Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](OCC)(=O)[CH3:13].CCCCCC>C(O)C.S(=O)(=O)(O)O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1ccc(C)c(I)c1
Yield: 95 %

Procedure:
To a solution of 3-iodo-4-methylbenzoic acid (1.5 g, 5.7 mmol) in 25 ml of ethanol was dropped in 0.5 ml of concentrated sulfuric acid. The reaction was refluxed overnight. TLC (Ethyl Acetate/Hexane 1:10) indicated the completion of the esterification. The extra ethanol was evaporated and the residue was dissolved in 30 ml of dichloromethane, which was washed with water (10 ml) and brine (10 ml), dried, and evaporated to a thick oil. A white solid was obtained after drying under vacuo (1.56 g, in 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH:15]([CH3:19])[CH2:16][CH2:17][OH:18])[C:13]([CH2:20]O)=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[CH:15]([CH3:19])[CH2:16][CH2:17][O:18][CH2:20][C:13]4=[N:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(CCO)n1c(CO)nc2cnc3cc(Br)ccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CCOCc2nc3cnc4cc(Br)ccc4c3n21
Temperature: 120 °C
Yield: 84.4 %

Procedure:
A solution of 3-[7-bromo-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-ol (3.27 g, 9.34 mmol) in concentrated hydrochloric acid (35 mL) was stirred and heated at 120° C. for three hours and then poured into ice-cold deionized water (80 mL). Aqueous sodium hydroxide (50% w/w) was added to adjust the solution to pH 7, and a precipitate formed. The mixture was extracted with dichloromethane, and the dichloromethane was removed under reduced pressure. The solid residue was triturated with diethyl ether and isolated by filtration to provide 2.62 g of 3-bromo-12-methyl-11,12-dihydro-8H,10H-[1,4]oxazepino[4′,3′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[F:23][C:18]1[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cccnc2F)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ncccc1C1CCNCC1
Yield: 310.1 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2-fluoropyrid-3-yl)piperidine (0.36 g) in 5 mL of trifluoroacetic acid was heated to reflux for 30 minutes and evaporated. The residue thus obtained was dissolved in chloroform and evaporated. After repeating this process three times, the named product was obtained as an oil (0.64 g); MS: 181; NMR: 1.6-2.1 (m, 4), 3.0-3.4 (m, 5), 7.2-7.5 (m, 2), 7.8-7.9 (m, 4), 8.1 (m, 1), 8.2-8.8 (br, 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][O:18][CH2:19][C@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH2:22][OH:23])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][O:18][CH2:19][C@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH:22]=[O:23])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CO[C@@H](CO)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)OCC(=C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=C(C)CO[C@@H](C=O)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)OCC(=C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-((2S,3S)-4-hydroxy-2,3-bis((2-methylallyl)oxy)butoxy)propanoate (3.96 g, 8.51 mmol) in CH2Cl2/DMSO (56.7 mL, ratio: 5/1) at 0° C. was added TEA (5.93 ml, 42.5 mmol) followed by sulfur trioxide pyridine complex (4.06 g, 25.5 mmol) and the reaction was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to provide the title compound as a colorless oil (3.26 g, 83% yield): IR (neat) 3360, 2951, 1721, 1512, 1209, 1053 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=1.0 Hz, 1H), 7.41-7.27 (m, 5H), 5.65 (d, J=8.7 Hz, 1H), 5.17-5.08 (m, 2H), 4.96-4.92 (m, 2H), 4.90 (d, J=14.8 Hz, 2H), 4.47 (dt, J=8.7, 2.9 Hz, 1H), 4.10 (d, J=12.4 Hz, 1H), 3.97-3.88 (m, 4H), 3.85-3.78 (m, 2H), 3.75 (s, 3H), 3.65 (dd, J=9.5, 3.2 Hz, 1H), 3.62 (d, J=4.5 Hz, 2H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 202.61, 170.65, 156.16, 141.73, 141.27, 136.42, 128.63, 128.26, 128.17, 113.83, 113.23, 82.49, 78.16, 75.45, 75.01, 71.55, 69.39, 67.16, 54.49, 52.70, 19.62, 19.55; ESIMS m/z 486.2 ([M+Na]+).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCCc1cccs1
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1cccs1

Procedure:
To a mechanically stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (WRAIR; 5.67 g, 0.023 mol), 1-bromo-5-(2-thienyl) pentane from previous step a (5.32 g, 0.023 mol) and HMPA (40 ml), at 115°-120° C., was added dropwise, during 45 min, a solution of Et3N (5 ml) and propylene oxide (10 ml). The mixture was heated at 115°-120° C. for 5 hr, allowed to cool and extracted with a solution of pet. ether (20°-40° C.) and Et2O (1:1 v/v, 200 ml). The extract was washed with 10% NaOH solution (3×75 ml) and the combined basic washings were re-extracted with pet. ether (20°-40°) and Et2O solution (1:1 v/v, 2×100 ml). The combined organic layers were washed with H2O (2×100 ml), dried (K2CO3), and treated with carbon (Darco G-60). Solvent evaporation gave 6-methoxy-4-methyl-8-nitro-5-[5-(2-thienyl) pentoxy] quinoline as a yellow solid, 5.61 g (61%), mp 51°-54° C. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]([F:15])=[C:12]([F:14])[F:13].[OH-].[K+].CN(C)C=O>O.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([O:8][C:12]([F:14])([F:13])[CH:11]([F:15])[Cl:10])[N:7]=1
Reactant: FC(F)=C(F)Cl
Reactant: Cc1cc(O)nc(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)(F)C(F)Cl)nc(N)n1
Yield: 18 %

Procedure:
25 g of 2 -amino-4-hydroxy-6-methyl-pyrimidine, 25.6 g of chlorotrifluoroethylene, 13.8 of potassium hydroxide and 200 ml of dimethylformamide are stirred together at 60° in an autoclave for 8 hours. The mixture is diluted with water and extracted with ethyl acetate and the extract is evaporated to give a dark oil. A little methylene chloride is added and the crystalline precipitate formed is separated off to give 8.7 g of 2-amino-4-methyl-6-(1,1,2,-trifluoro-2-chloro-ethoxy)-pyrimidine of melting point 73°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[C:13]([Cu])#[N:14].[O-]S([O-])(=O)=O.[Na+].[Na+].CC(OC)(C)C>CN1C(=O)CCC1>[F:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: N#C[Cu]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: N#Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 160 °C
Reaction time: 7.5 h
Yield: 68.1 %

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 mL) was set to a pre-heated 160° C. oil-base and stirred at 160° C. under N2 over 450 min. The mixture was cooled to RT, charged with Na2SO4 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The material was recrystallized from EtOH/water (2/1) to yield 2,5-Difluoro-4-nitro-benzonitrile (50 g, 68% yield) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 7.96-7.95 (dd, 1H), 7.67-7.64 (dd, 1H).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C=O)C>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([Cl:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(F)=C(F)F
Solvent: CN(C)C=O
Product: O=C(Cl)CC(F)=C(F)F

Procedure:
Reaction of 3,4,4-trifluoro-3-butenoic acid (IV) with oxalyl chloride in the presence of DMF as a catalyst without any solvent to give 3,4,4-trifluoro-3-butenoyl chloride (V).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]#[N:13])[CH2:10][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(C#N)CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC1(c2cccc(O)c2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-methoxyphenyl)cyclopropanecarbonitrile (Step A, 6.4 g, 37 mmol) in methylene chloride (30 ml) was added BBr3 (1M in CH2Cl2, 80 ml) at −78° C. under argon, the cold bath was substituted by ice bath after 30 minutes and reaction was stirred at the same temperature for 2 hours and then 30 minutes at room temperature. The reaction mixture was quenched by addition of ice and worked up by washing with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (methylene chloride:ethyl acetate, 5:1) to give the title compound.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8][C:7]=1C(O)=O)([OH:3])=[O:2].N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.[Cu]>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([O:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][S:8][C:9]=2[CH:14]=1
Reactant: O=C(O)COc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: O=C(O)COc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 190 °C
Yield: 77.4 %

Procedure:
The mixture of 3-(carboxymethoxy)-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxylic acid (92.0 mg), copper (13.7 mg) and quinoline (1.5 mL) was heated at 190° C. for 10 min. The mixture was diluted with EtOAc. The mixture was washed successively with 1N HCl and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane), and washed with hexane to give the title compound (63.9 mg).
Reaction SMILES: C[O:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:16].B(Br)(Br)Br>ClCCl.O>[OH:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:16]
Reactant: COc1c(C)c(=O)c2ccccc2[nH]c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(O)c(=O)[nH]c2ccccc2c1=O
Yield: 70.5 %

Procedure:
To a solution of 3-methoxy-4-methyl-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.47 g) in dichloromethane was added boron tribromide (6.5 mL). The precipitate which formed was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was recrystallized from hot toluene to give the title compound (0.31 g); mp 252.3° C.; NMR: 2.07 (s,3); MS(EI): m/z=203(M). Analysis for C11H9NO3.0.2 H2O: Calculated: C, 63.89; H, 4.58; N, 6.77; Found: C, 63.79; H, 4.49; N, 6.73.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO>[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C2=CCN(CC(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(CC(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 3 h

Procedure:
To a solution of [4-(3-Methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetic acid tert-butyl ester (145 mg, 0.416 mmol) in methanol (15 mL, 370 mmol) was added 10% Palladium on Carbon (50% Wet, 44.3 mg, 0.0208 mmol). The mixture was shaken in a Parr apparatus under an atmosphere of Hydrogen (50 PSI) for 3 h. Filtration through Celite and evaporation of the solvent provided crude [4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetic acid tert-butyl ester, which was used without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][O:2]1.S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]([NH2:35])[N:29]=2)=[CH:24][C:23]=1[CH3:36].CCN(CC)CC>ClCCl.CN(C=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:35][C:30]4[N:29]=[C:28]([C:25]5[CH:26]=[N:27][C:22]([O:21][CH3:20])=[C:23]([CH3:36])[CH:24]=5)[C:33]([CH3:34])=[CH:32][CH:31]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)COC3)CC1
Reactant: COc1ncc(-c2nc(N)ccc2C)cc1C
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)COC5)CC3)ccc2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of 1-(1,3-dihydroisobenzofuran-5-yl)cyclopropanecarboxylic acid (40.8 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionyl chloride (43.8 μL, 0.60 mmol) followed by DMF (1 drop) and the reaction was stirred at room temperature for 30 minutes and then the solvent was evaporated. Toluene (˜1 mL) was added and mixed with the residue and then removed by rotovap. The residue was then dissolved in dichloromethane (1 mL) and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (45.8 mg, 0.20 mmol) and Et3N (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) was added. The reaction was stirred at room temperature for 12 hours. The reaction was then concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC (10-99% CH3CN in water) to yield 40 mg of the desired product. ESI-MS m/z calc. 415.2. found 416.5 (M+1)+. Retention time 1.87 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12]C)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]#[C:15][Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1C#C)([CH3:23])([CH3:22])[CH3:21].IC1C=CC2C=CS(=O)(=O)C=2C=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:15]#[C:14][C:3]1[CH:2]=[CH:7][C:6]2[CH:12]=[CH:11][S:8](=[O:9])(=[O:10])[C:5]=2[CH:4]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Agent: O=S1(=O)C=Cc2ccc(I)cc21
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C=C2

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-iodo-1-benzothiophene 1,1-dioxide (Intermediate 236), the title compound was obtained as a yellow solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CC#N.O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (4.24 g, CAS Reg. No. 350-46-9), 1,1,1-trifluoro-propan-2-ol (4.56 g, CAS Reg. No. 374-01-6) and cesium carbonate (13.04 g) in CH3CN (50 mL) was heated to reflux for 10 hours. Then, the reaction mixture was cooled, acidified with conc. HCl and then distributed between ethyl acetate and water. The organic layer was separated, washed with brine and evaporated to provide the title compound (6.74 g) that was used without further purification. Rf: 0.38 (silica gel, ether/heptane 1:4).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:30])[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)[C:15](O)=[O:16].C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:30])[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)[C:15]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
To a stirred mixture of benzenesulphonamide (0.89 mmol), dichloromethane (1 mL) and dimethylformamide (one drop), a solution of 3,5-dibromo-4-(3-bromo-benzyloxy)benzoic acid (0.17 mmol) and N,N-diisopropylethylamine (0.86 mmol) in dichloromethane (1 mL) was added. After 15 minutes bromotripyrrolidino phosphoniumlhexafluoro phosphate (0.21 mmol) and 1-hydroxybenzotriazole hydrate (0.045 mmol) were added. The reaction mixture was stirred at room temperature over night. Dichloromethane was added (3 mL) and the mixture was washed with an aqueous solution of citric acid (10%, 3×3 mL). The organic layer was washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol 19:1) and further purified on semi-preparative HPLC (column and eluents as described for Examples 27, 28 and 30) to give 16 mg (16%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]benzene-sulphonamide.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][C@@H:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11].O.O.C[N+]([O-:34])(C)C>C1COCC1.CCOCC>[CH2:10]([O:12][C@@H:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][OH:34])=[CH:24][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11]
Reactant: C=Cc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Reactant: C[N+](C)(C)[O-]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)[C@H](Cc1ccc(CCO)cc1)OCC
Reaction time: 22 h
Yield: 60.9 %

Procedure:
9-BBN (3.0 mmol, 6 mL of a 0.5 M solution in hexanes) was added to a stirred solution of ethyl(2S)-2-ethoxy-3-(4-vinylphenyl)propanoate (0.37 g, 1.48 mmol) in dry THF under argon. The reaction mixture was stirred for 22 h under argon. Trimethylamine N-oxide dihydrate (0.60 g, 5.4 mmol) was added and the mixture was heated to reflux overnight and diluted with ether (50 mL). The organic layer was washed with brine (×3), dried (MgSO4), filtered, and evaporated. The crude product was purified by flash chromatography (silica, heptane/ethyl acetate 3:1) to give the title compound as an colorless oil (0.24 g, 62%).
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]([CH3:14])=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1.C[O-].[Na+].C(OCC)(=O)C.C1(C)C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CO>[SH:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]([CH3:14])=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1
Reactant: Cc1cc(=O)oc2cc(SC(=O)N(C)C)ccc12
Agent: C[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(=O)oc2cc(S)ccc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
26.3 g (0.1 mol) of S-(4-methyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate are suspended in 300 ml of methanol under a nitrogen atmosphere. 0.2 mol of sodium methylate (8% solution of Na (w/v) in methanol) is added at room temperature and the mixture is heated at 45° C. for 4 hours. The disappearance of the starting material is monitored by thin layer chromatography using an ethyl acetate/toluene mixture (1/4 v/v) as the eluent. After cooling, the reaction medium is hydrolyzed on an ice/concentrated hydrochloric acid mixture and, after stirring for 30 minutes, the precipitate obtained is filtered off and then washed with water. After drying over P2O5, 19.2 g (yield≈100%) of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:34][N:33]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.7 mmol) and 5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamine (1.48 g, 7.7 mmol) were combined in toluene (3.0 ml) under nitrogen. The reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was cooled to RT and filtered. The solids were washed with additional toluene (25 ml total) and dried in vacuo to produce a yellow powder (338 mg, 0.78 mmol). mp 278-280° C. (dec.); MS (APCI +) 498, 500 (100); 1H NMR δ(400 MHz, CDCl3) 10.71-10.64 (m, 2H), 9.01 (s, 1H), 8.10-8.09 (m, 1H), 7.89 (d, J=0.10 Hz, 1H), 7.52-7.30 (m, 1H), 5.97-5.89 (m, 1H), 3.87-3.84 (m, 2H), 3.53-3.50 (m, 2H), 3.22-3.09 (m, 4H), 2.83-2.82 (m, 3H), 2.60 (s, 3H), 2.21-2.15 (m, 2H), 1.94 (br, 2H), 1.81-1.78 (m, 2H), 1.62-1.60 (M, 2H); Anal. Calc'd for C23H28BrN7O13.00H2O1.65HCl0.60C2H5OH: C, 43.70; H, 5.74; N, 14.74. Found; C, 43.76; H, 5.79; N, 14.39.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[CH:5][C:6]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:7]([CH:20]=1)[C:8]([N:10](CC)[CH:11](OC)[C:12](C)(C)C)=[O:9].I[Si](C)(C)C>ClCl>[CH3:25][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([Si:21]([CH3:23])([CH3:22])[CH3:24])=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH3:12])=[O:9]
Reactant: CCN(C(=O)c1cc(N(C)C)ccc1[Si](C)(C)C)C(OC)C(C)(C)C
Agent: C[Si](C)(C)I
Agent: ClCl
Product: CCNC(=O)c1cc(N(C)C)ccc1[Si](C)(C)C
Reaction time: 2 h

Procedure:
The compound of Example 222 (0.31 g, 0.85 mmol) was dissolved in CH2 Cl2 (20 mL) and was treated with iodotrimethylsilane (2.1 mL, 15 mmol) in a foil-covered flask. The reaction was stirred for 2 h and was quenched with sat NaHCO3. The mixture was extracted with ether, the organic layers were washed with brine and sat sodium bisulfite, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallized from hexanes to afford 68 mg (5%) of the title compound as a white solid. m.p. 141°-143° C.