Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][S:14]([O:17]C)(=[O:16])=[O:15])[O:3]1.Cl[C:20]1[S:24][C:23]([C:25]([NH2:27])=[O:26])=[N:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:25]([C:23]1[S:24][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][S:14]([OH:17])(=[O:15])=[O:16])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][N:22]=1)(=[O:26])[NH2:27]
Reactant: COS(=O)(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: NC(=O)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2nnc(C(N)=O)s2)cc2c1C(CS(=O)(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl (1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methanesulfonate (0.46 g, 1.71 mmol, 1 eq.) and 5-chloro-1,3,4-thiadiazole-2-carboxamide (0.42 g, 2.56 mmol, 1.5 eq.) in 10 ml DMF was added cesium carbonate (2.22 g, 6.82 mmol, 4 eq.) portionwise. The reaction was stirred at room temperature overnight. It was then quenched by water, extracted with EtOAc. The aqueous layer was collected and prep HPLC gave the product as white flakes. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.01 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 5.42 (d, 7.6 Hz, 1H), 3.04 (dd, J=14.4, 1.2 Hz, 1H), 2.46 (m, 1H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([N:17]=[C:18]=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1>CN(C=O)C>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([NH:17][C:18]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(Cl)c(C)c1N=C=O
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C)c1NC(=O)N=C1NC(=O)CN1C
Reaction time: 4 h

Procedure:
To a stirring suspension of 7.92 g (0.07 mole) of creatinine in 50 ml of dry DMF is added 9.08 g (0.05 mole) of 3-chloro-2,6-dimethylphenyl isocyanate. After stirring for four hours, the reaction mixture is filtered through a diatomaceous earth pad to remove unreacted creatinine. Addition of a large excess of ice water precipitates a gummy semisolid mass which eventually crystallizes. After blowing the product to dry it for about eighteen hours, it is recrystallized from acetone-ether. Finally the product is taken up in dichloromethane and the resulting solution is filtered through diatomaceous earth. Concentration and dilution with ether gives pure product, 1-(3-chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea; m.p. 140°-141.5°C.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH2:40]>>[CH3:39][NH:40][C:28]([C:25]1([C:22]2[N:23]=[N:24][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:38])[CH3:37])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1)=[O:29]
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN
Product: CNC(=O)C1(c2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)nn2)CC1
Yield: 49 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 49% of theory; LC (method 1): tR=1.76 min; Mass spectrum (ESI+): m/z=529 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.[C:25]1(B(O)O)[CH2:29][CH2:28][CH2:27][CH:26]=1>>[C:25]1([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:21]([F:23])([F:24])[F:22])[N:3]=2)[CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Reactant: OB(O)C1=CCCC1
Product: O=C(O)Cc1ccc(Nc2cc(C3=CCCC3)nc(C(F)(F)F)c2)cc1
Yield: 24.1 %

Procedure:
Following General Procedure F, ethyl 2-(4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate (0.115 g, 0.32 mmol) was reacted with cyclopent-1-en-1-ylboronic acid (0.039 g, 0.35 mmol) to afford the title compound (0.028 g, 24%) as a yellow oil. MW=362.35. 1H NMR (CDCl3, 500 MHz) 8.7.35-7.28 (m, 2H), 7.18-7.11 (m, 2H), 7.02-6.95 (m, 1H), 6.89 (s, 1H), 6.69-6.63 (m, 1H), 6.18 (s, 1H), 3.65 (s, 3H), 2.05 (q, J=7.5 Hz, 4H), 1.30-1.22 (m, 2H); APCI MS m/z 363 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH:37]([CH3:39])[CH3:38])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][C:20]=1[Br:36])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[Br:36][C:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][N:11]([C@H:10]([C:9]([OH:40])=[O:8])[CH:37]([CH3:38])[CH3:39])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)O)C(C)C

Procedure:
A solution of 2.4 g (4 mmol) of N-[(3-bromo-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester in 90 ml of dioxane is hydrogenated at 5 bar and at room temperature with the addition of 1.2 g of Pd/C (10%) until the calculated amount of hydrogen has been absorbed. After evaporation of the filtered solution, the evaporation residue is dissolved in 2N sodium hydroxide solution and extracted with ether, and the aqueous phase is rendered acidic with 2N hydrochloric acid. The title compound is obtained by extracting with ethyl acetate, drying and evaporating as a colourless foam (Rf 0.40, system A2), FAB-MS: m/e=514 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:13][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCOCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethyleneglycol monomethyl ether (10 mmol) and benzyl bromoacetate (11 mmol) are added to a suspension of anhydrous K2CO3 (15 mmol) in 50 ml anhydrous DMF. The suspension is stirred at room temperature overnight. Water is added and the emulsion is extracted with ethyl acetate (3×200 ml), washed with water, brine, and dried with MgSO4. The solvent is evaporated and the residual oil purified by flash chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:43]=[CH:42][C:15]([C:16]([N:18]([CH3:41])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:33])=[O:17])=[CH:14][C:13]=1[O:44][CH3:45])=[O:10].[CH:46]([CH:48]=O)=O.S([O-])(O)=O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH3:45][O:44][C:13]1[CH:14]=[C:15]([CH:42]=[CH:43][C:12]=1[NH:11][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[CH:46][CH:48]=[N:8]2)=[O:10])[C:16]([N:18]([CH3:41])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1)=[O:33])=[O:17]
Reactant: O=CC=O
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2nccnc12
Yield: 63.2 %

Procedure:
A mixture of 4-(2,3-diaminophenyl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg), glyoxal (47 mg) and sodium hydrogen sulfite (169 mg) in ethanol (15 ml) was refluxed for 5 hours. The solution was diluted with chloroform (30 ml) and the solution was washed with water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The crude product was purified by silica gal column (1% methanol in chloroform) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(quinoxalin-5-yl)carbonylaminobenzamide (131 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.Cl.CCOC(C)=O>C1COCC1>[C:17]([C:11]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:18]
Reactant: N#CC1CCCCC1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C#N)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Solid KHMDS (4.36 g, 22.0 mmol) is dissolved in THF (80.0 mL) and cooled to 0° C. Cyclohexanecarbonitrile (2.38 g, 22.0 mmol) is added, and the resulting solution is stirred for 40 minutes. A solution of 4-fluorobenzonitrile (1.33 g, 10.95 mmol) in THF (10.0 mL) is added, and the mixture is stirred for 2 hours at 0° C. and 10 hours at room temperature. 1N HCl (50.0 mL) is added, and the aqueous phase is extracted with EtOAc (4×50.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 30% EtOAc) (1.55 g, 7.38 mmol, 67%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23-1.38 (m, 1H) 1.52-1.68 (m, 2H) 1.68-1.78 (m, 1H) 1.78-1.93 (m, 4H) 2.00-2.11 (m, 2H) 7.75 (d, J=8.79 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H).
Reaction SMILES: C([O-])(=O)C.[NH4+].C=O.[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:15][OH:16])([CH3:11])([CH3:10])[CH3:9]>O.C(O)(=O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])[CH:15]=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Yield: 68.3 %

Procedure:
A 500 ml reaction flask fitted with a mechanical stirrer, heating mantle, thermometer and water-cooled condenser was charged with 100 ml of glacial acetic acid and 17 ml of water. To the stirred solution there were added 30.8 g (0.4 mole) of ammonium acetate, 48.7 g of 37% formalin (0.60 mole formaldehyde) and 11.8 g (0.05 mole) of 3,5-ditert.butyl-4-hydroxybenzyl alcohol. The reaction flask was equipped with a take-off head to remove the methanol which is present in commercially available formalin. The mixture was refluxed (100°-2°) for 2 hours. The cooled mixture was poured on a vacuum filter and the product cake was washed with water. After drying, there was obtained 8.0 g of crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 191°-93° (68.4%).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[C:19]2[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH:20]=2)[CH:8]=1>CO.CCOC(C)=O.[Pd]>[F:27][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH:19]2[CH2:20][CH2:21][CH2:22][C:23]2([CH3:24])[CH3:25])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a dry flask containing 83.3B (0.86 g, 2.30 mmol) in MeOH (10 mL) and EtOAc (2 mL) was added palladium, 10% wt on activated carbon (0.25 g, 0.23 mmol). After purging, the mixture was stirred under an atmosphere of hydrogen at room temperature. The reaction was monitored with TLC and LC-MS. After 22.5 hours, the reaction was filtered through Celite. After concentration, the residue was identified 83.3C and used without purification (0.86 g, 99%). MS ESI (pos.) m/e: 376.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[N:15]1([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:25][C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:27][CH:26]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCOCC4)cc3)cc21
Reaction time: 8 h
Yield: 52 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(4-morpholinyl)aniline (0.26 g, 1.1 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified that purified by silica gel chromatography eluting with EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one (94 mg, 52%): mp (2-propanol/hexanes) 219-223° C.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][N:22]=[C:23]([C:24]([O:26]CC)=[O:25])[C:17]=3[CH2:16]2)=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11]>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:17]=3[CH2:16]2)=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOC(=O)c1noc2c1CN(C(=O)Nc1ccc(Cl)c(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1noc2c1CN(C(=O)Nc1ccc(Cl)c(Cl)c1)CC2
Reaction time: 15 h

Procedure:
Lithium hydroxide monohydrate (56%) (0.25 g, 6.038 mmol) dissolved in water (8 ml) was added to a solution of ethyl 5-(3,4-dichlorophenylcarbamoyl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate (1.2 g, 3.019 mmol) in methanol (25 ml), and the mixture was stirred for 15 h. The solvent was removed in vacuo. The aqueous phase was adjusted to an acidic pH value with dilute HCl solution (aq.) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 0.94 g (87%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][CH2:8][C:9]([CH3:11])([OH:7])[CH3:10]
Reactant: Cc1cccc(N)c1Br
Reactant: CC1(C)CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(NCC(C)(C)O)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium perchlorate (2.13 g, 20 mmol) in diethyl ether (4 mL) was added 1,2-epoxy-2-methylpropane (0.195 mL, 2.2 mmol), followed by 2-bromo-3-methylaniline (0.250 mL, 2 mmol) under an atmosphere of nitrogen gas. The reaction mixture was stirred overnight at RT. Water was added dropwise, and the product was extracted from the reaction mixture with DCM. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc). 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol was obtained as a clear colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.30 (d, 2H, J=8.8 Hz), 7.36-7.44 (m, 4H), 7.47 (d, 1H, J=2.4 Hz), 7.54-7.63 (m, 4H), 7.21 (d, 1H, J=8.8 Hz), 9.92 (s, 1H). MS: m/z 473.4 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)cc1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1ccc(C)cc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-p-tolyl-propionic acid methyl ester with thiourea. LC-MS: tR=0.77 min; [M+H]+=249.3.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][C:15]=1[NH2:16].[H-].[Na+].Cl>CN1CCCC1=O>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)(=[O:22])=[O:23])=[CH:17][C:15]=1[NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Reactant: CCOC(=O)c1cncnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cncnc1Nc1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
A mixture of ethyl 4-chloropyrimidine-5-carboxylate (0.4 g), 2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline (0.69 g) and sodium hydride (55%, 98 mg) in 1-methyl-2-pyrrolidone (8 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give ethyl 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-yl sulfonyl)phenylamino]pyrimidine-5-carboxylate (0.42 g). To this material were added ethanol (8 mL), tetrahydrofuran (2 mL) and 5 mol/L aqueous sodium hydroxide solution (1.77 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenylamino]pyrimidine-5-carboxylic acid (0.37 g). The obtained 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenylamino]pyrimidine-5-carboxylic acid (0.1 g) was dissolved in 1,4-dioxane (2 mL). To the solution were added triethylamine (0.094 mL) and diphenylphosphoryl azide (0.058 mL), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2−ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:21]=2)=[O:15])=[CH:12][CH:11]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:28][CH:27]=2)=[CH:21][C:20]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OCCO)cc2)ccc1Cl
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide (1.84 g, 3.92 mmol) is dissolved in tetrahydrofuran (50 mL), and treated with a solution of tetrabutylammonium fluoride reagent (1 M in tetrahydrofuran, 2.2 mmol). The reaction is allowed to stir for 1 hour. The reaction is diluted with water and extracted with ether. The organic phase is separated and concentrated in vacuo affording 1.39 g (100% yield) of the title compound. 1H NMR (DMSO) δ 3.75 (t, 2H, J=4.55 Hz), 4.12 (t, 2H, J=4.80 Hz), 4.95 (s, 2H), 7.12 (d, 2H, J=8.84 Hz), 7.76-7.90 (m, 4H), 8.24 (d, 1H, J=2.02). MS (m/z): 354 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>O1CCCC1>[OH:6][CH2:5][C:4]1[C:3]([CH3:11])=[C:2]([OH:1])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1c(O)cccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
3-Hydroxy-2-methyl-benzoic acid (1.0 g, 7.2 mmol) in tetrahydrofuran (80 mL) was treated with dropwise added BH3-tetrahydrofuran (1M in tetrahydrofuran)(10 mL). The reaction mixture was stirred at rt overnight. Quenched with 10% NaOH, the mixture was adjusted pH to 7 with 10% HCl and extracted with isopropanol/dichloromethane (1:3) (2×), The organic layers were combined and washed with water, brine, dried to afford the title compound (795 mg, 80%). MS (DCI/NH3) m/z 139 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH3:10][NH:11][S:12](Cl)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][S:12](=[O:14])(=[O:13])[NH:11][CH3:10]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccccc1O
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)Oc1ccccc1OC
Yield: 65.8 %

Procedure:
A solution of 12.4 g (0.1 mole) of 2-methoxyphenol (guaiacol; Aldrich) and 13.1 g (0.1 mole) of methylsulfamoyl chloride (Preparation 22) in 150 ml of toluene was stirred and treated at reflux for 2 hr. The solvent was evaporated under reduced pressure and the only residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A, PrepPAK® 500A silica, ethyl acetate-hexanes, 1:2; flow rate 150 ml/min). Fractions containing the product were combined and the solvents evaporated under reduced pressure to yield an oil that solidified upon standing. The solid was recrystallized from benzene-petroleum-ether (30°-60° C.) to give 14.3 g (66%) of the title compound as a white solid, mp 68°-71° C.