:30:8, V/V) to obtain the desired compound (75 mg, Yield: 65%) as pale white solid. 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.21 (s, 1H), 7.28-7.20 (m, 4H), 6.00-5.99 (m, 1H), 4.77-4.75 (m, 1H), 4.28-4.23 (m, 2H), 3.92-3.88 (m, 1H), 2.92 (brs, 1H), 2.83-2.81 (m, 2H), 2.59-2.56 (m, 2H), 2.32 (s, 3H), 1.74-1.64 (m, 2H), 1.27 (s, 9H) ppm; ESI-MS (m/z): 525.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1)=[NH:8].[Br-].[CH2:24]([Zn+])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)C>[Pd]>[CH2:24]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:20][CH:19]=[CH:18][C:17]=2[O:21][CH3:22])=[NH:8])=[N:11][CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1ccc(I)cn1
Reactant: [Zn+]Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Br-]
Product: COc1cccc(OC)c1CNC(=N)Nc1ccc(Cc2ccccc2)cn1
Yield: 22.5 %

Procedure:
The preparation was carried out analogously to Example 67, using 0.200 g (0.485 mmol) N-(2,6-dimethoxybenzyl)-N′-(5-iodopyridin-2-yl)guanidine and 2.43 mL (1.213 mmol) of the benzyl zinc bromide solution (0.5 M in tetrahydrofuran) under Pd catalysis with 20 mg (0.055 mmol) [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride-methylene chloride. The mixture was likewise heated under a nitrogen atmosphere, first under reflux for 6 hr, and then after repeated additions of 2×2.43 mL (1.213 mmol) of the 0.5 M benzyl zinc bromide solution and the same quantity of Pd catalyst for an additional 6 hr and 4 hr, respectively, for a total of 16 hr of heating. After appropriate workup and purification via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid), 48 mg (0.109 mmol, 23%) pure N-(5-benzylpyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][C:15](OCC)=[O:16])[CH2:8]1>C(OCC)C>[O:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:8]1
Reactant: CCOC(=O)CCC1CCCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCC1CCCOC1
Temperature: 0 °C
Reaction time: 9 h
Yield: 93.3 %

Procedure:
To a stirred solution of lithium aluminium hydride (24.8 ml, 1.0M in diethyl ether) in dry diethyl ether (77 ml) at 0° C. was added a solution of ethyl 3-(tetrahydro-2H-pyran-3-yl)propanoate (4.61 g) in dry diethyl ether (77 ml) dropwise over 20 minutes. After 15 minutes at 0° C. the reaction mixture was warmed to room temperature and stirred for a further nine hours. The reaction was quenched by the dropwise addition of water over a period of one hour, whilst cooled over ice. The resulting solids were filtered from the mixture and washed with diethyl ether. The organic layer was decanted off from the aqueous layer, dried over magnesium sulphate, filtered and concentrated in vacuo. to give a clear oil (3.33 g). The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a clear oil (2.64 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[CH3:17][O:18]/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N#N.FC(F)(F)C(C)(C)C(Cl)=O>C(Cl)(Cl)Cl.C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])/[C:4](/[OH:5])=[CH:22]/[C:21](=[O:23])/[CH:20]=[CH:19]/[O:18][CH3:17]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: CO/C=C/C(C)=O
Agent: CC(C)(C(=O)Cl)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CO/C=C/C(=O)/C=C(\O)C(C)(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 5.2 %

Procedure:
To a mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (10 g, 64.1 mmol) in CHCl3 (100 mL) cooled to 0° C. was added oxalyl chloride (7.29 mL, 83 mmol) dropwise. The mixture was stirred at 70° C. for 4 h. Then the mixture was concentrated. To a mixture of (E)-4-methoxybut-3-en-2-one (12.83 g, 128 mmol) in THF (100 mL) cooled to −78° C. was added LiHMDS (128 mL, 128 mmol) dropwise under N2. The mixture was stirred at −78° C. for 1 h. Then to the mixture was added a solution of 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride in THF (100 mL) at −78° C. The whole mixture was allowed to warm to rt over 2 h and quenched by NH4Cl (saturated aqueous, 30 mL). THF was removed under vacuum. To the mixture was added H2O (80 mL) and then extracted with EA (100 mL×3). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=2:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.5) were combined to yield an off-white oil of (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one (1 g, 3.36 mmol, 5.2% yield): 1H NMR (400 MHz, CDCl3): δ 15.90 (s, 1H), 7.65 (d, J=12.4 Hz, 1H), 5.63 (s, 1H), 5.33 (d, J=12.4 Hz, 1H), 3.74 (s, 3H), 1.38 (s, 6H). ES-LCMS m/z 239.1 (M+H).
Reaction SMILES: [CH:1]([C:3]1[O:7][CH:6]=[C:5](B(O)O)[CH:4]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1>C(O)C.[Pd]>[CH:1]([C:3]1[O:7][C:6]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: O=Cc1cc(B(O)O)co1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(C=O)o2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 396.9 %

Procedure:
To the stirred solution of 5-formylfuran-3-boronic acid (0.31 g, 2.2 mmol), palladium (10%) in carbon (0.090 g) and sodium carbonate (0.85 g, 8.0 mmol) in ethanol (10 ml) was added a solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.50 g, 0.19 mmol) in ethanol (10 ml) under nitrogen atmosphere. The reaction mixture was refluxed for two hours, and then cooled to RT and diluted with ethanol. The mixture was filtered through a pad of Celite, washed with ethanol and the filtrate was evaporated to dryness. Combiflash purification using heptane/ethyl acetate as eluent system afforded 0.20 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.73 (d, 1H), 7.76 (d, 1H), 8.31 (m, 1H), 8.33 (m, 1H), 8.39 (m, 1H), 9.71 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>O1CCCC1.CCCCCC>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[CH:9]=[CH:8]1
Reactant: O=C=O
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(C(=O)O)ccc2O1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-2H-benzo[b]pyran (see J. Med. Chem., 33, 3028 [1990]) (5.0 g) in dry tetrahydrofuran (100 ml) at -70° C. under nitrogen was added, dropwise, a 1.6M solution of n-butyllithium in hexane (17 ml). The reaction mixture was stirred at -70° C. for 15 minutes then treated with an excess of finely ground solid CO2. The reaction was further stirred for one hour, the solvent evaporated in vacuo and the residue taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The organic layer was concentrated in vacuo to a solid which was triturated with hexane to provide a white solid, 1.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.[C:27](=O)([O-])O.[Na+].IC.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[C:9]([S:25][CH3:27])=[N:8][C:7]=2[N:26]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(SC)nc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (1.2 g), 1M aqueous sodium hydrogen carbonate solution (3.1 ml), iodomethane (0.98 ml) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 1 hr. The reaction mixture was allowed to be cooled, diluted with ethyl acetate (100 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.24 g).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:40])[C@@H:19]([NH:29]C(=O)OCC2C=CC=CC=2)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3]>COCCOC.O>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:40])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Solvent: O
Solvent: COCCOC
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Temperature: 110 °C
Yield: 38 %

Procedure:
Step E (2): Ba(OH)2.H2O (267 mg, 1.41 mmol) was added to a vial charged with benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (diastereomer A, 260 mg, 0.471 mmol) from stepE(1), DME/H2O (3 mL/2 mL). The sealed vial was heated at 110° C. for 18 h. Filtered the reaction mixture through a Pasture pipette/Kimwipe plug to remove solids. Rinsed the vessel and solids with fresh DME. The filtrate was evaporated in vacuo. Residual solvents were removed under high vacuum. The crude residue was purified by silica gel chromatography (1-20% MeOH (containing 0.1% triethylamine)/chloroform linear gradient) to give 74 mg (38% yield) the of the title compound as a clear viscous oil. LC-MS (M+H)+=419.24; 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J=8.24 Hz, 1H), 6.92 (d, J=2.14 Hz, 1H), 6.85 (dd, J=8.24, 2.44 Hz, 1H), 6.71-6.80 (m, 2H), 6.60-6.71 (m, 1H), 5.84-6.03 (m, 1H), 5.30 (dd, J=17.24, 1.68 Hz, 1H), 5.18 (dd, J=10.38, 1.53 Hz, 1H), 4.77 (dd, J=6.10, 3.97 Hz, 1H), 4.08-4.12 (m, 2H), 4.05 (dd, J=6.87, 4.43 Hz, 1H), 3.79 (s, 3H), 3.47-3.52 (m, 1H), 3.04-3.10 (m, 1H), 2.90-3.00 (m, 2H), 2.75 (dd, J=11.90, 8.55 Hz, 1H), 2.61-2.68 (m, 1H), 2.49 (dd, J=13.43, 9.77 Hz, 1H), 1.94-2.00 (m, 1H).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:5]2[CH2:4][CH:3]=[CH:2]1)=O.[CH2:12]([O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH2:19])[CH:13]=[CH2:14]>C(O)(=O)C>[CH2:12]([O:15][C:16]1[CH:17]=[C:18]([N:19]2[C:10](=[O:11])[C:5]3[CH2:4][CH2:3][CH2:2][CH2:1][C:6]=3[C:7]2=[O:9])[CH:20]=[CH:21][C:22]=1[Cl:23])[CH:13]=[CH2:14]
Reactant: O=C1OC(=O)C2CC=CCC12
Reactant: C=CCOc1cc(N)ccc1Cl
Solvent: CC(=O)O
Product: C=CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.4 g of THPA, 5.3 g of 3B and 60 mL of glacial acetic acid was refluxed for 1 hour, then poured into 300 mL of ice water. The resulting mixture was allowed to stand for 10 minutes, then filtered. The collected solid was washed with cold water, dried under reduced pressure and recrystallized from ethyl acetate/hexane, to give N-(3-(allyloxy)-4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide (3C), as yellow crystals, m.p.: 118.5°-120° C.
Reaction SMILES: [Br-].[Na+].Br([O-])(=O)=O.[Na+].[CH3:8][O:9][C:10]1[N:15]=[C:14]([C:16]2[C:20]3[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=3[S:18][C:17]=2[C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)[OH:32]>O>[CH3:8][O:9][C:10]1[N:15]=[C:14]([C:16]2[C:20]3[N:21]=[C:22]([S:25]([CH3:26])=[O:32])[N:23]=[CH:24][C:19]=3[S:18][C:17]=2[C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1sc2cnc(SC)nc2c1-c1cccc(OC)n1
Reactant: O=S(=O)(O)O
Agent: [Br-]
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Product: COC(=O)c1sc2cnc(S(C)=O)nc2c1-c1cccc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
24 mg of sodium bromide and 18 mg of sodium bromate are added, with stirring, to a suspension of 55 mg of methyl 7-(6-methoxypyridin-2-yl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate, prepared by analogy to the method described in example 5, (at 50%) in 2 ml of water, and then 6.5 μl of concentrated sulfuric acid are slowly added. The yellow suspension rapidly turns orange. After 2 h 30 minutes of stirring at ambient temperature, the yellow suspension is filtered through a number 4 sintered glass filter. The yellow solid is dried under vacuum so as to obtain 28 mg of methyl 7-(6-methoxypyridin-2-yl)-2-(methylsulfinyl)thieno[3,2-d]pyrimidine-6-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([C:22]1[CH:23]=[C:24]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:29]([C:26]1[CH:25]=[C:24]([CH2:33][CH2:34][C:35]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:36])[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:27]=1[OH:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCC(=O)NCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCC(=O)NCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -10 °C

Procedure:
A mixture of 13.9 g (0.055 mole) N-(2-hydroxyethyl)lauramide, 13.9 g (0.05 mole) 3(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 0.5 g Tyzor TBT catalyst and 100 ml xylene was refluxed until evolution of water ceased (3 hours). The xylene was removed by vacuum stripping. The residue was taken up in acetonitrile. White crystals separated upon cooling at about -10° C. The acetonitrile was decanted and the recrystallization was repeated. The last traces of acetonitrile were removed under vacuum, and the title product thus obtained was a yellow oil at room temperature.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[O:18])[N:12]([CH3:17])[CH2:13][CH2:14][C:15](=O)[C:9]=2[CH:8]=[CH:7]1.C([O-])(=O)C.[Na+].Cl.[CH2:25]([O:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][N:33]=[C:15]1[CH2:14][CH2:13][N:12]([CH3:17])[C:11](=[O:18])[C:10]2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:7]=[CH:8][C:9]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NOCc1ccccc1
Reactant: CN1CCC(=O)c2ccn(CCCCCl)c2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCC(=NOCc2ccccc2)c2ccn(CCCCCl)c2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 13.44 g (50 mmol) of Compound 23 obtained in Example 14, 8.20 g (100 mmol) of sodium acetate and 15.96 g (100 mmol) of O-benzylhydroxylamine hydrochloride in 250 ml of methanol was stirred for 4 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-bromopyridine-2-sulfonyl chloride (2.7 g, 10 mmol) in DCM (100 mL) was cooled to 0° C. and treated with tert-BuNH2 (5.5 mL, 52 mmol). The resulting mixture was stirred at rt for 48 h. Water (50 mL) was added and the DCM layer were separated, dried and concentrated to obtain compound 32a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.75 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.2, 2.3 Hz, 1H), 7.90-7.94 (m, 1H), 5.02-5.07 (m, 1H), 1.23 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4](N)[CH:5]=[N:6][C:7]=1[CH3:8].[B-](F)(F)(F)[F:12].N#[O+].F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([F:12])[C:3]=1[CH3:10]
Reactant: F[B-](F)(F)F
Reactant: Cc1ncc(N)c(C)c1Br
Agent: CCCC[n+]1ccn(C)c1
Agent: N#[O+]
Solvent: CCOC(C)=O
Product: Cc1ncc(F)c(C)c1Br
Temperature: 60 °C
Yield: 43.3 %

Procedure:
A mixture of 5-bromo-4,6-dimethyl-pyridin-3-amine (500 mg, 2.49 mmol) and nitrosyl tetrafluoroborate (445 mg, 3.73 mmol) in 1-butyl-3-methylimidazolium tetrafluoroborate (9.48 mL, 49.74 mmol) was heated at 60° C. for 2 hours (caution: exothermic). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL), and then saturated aqueous sodium bicarbonate (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-50% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as pale yellow oil (220 mg, 43%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[CH:25][C:26]2=3)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 41 %

Procedure:
The compound was prepared from 4-chloro-3-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with brine and 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 54 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.44 (s, 0.8H), 7.59 (m, 1H), 7.57 (s, 0.2H), 7.41-7.51 (m, 4H), 7.17 (m, 2H), 4.03 (s, 0.3H), 3.95 (m, 0.3H), 3.91 (s, 1.7H), 3.78 (m, 1.7H), 2.82-2.85 (m, 2H), 2.05 (m, 2H); MS: (ES) m/z calculated for C21H17ClF4N3O [M+H]+ 438.1, found 438.1.