Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[C:20](OC)=[CH:19][C:18]2[CH2:17][CH:16]([N:23]([CH2:38][CH3:39])[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([N:23]([CH:16]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:40])=[O:5])[CH:20]=[CH:19][C:18]=2[CH2:17]1)[C:24]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=1)=[O:25])[CH3:39]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(OC)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)O)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester (0.02 g; 0.03 mmol) dissolved in CH2Cl2 (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H2O gradient to yield 2-{6-[1ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid as a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C:14]2[N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:11]3[C@@H:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=4[F:36])[O:19][C:20]4([CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:10]=3[C:9]=2[C@@H:8]([O:37][Si](C(C)(C)C)(C)C)[CH2:7][C:6]1([CH3:46])[CH3:45])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:36][C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:26]=1[C@@H:18]1[C:11]2[C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][C:14]3[C@@H:5]([OH:4])[C:6]([CH3:45])([CH3:46])[CH2:7][C@H:8]([OH:37])[C:9]=3[C:10]=2[C:20]2([CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[O:19]1
Reactant: CC(=O)O[C@@H]1c2nc(C(C)C)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)CC1(C)C)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1F)OC31CCOCC1)[C@@H](O)CC(C)(C)[C@@H]2O
Reaction time: 36 h

Procedure:
17 mg (3S,6S,9S)-9-(tert-butyldimethylsilyloxy)-3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-isopropyl-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-6-yl acetate are dissolved in 2 ml methanol and treated with 70 mg potassium carbonate. The mixture is stirred for 36 hours. Then the solvent is evaporated in vacuo. The residue is partitioned between water and diethylether. The organic phase is separated and dried with magnesium sulphate. The solvent is evaporated in vacuo and the residue is taken up in 1 ml tetrahydrofurane. 50 μl Tetrabutylammonium fluoride are added and the mixture is stirred for 3 hours at room temperature. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (n-hexane/ethylacetate 80:20).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:27])=[O:26]
Reactant: OCCBr
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCO)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 2-bromoethanol. 1H NMR (DMSO-d6) δ 7.98-7.95 (m, 1H), 7.62-7.58 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.04-7.01 (m, 2H), 6.80-6.78 (m, 1H), 6.14 (s, 1H), 5.00 (s, 2H), 4.75 (bs, 1H), 3.59-3.53 (m, 1H), 3.26-3.17 (m, 2H), 3.02-2.92 (m, 1H), 2.39 (s, 3H); MS: ESI (negative): 399 (M−H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2]>[Fe].O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CCc1ccc(O)cc1
Agent: [Fe]
Solvent: O
Product: C=Cc1ccc(O)cc1

Procedure:
To 500 g of crude p-vinyl phenol, obtained by the dehydrogenation of p-ethyl phenol (composition: p-vinyl phenol 25.5%, p-ethyl phenol 69.2%, p-cresol 2.1%, phenol 0.9%, p-vinyl phenol polymer 0.5% and other unknown substances 1.8%), 50% by weight water, 10 ppm of an iron powder based on the amount of the p-vinyl phenol were added, respectively. The mixture was put in a 1 liter glass flask equipped with a stirrer and sulfuric acid was added as a polymerization accelerator in an amount of 500 ppm based on the amount of the p-vinyl phenol with stirring on a water bath. The mixture was reacted at 60° C. for 3 hours.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([O:18]CC)=[O:17])=[CH:8][C:7]=2[CH:21]=1)#[N:2].[OH-].[Na+]>C1COCC1.C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:13])[F:14])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: CCOC(=O)C1=Cc2cc(C#N)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the ester (Step 2) (0.077 g, 0.259 mmol) in THF-EtOH-H2O (7:2:1, 2 mL) in a 5 mL pear-shaped flask was added aqueous NaOH (0.13 mL, 2.5 N solution) in one portion. After stirring for 6 hours at room temperature the solution was partially concentrated in vacuo to remove most of the THF and EtOH. The resulting solution was diluted with H2O and washed with diethyl ether. The resulting aqueous phase was sparged with nitrogen to remove trace diethyl ether and was acidified with concentrated HCl yielding a sticky suspension. The suspension was extracted with diethyl ether and the ether was dried over MgSO4, filtered and concentrated in vacuo yielding a pale yellow oil. This oil was crystallized from methylene chloride-hexanes yielding the title compound (0.041 g, 59%) as a tan powder: mp 185.1–186.1° C. 1H NMR (acetone-d6/300 MHz) 7.99–7.94 (m, 2H), 7.83 (dd, 1H, J=8.5, 2.0 Hz), 7.25 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.0 Hz). FABLRMS m/z 270 (M+H). EIHRMS m/z 269.0316 (M+, Calc'd 269.0300).
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H].C(OC(C)C)(C)C>[C].[Pd].C(O)(=O)C>[CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107.1 %

Procedure:
tert-Butyl [(1S)-1-methyl-2-(pyridin-4-yloxy)ethyl]carbamate (30 g), acetic acid (300 mL) and 10% palladium-carbon (7.5 g) were charged into pressure-resistant reactor vessel, and the mixture was stirred at 80° C. for 6 hr at 0.8 MPa hydrogen pressure. The mixture was allowed to cool to room temperature, and the pressure was reduced to normal level. The insoluble material was removed by filtration, and the filtrate was concentrated. Ethyl acetate (300 mL) was added to the residue, and the mixture was extracted with 10% aqueous citric acid solution (300 mL). The ethyl acetate layer was extracted again with 10% aqueous citric acid solution (150 mL). The aqueous layers were combined, adjusted to pH 12 with 8M aqueous sodium hydroxide solution, and extracted twice with toluene (300 mL). The toluene layers were combined and concentrated. Methanol (30 mL), ethyl acetate (120 mL) and succinic acid (12.1 g) were added to the residue and the mixture was stirred to give crystals. After stirring for 1 hr, diisopropyl ether (150 mL) was added, and the mixture was stirred for 1 hr. The resulting crystals were collected by filtration, washed with diisopropyl ether (150 mL) and dried to give the title compound (32.9 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Br)cc1C(=O)O
Reaction time: 6 h

Procedure:
The starting material is prepared as follows: The solution of 110 g of 5-bromosalicylic acid in 900 ml of water and 48 g of sodium hydroxide is stirred while 60 ml of dimethyl sulfate are added. The mixture is stirred at 70° for 3 hours, whereupon 50 ml of 50% aqueous sodium hydroxide are added, followed slowly by 60 ml of dimethyl sulfate. After stirring at 70° for 6 hours the last step is repeated and the mixture warmed 17 hours longer. It is cooled in an ice bath, filtered, the filtrate stirred with methylene chloride and neutralized with cold 5 N aqueous hydrochloric acid. The organic phase is separated, dried and evaporated to yield the 5-bromo-2-methoxybenzoic acid melting at 115°-117°.
Reaction SMILES: C(N(CC)C=O)C.[C:8](Cl)(=O)[C:9]([Cl:11])=[O:10].[F:14][C:15]([F:22])([F:21])[CH2:16]CC(O)=O>C(Cl)Cl>[F:14][C:15]([F:22])([F:21])[CH2:16][CH2:8][C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC(F)(F)F
Agent: CCN(C=O)CC
Solvent: ClCCl
Product: O=C(Cl)CCC(F)(F)F
Temperature: 25 °C
Yield: 85 %

Procedure:
Diethyl formamide (1.0 ml) and oxalylchloride (239 ml) were added to a 0° C. solution of 4,4,4-trifluorobutyric acid (343 g) in dry methylene chloride (230 ml) and warmed to room temperature overnight. The methylene chloride was removed by distillation and the residue distilled to yield 4,4,4-trifluorobutyryl chloride (328 g, 85%); bp 103°-106° C.; partial NMR (300 MHz, CDCl3): 2.47-2.64 (m, 2H, CF3CH2) 3.19 (t, H, CH2COCl).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[CH:3]1[OH:10].CC(C)=[O:14]>>[Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[CH:3]1[OH:10].[Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[C:3]1([OH:14])[OH:10]
Reactant: CC(C)=O
Agent: OC1C(F)(Cl)CCCC1(Cl)Cl
Product: OC1(O)C(F)(Cl)CCCC1(Cl)Cl

Procedure:
0.5 g (2.26 mmol) of alcohol 1b in solution in 3 cm3 of acetone were introduced into a 10-cm3 round bottom flask fitted with a condenser and with magnetic stirring. 5 cm3 of the Jones reactant were introduced gently; the reaction was highly exothermic; the reaction mixture was then heated to 45°-50° C. for 16 h (1 cm3 of Jones reactant having been added after 4 h and 2 cm3 after 9 h of reaction). At the end of reaction the Jones reactant was destroyed with 10 cm3 of isopropanol, the mixture was diluted with 10 cm3 of water, extracted with dichloromethane and dried over magnesium sulfate, and the solvents were evaporated off. The material was incorporated onto silica and purified by flash chromatography. 0.16 g of starting alcohol 1b (32%) and 0.30 g of pure diol 3a were isolated, that was a 56% yield of compound 3a (Yld based on the unrecovered alcohol 1b=85%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]2=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=[C:7]2[O:6][N:5]=1)[CH3:3].CC(C1OC2C(=C(O)C=CC=2)N=1)C.Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:3][CH:2]([C:4]1[C:8]2[C:9]([O:13][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=3)=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:1]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)c1noc2cccc(O)c12
Agent: CC(C)c1nc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Temperature: 110 °C

Procedure:
A mixture of 3-(1-methylethyl)-1,2-benzisoxazol-4-ol and 2-(1-methylethyl)-1,3-benzoxazol-4-ol (Intermediate 40, 13 mg), was dissolved in DMF (2.0 mL) and 2-chloro-5-nitropyridine (11.6 mg, 0.073 mmol) was added, followed by potassium carbonate (30 mg, 0.22 mmol). The reaction mixture was heated under microwave irradiation at 110° C. for 1 hour. After the removal of the volatiles, the residue obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from 10/0 to 9/1, then 9/1, then from 9/1 to 8/2) to afford the title compound (8.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:21])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccc(F)c(O)c2)c2c(N)ncnc21
Yield: 44 %

Procedure:
A solution of BA62 (3-(4-fluoro-3-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 30 mg, 0.10 mmol) was dissolved in CH2Cl2 (5 ml) and stirred under an argon atmosphere. BBr3 (500 uL, 0.5 mol) was added slowly with a syringe, while stirring. The reaction was stirred at room temperature for 3 hours then concentrated in vacuo and purified using silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA62d (23 mg, 44% yield). ESI-MS (M+H)+ m/z calcd 288.1, found 288.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:7]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCC=CCCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCC=CCCc2ccccc2)cc1
Reaction time: 16 h

Procedure:
4-Toluenesulphonyl chloride (1.3 g) was added in portions to a stirred solution of the product of step (c) (1.5 g) in pyridine at 0°-5° C. The mixture was stirred for 16 hours at 0°-5° C. then poured onto ice-hydrochloric acid and extracted with ether. The extract was washed with sodium bicarbonate and sodium chloride solutions, dried and evaporated to give the title compound as a pale oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[C:13]#[CH:14].O>CN(C=O)C.[Cu-]=O>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=1
Reactant: COCOc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: O=[Cu-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1ccc(OCOC)cc1
Temperature: 110 °C
Yield: 52 %

Procedure:
Under an Ar atmosphere, a mixture of 1-iodo-4-(methoxymethoxy)benzene (500 mg, 1.89 mmol), Ethyl propiolate (371 mg, 3.78 mmol) and Copper(I) oxide (270 mg, 1.89 mmol) in DMF (10 ml) was heated at 110° C. for 16 h. After cooling, H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 15:1) gave 2e (52%). 2e: colorless oil; 1H-NMR (CDCl3) δ 1.36 (3H, t, J=7.1), 3.48 (3H, 2), 4.29 (2H, q, J=7.1), 5.20 (2H, s), 7.02 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.[Cl:35]CCl.Cl>C(OCC)C>[ClH:35].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N(CCN[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C[C@@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Reaction time: 1 h

Procedure:
Combine 2-[(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (1.64 g, 3.53 mmol) and dichloromethane (30 mL). Slowly pass hydrogen chloride gas through the solution for 20 minutes. Stir for 1 hour. Add diethyl ether (150 mL) to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3O2 .0.75 H2O: C, 58.70; H, 6.98; N, 9.14. Found: C, 58.71; H, 6.98; N, 9.14.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH:11]=O)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:21]O.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]#[N:21])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: O=Cc1coc2c(Br)cc(F)c(F)c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#Cc1coc2c(Br)cc(F)c(F)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
The compound (360 mg, 1.38 mmol) obtained in Step 3 was dissolved in acetic acid (5 mL), and sodium acetate (450 mg, 5.5 mmol) and hydroxylamine hydrochloride (140 mg, 2.1 mmol) were added thereto, and stirred at 60° C. for 2 hours. After that, acetic anhydride (0.26 mL, 2.75 mmol) was added thereto, and stirred at 100° C. for 2 hours. After cooling, the solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:5][C:4]=1[CH2:23][S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].[N:37]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[C:27]1([S:24]([C:23]2[C:4]3[C:3](=[CH:22][CH:21]=[C:6]([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:12])=[O:13])[CH:5]=3)[NH:2][N:37]=2)(=[O:25])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethanol (430 mL) in two portions and 1 N hydrochloric acid (200 mL) were added to toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester (6.5 g, 13 mmol). A solution of sodium nitrite (1.5 g, 22 mmol) in water was then added to the reaction mixture. The reaction was heated to aid in solubility. After stirring at ambient temperature for 2 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred at ambient temperature for one hour. It was then solvent evaporated and partitioned in water and ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform. Drying at 63° C. in vacuo yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester a buff-colored foam (3.9 g, 59%); Mass Spectrum (+EI, [M+H]+) m/z 523. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.76 (d, 1H, J=8.78 Hz), 8.52-8.55 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.64-7.74 (m, 3H), 7.55-7.63 (m, 2H), 7.50 (d, 1H, J=9.15 Hz), 7.27 (d, 2H, J=8.05 Hz), 7.14 (d, 1H, J=2.20 Hz), 6.94 (dd, 1H, J=9.15 Hz and 2.44 Hz), 4.32-4.34 (m, 2H), 4.18-4.20 (m, 2H), 2.25 ppm (s, 3H). Elemental Analysis for C26H22N2O6S2: Calcd: C, 59.76; H, 4.24; N, 5.36; Found: C, 59.69; H, 4.28; N, 5.14.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9](OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH2:9]([C:10]1[CH:11]=[CH:2][C:3]([CH2:20][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH:11]=[C:2]([OH:1])[C:3]([C:20]([O:22][CH3:23])=[O:21])=[CH:4]3)=[CH:4][CH:5]=1)[CH3:8]
Reactant: COC(=O)c1cc2cccc(OS(=O)(=O)C(F)(F)F)c2cc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cccc3cc(C(=O)OC)c(O)cc23)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 151.4 %

Procedure:
Under a nitrogen stream, the known compound methyl 3-hydroxy-5-trifluoromethanesulfonyloxy-2-naphthoate (Bull. Korean Chem. Soc. 2000, 21, 757; 82.3 mg, 0.23 mmol), diphenylphosphino ferrocene palladium dichloride (17.3 mg, 0.021 mmol), 2-[(4-ethylphenyl)methyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborane (57.8 mg, 0.24 mmol) and cesium carbonate (228.6 mg, 0.70 mmol) were dissolved in tetrahydrofuran (2.0 mL). Water (0.2 mL) was added thereto, and then the mixture was stirred for 30 minutes at 100° C. in a microwave apparatus. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:20)), to thereby obtain the titled compound (55.8 mg, 74%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].[Br:45]Br>ClCCl>[Br:45][CH:14]1[S:13]/[C:12](=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[CH:32][N:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=4)[N:30]=3)=[CH:27][CH:28]=2)=[O:19])/[N:11]([C:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:15]1=[O:16]
Reactant: BrBr
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(N2C(=O)C(Br)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To a dry 2 dram vial equipped with magnetic stirrer was added (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.20 g, 0.32 mmol) and anhydrous dichloromethane (0.5 mL). To this solution was added bromine (0.033 mL, 0.64 mmol). The reaction was stirred overnight at room temperature. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a clear colorless oil (0.041 g, 18%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[NH2:18][C:19](N)=[O:20]>O>[OH:20][C:19]1[N:1]=[C:2]2[N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]=[CH:4][C:3]2=[C:15]([OH:17])[N:18]=1
Reactant: Nc1c(C(=O)O)cnn1CCc1ccccc1
Reactant: NC(N)=O
Solvent: O
Product: Oc1nc(O)c2cnn(CCc3ccccc3)c2n1
Temperature: 180 °C
Yield: 105 %

Procedure:
A mixture of 5-amino-1-(2-phenylethyl)-1H-pyrazole-4-carboxylic acid (1.87 g, 8.1 mmol) and urea (1.46 g, 24 mmol) was heated at 180° C. for 5 h, cooled and the resulting solid suspended in boiling water, filtered and washed with water to give the impure title compound (2.18 g, 105%,) as a cream solid.