Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=CC=C[C:31]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:32]([NH:28][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:18]=1)=[O:22])([CH3:33])[CH3:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC(C)C)s1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (77 mg, 0.24 mmol) in DMF (3 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (86 mg, 0.27 mmol), N,N-diisopropyl ethyl amine (208 μL, 1.21 mmol) and isopropylamine (16 mg, 0.27 mmol). The resulting reaction mixture was stirred for 2 h and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 1:1 to 0:1) afforded the title compound (81 mg, 93%) as an off white solid. MS: m/e=357.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH:13]=[O:14])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CCC(CCC=O)CC1
Agent: CC(C)Cc1ccc(C=O)cc1
Product: CC(C)Cc1ccc(CCC=O)cc1

Procedure:
4-Isobutyl cyclohexanepropanal was similarly prepared as described in Examples I and II. First, 4-isobutyl benzaldehyde (600 g, commercially available from Mitsubishi Gas Chemical Company, Inc.) was used to obtain 3-(4-isobutyl-phenyl)-propionaldehyde (568 g) with a boiling point of 119° C. at a pressure of 5 mmHg. 3-(4-Isobutyl-phenyl)-propionaldehyde (400 g) was consequently used to provide 4-isobutyl cyclohexanepropanal (245 g) with a boiling point of 107° C. at a pressure of 4.4 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:14](=[O:20])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]3([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:20])[N:13]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1ccc(C2=NNC(=O)C23CCCC3)cc1OC
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC

Procedure:
Prepared analogous as described for the example B1 (Alternative 1) using 4-(3,4-dimethoxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1-one (compound C10) and tert-butyl 4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B10*HCl)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=2)[CH:7]=1)[CH3:5].[C:23]([O-])([O-])=O.[K+].[K+].[I-].[Na+].ClC(C)C(OC)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH3:23])[CH:12]=2)[CH:7]=1)[CH3:5]
Reactant: COC(=O)COc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reactant: O=C([O-])[O-]
Agent: COC(=O)C(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc2cc(C(C)C(=O)OC)ccc2c1
Yield: 84.8 %

Procedure:
To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid methyl ester 7 (150 g, 652 mmol), anhydrous K2CO3 (455 gr, 3.292 mol) and sodium iodide (22.5 grams, 150 mmol) in anhydrous acetone (2000 ml) was added methyl 2-chloropropionate (107.5 g, 877 mmol) and refluxed for 50 hours. Acetone was distilled off and water (1500 ml) was added. Crude 8 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 8 (175 g, 85%) as a light yellow syrup. The structure was confirmed with NMR.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.[N-:25]=[N+]=[N-].[Na+].O.Cl>CN(C)C=O.C(OCC)(=O)C>[NH2:25][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reaction time: 1 h
Yield: 8.4 %

Procedure:
In 280 ml of N,N-dimethylformamide was dissolved 40.1 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Thereto was added 13.9 g of sodium azide. The mixture was stirred for 1 hour at 70°-75° C. The reaction mixture was introduced into a mixed solvent consisting of 1.5 liters of water and 300 ml of ethyl acetate. The mixture was adjusted to pH 0.1 with conc. hydrochloric acid. The aqueous layer was separated, washed with 200 ml of ethyl acetate, adjusted to pH 4.0 with a 10% aqueous sodium hydroxide solution, and extracted with two 500-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The crystal was recrystallized from ethanol to obtain 2.84 g (yield: 82.1%) of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1 -benzopyran-4-one having a melting point of 162°-163° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:17])[C:13]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:17])[C:13]=3[C:14](=[O:16])[C:6]=2[CH:7]=1
Reactant: Cn1ncc(Nc2ccc(F)cc2)c1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc2[nH]c3ccc(F)cc3c(=O)c21
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A suspension of 4-[(4-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 1, step 1, 280 mg, 1.19 mmol) in phosphorus oxychloride (6 ml) was refluxed for 3 h. After cooling to room temperature, the mixture was concentrated and dried in vacuo. The residue was dissolved in 50% aqueous acetic acid (6 ml) and refluxed for 8 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (100 ml) and dried over magnesium sulfate. Removal of solvent and recrystallization from ethyl acetate gave 98 mg (38%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(OCCCCl)ccc2[nH]1
Temperature: 80 °C
Reaction time: 160 h
Yield: 0.1 %

Procedure:
To a solution of ethyl-5-hydroxyindole-2-carboxylate (15 g, 73 mmol, 1.0 eq.) and 1-bromo-3-chloropropane (8.8 mL, 88 mmol, 1.2 eq.) in 2-butanone (200 mL) was added potassium carbonate (12.1 g, 88 mmol, 1.2 eq.). The reaction mixture was stirred 160 h at 80° C. The reaction mixture was cooled down and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine then dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography on silica eluting with cyclohexane/ethyl acetate 9:1 to yield 15.3 mg (74%) of the title compound as a light yellow solid. MS (m/e): 282.7 (MH+, 100%).
Reaction SMILES: O(C)[Na].[O:4]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:22]([O:24]C)=O)[C:18]([O:20]C)=O)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:26][C:27]([NH2:29])=[O:28].Cl>>[O:4]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:18](=[O:20])[NH:29][C:27](=[O:28])[NH:26][C:22]2=[O:24])=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Reactant: NC(N)=O
Agent: CO[Na]
Agent: Cl
Product: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
To a NaOCH3 solution (prepared by allowing 0.23 g of Na metal to react with 7.2 mL dry CH3OH) was added dimethyl 2-(4-phenoxyphenyl)malonate (1.0 g, 3.33 mmol) followed by urea (0.4 g, 6.66 mmol). The resulting white reaction mixture was refluxed for 24 hours and then cooled to 0° C. and acidified with 3N HCl. The white solids were filtered and washed with water and dried to give 900 mg of crude product. This was further purified by trituration with EtOAc/hexanes (1:1) to afford 5-(4-phenoxyphenyl)pyrimidine-2,4,6-trione as a white powder (830 mg): 1H NMR (400 mHz, CDCl3) 3:2 keto/enol form δ 11.38 (2×NH keto form, s), 10.58 (2×NH enol form, s), 7.46-6.91(9H, m), 4.85 (H-5, s); HRMS Calcd for C16H12N2O4 296.0796; Found 296.0806.
Reaction SMILES: [OH:1][CH:2]([CH3:28])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:29]([O:1][CH:2]([CH3:28])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(C)O)cc2)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(C)OC(=O)CCC)cc2)nc1
Reaction time: 4 h
Yield: 88.7 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-1-butenyl)phenyl)-5-decyloxypyrimidine was dissolved in 20 ml of pyridine, added with 0.5 g of butyryl chloride and stirred at 25°-30° C. for 4 hours. The reaction mixture was diluted with 100 ml of toluene and washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order. The toluene layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.05 g of (+)-2-(4-(3-butyryloxy-1-butenyl)phenyl)-5-decyloxy-pyrimidine.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=[N:47]C=2C=1.N[C@H](C(O)=O)CC1C=CC=CC=1.C1(SC)C=CC=CC=1>CN(C=O)C>[NH2:1][C@H:2]([C:10]([NH2:47])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCC1c2ccccc2-c2ccccc21
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CSc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 1 h

Procedure:
Fmoc-Phe-OPfp (0.5 mmol) and HOBt (0.5 mmol) were added to a suspension of resin B (prepared from 185 mg, 0.1 mmol of the Fmoc-derivative) in DMF (5 ml) and the mixture was shaken for 1 hour. The resin was successively washed with DMF (5 ml×5), then treated with 20% piperidine in DMF (5 ml) for 15 min. The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) and dried in vacuo; yield 179 mg. The dried resin (5 mg) was treated with 1M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min. H-Phe-NH2 liberated was determined by TLC scanner. The latter treated resin was subjected to 6N HCl hydrolysis. No Phe was detected by amino acid analyser. This result shows that phenylalanine had been cleaved almost completely from the resin. It was therefore established that resin B is useful as an amide precursor for amino acids and that the thioanisole-containing solution described above is a superior cleavage reagent.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[OH:9])[CH:7]=[N:6][CH:5]=1
Reactant: OB(O)c1ccccc1O
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccccc1-c1cncc(Cl)n1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a mixture of 2,6-dichloropyrazine (1.00 g, 6.71 mmol), 2-hydroxyphenylboronic acid (972 mg, 7.05 mmol) and trans dichlorobis(triphenylphosphine) palladium (II) (471 mg, 0.671 mmol) were added acetonitrile (20 mL) and sodium carbonate (13.4 mL, 1.0 M in water, 13.4 mmol), and the resulting mixture was degassed by a nitrogen sparge. The reaction flask was equipped with a reflux condenser, then was placed in a pre-heated oil bath (75° C.) and was stirred rapidly. After 5 h, the reaction mixture was allowed to cool to room temperature, then was poured into water and extracted with EtOAc. The organic phase was separated and concentrated in vacuo. Purification by chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 207.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.64 (s, 1H), 9.11 (s, 1H), 8.53 (s, 1H), 7.85 (dd, J=8.0, 1.5 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]=[O:8])[C:5](=[O:9])[CH2:4][N:3]1[CH2:10][C:11]#[CH:12].[C-:13]#[N:14].[Na+].S(=O)(O)[O-].[Na+]>CCOCC.O>[C:13]([CH:7]([N:6]1[C:5](=[O:9])[CH2:4][N:3]([CH2:10][C:11]#[CH:12])[C:2]1=[O:1])[OH:8])#[N:14]
Reactant: [C-]#N
Reactant: C#CCN1CC(=O)N(C=O)C1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C#CCN1CC(=O)N(C(O)C#N)C1=O
Reaction time: 2 h

Procedure:
To a solution of 2,4-dioxo-1-propargyl-3-imidazolidine-carbaldehyde (1.8 mmol) in 25 ml of ether is added 25 ml of water followed by sodium cyanide (3.04 mmol). The mixture is stirred vigorously while a solution of sodium bisulfite (2.45 mmol) in 15 ml of water is added over about 5 minutes. The reaction mixture is stirred for two hours. The organic phase is separated, washed with water, dried over calcium sulfate and solvent evaporated to give cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nccc(C(F)(F)F)n2)cc1Br
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To 3-bromo-4-fluoroaniline (0.76 g, 4.0 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (0.73 g, 4.0 mmol) was added dioxane (13.33 mL) and p-TSA (0.761 g, 4.0 mmol). The reaction was sealed and was heated at reflux overnight. The reaction was cooled to room temperature and was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and the organic was dried over sodium sulfate and filtered before concentration. The crude product was purified by flash chromatography (25:75 ethyl acetate:hexanes) to afford N-(3-bromo-4-fluorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (1.2 g, 3.57 mmol, 89%) as a pale yellowish solid. 1H NMR (500 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H); 7.99-7.96 (m, 1H); 7.51 (d, J=8.4 Hz, 1H); 7.29 (s, 1H); 7.14 (t, J=8.5 Hz, 1H); 7.10 (d, J=4.9 Hz, 1H). rhSYK activity=+
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][N:15]=3)[N:12]=[CH:11][CH: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[N:13]([C:14]3[CH:19]=[C:18]([CH:17]=[CH:16][N:15]=3)[C:20]([OH:22])=[O:21])[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccnn2-c2cc(C(=O)O)ccn2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccnc(-n2nccc2-c2cccc(O)c2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-[5-(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid (160 mg, 0.54 mmol) in CH2Cl2 (5 mL) was added 1 M BBr3 in CH2Cl2 (5 mL) at 0° C., then stirred at 45° C. overnight. The reaction mixture was cooled, concentrated and dissolved with EtOAc, then washed with water and brine. The organic phase was dried, concentrated and purified by prep-HPLC to give the title compound (54 mg, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.60-6.65 (3H, m), 6.71 (1H, dd, J=8.4, 2.0 Hz), 7.11 (1H, t, J=8.0 Hz), 7.78-7.82 (2H, m), 8.04(1H, s), 8.48 (1H, d, J=5.2 Hz), 9.46 (1H, s), 13.93 (1H, br s). [M+H] Calc'd for C15H11N3O3, 282; Found, 282.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol) dissolved in DCM (300 ml), cooled to 0° C. and added oxalyl chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to this mixture and stirred at rt for 2 h. After 2 h, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 1-benzylpiperidine-4-carbonyl chloride quantitatively. 2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 1-benzylpiperidine-4-carbonyl chloride (29 g, 0.12 mol) in DCM (100 ml). After continuing stirring at rt for 2 h, DCM was removed on the rotavapour to obtain the titled compound (47.6 g), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1.[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19].C(N(CC)CC)C>C(O)(C)C>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1[N+](=O)[O-]
Reactant: NCC(O)CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(NCC(O)CO)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1.0 g (0.004 mol) 9 in 15 ml isopropanol is added 0.36 g (0.004 mol) 10 and 0.4 g (0.004 mol) triethylamine at room temperature. The reaction mixture becomes reddish in color and is stirred at room temperature for 16 hours. The solvent is removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel followed by elution with 10% methanol/chloroform. Pure 15 has Rf 0.4 and is obtained as a yellow solid, m.p. 107°-9°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3S(C3C=CC=CC=3)(=O)=O)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10].[OH-].[Na+]>C(O)(C)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:44][CH2:45][N:46]([CH:49]([CH3:50])[CH3:51])[CH2:47][CH2:48]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:10])=[O:11]
Reactant: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
2,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide (81 mg, 0.106 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.53 ml, 1.060 mmol) was added. The reaction mixture was stirred at RT for 2 h, the solvent removed and the residue dissolved in water (1 ml) and acidified to pH˜6 by the addition of 2M hydrogen chloride (aq). The resultant suspension was extracted with dichloromethane (3×2 ml), the organic layer separated (hydrophobic frit) and concentrated in vacuo to give a brown solid which dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (45 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]12S[CH:12]1[CH:13]1[S:18][C:14]1(O)[CH:15]=[CH:16]2.CC(O)=O>C(Cl)Cl.[Zn]>[SH:18][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC12C=CC3(O)SC3C1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Nc1ccc(S)cc1)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride (5.14 mL, 44.28 mL) was added dropwise to a mixture of 4-aminophenol disulfide (5.0 g, 20.13 mmol) and TEA (7.01 mL, 50.3 mmol) in 60 mL DCM at 0° C. The reaction was allowed to stir overnight. The resulting precipitate was collected by filtration. The solid was washed with MeOH and water and then dried. The solid was combined with 200 mL of concentrated HOAc, and 5.0 equiv of zinc powder was added. The reaction was monitored by LCMS. When the reaction was complete, the acetic acid solution was concentrated to approximately 20 mL in volume. The crude mixture was then extracted with water and EtOAc. The organic layer was dried with MgSO4 then concentrated. MS: 228 [M+H]+; 1H NMR (DMSO-d6): 10.23 (s, 1H), 7.94 (d, 2H), 7.81 (d, 2H), 7.56 (m, 3H), 7.28 (d, 2H), 5.31 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(O[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C1C=CC(C)=CC=1)(=O)=O>C1C=CC=CC=1.[Na]>[O:26]([CH2:25][CH2:24][O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2)cc1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Na]
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OCCOc2ccccc2)CC1(C)C

Procedure:
30 parts of 1,2,2,6,6,-pentamethylpiperidin-4-ol were dissolved in 250 parts of benzene and 4 parts of sodium added. The solution was heated overnight at reflux temperature and then cooled. 38 parts of 2-phenoxyethanol tosylate were added dropwise and the solution heated at reflux for 5 hours. On cooling the precipitate was filtered off and the filtrate evaporated in vacuo. Treatment of the residue with dilute hydrochloric acid and then basification with dilute sodium hydroxide to a pH 10 was followed by extraction with ether. Evaporation afforded a pale yellow oil which was chromatographed on alumina to give 4-(2'-phenoxyethoxy)-1,2,2,6,6-pentamethylpiperidine as a colourless oil which gave the following elemental analysis by weight: