Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][OH:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][CH2:18][CH:15]2[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[O:16]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cccc(-c3c(F)cccc3F)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(F)cccc4F)c3O2)cc1
Yield: 63 %

Procedure:
Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.5 g, 13.35 mmol) with p-toluenesulfonyl chloride (3.05 g, 16.01 mol) generally according to the procedure described for Intermediate 10 gave 3.5 g (64%) of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.20 mmol) with sodium azide (1.87 g, 28.8 mmol) generally according to the procedure described for Intermediate 98 gave (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.20 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.69 g (90%) of (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 219-222° C.; Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.34; H, 4.87; N, 4.58.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43]O)=[CH:38][C:37]=1[CH3:45].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[C:37]([CH3:45])[CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CCO)ccc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)c(C)c3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 2-(4-fluoro-3-methylphenyl)ethanol (0.066 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 7 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluoro-3-methylphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0374 g, 0.062 mmol, 72.4% yield) as glassy paste. 1H NMR (500 MHz, CDCl3) δ 7.12-7.17 (m, 2H), 7.06-7.12 (m, 2H), 6.95-7.00 (m, 3H), 6.08 (s, 1H), 4.14-4.30 (m, 4H), 3.19 (d, J=11.2 Hz, 1H), 3.09 (t, J=7.0 Hz, 2H), 2.87 (t, J=12.0 Hz, 1H), 2.61 (s, 3H), 2.30 (d, J=1.9 Hz, 3H), 2.25-2.29 (m, 1H), 2.20 (s, 3H), 2.06 (t, J=11.7 Hz, 1H), 1.52-1.58 (m, 1H), 1.33-1.42 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.16-1.20 (m, 1H), 1.05-1.10 (m, 1H), 0.90 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=605.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([Br:14])[C:11]([CH3:15])=[C:10]([N+:16]([O-])=O)[C:9]2=[O:19])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.Cl.O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([Br:14])[C:11]([CH3:15])=[C:10]([NH2:16])[C:9]2=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(Br)c(C)c([N+](=O)[O-])c2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cn2cc(Br)c(C)c(N)c2=O)cc1
Reaction time: 3.5 h
Yield: 61.5 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-nitro-2-pyridone (0.23 g 0.65 mmol) in glacial acetic acid (3 mL) was added a solution of stannous chloride dihydrate (1.0 g) in concentrated HCl (2 mL). After 3.5 hours, the reaction mixture was diluted with water, neutralized with NaHCO3, and extracted with methylene chloride. The organic phase was dried, filtered, and evaporated to give 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-amino-2-pyridone (0.13 g, 0.40 mmol, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[CH2:12]([OH:16])[CH:13](O)[CH3:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:14][CH:13]1[CH2:12][O:16][C:6]2([CH2:5][C:4]([CH3:10])([CH3:9])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7]2)[O:8]1
Reactant: CC(O)CO
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Yield: 70.2 %

Procedure:
To a 2 liter flask fitted with a reflux condenser, a water separator and a stirrer is charged 265 g of 2,6,6-trimethylcyclohex-2-en-1,4-dione (prepared by the method described in Helv.Chim.Acta. 39, 2041(1956)), 266 g of propylene glycol, 500 ml of benzene and 1 g of p-toluenesulfonic acid. The reactants are stirred and refluxed until no additional water is collected in the water separator. The product is washed with water to a pH of 6 and the solvent is stripped off. The residue is vacuum distilled through a nine inch Goodloe column to yield 257 g of product, b.p. 92° at 1 mm Hg (80% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].N1C=CC=CC=1.[C:15]([CH2:20][CH2:21][C:22](Cl)=[O:23])([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:20][CH2:21][C:22]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:23])[CH3:19]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCN(CC)CCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)NCCN(CC)CC
Yield: 16.4 %

Procedure:
First, 20 milliliters (0.05 mole) N,N-diethylethylene diamine, 50 milliliters dry methylene chloride, and 5.2 milliliters (0.065 mole) pyridine were combined in a flask. Next, 9.03 grams (0.06 mole) 3-carboethoxy-propionyl chloride was added at -60° C. with stirring. The temperature was allowed to rise to 0° C. The reaction mixture was then washed with a 200 milliliter portion of water and a 100 milliliter portion of saturated sodium carbonate solution. The organic solution was stripped in vacuum to yield 2.0 grams of the desired product. nD30 1.4500.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-]>Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)nc1
Temperature: 5 °C
Yield: 76.3 %

Procedure:
6-bromopyridine-3-carboxylic acid (50 g, 0.25 mol) in thionyl chloride (4a, 130 ml, 1.76 mol) was heated at reflux for 3 hours. The mixture was then concentrated under vacuum and the residue was co-evaporated with benzene to remove the thionyl chloride. The resulting acid chloride was dissolved in benzene (120 ml, 1.33 mol) and treated with AlCl3 (82.5 g, 0.6 mol) portion wise with stirring at 5° C. After heating at reflux for 6 hours, the reaction mixture was cooled to room temperature and poured into 20% HCl (500 ml), stirred for 1 h, and layers were separated. The aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, 50% KOH, and water (100 mL each), dried (Na2SO4), filtered and concentrated under reduced pressure to afford the product, 4-b, (50 g, 77%). 1H NMR (CDCl3, 300 MHz,): δ 8.72 (d, J=2.4 Hz, 1H), 8.04 (dd, J1=8.4 Hz, J2=2.7 Hz, 1H), 7.74 (m, 2H), 7.61 (m, 1H), 7.48 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]1([C:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([O:31][CH2:30][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Reactant: OCC1CCCC1
Product: CC(O)(CNC(=O)c1cnc(OCC2CCCC2)c(-c2ccc(Cl)cc2)n1)C1CC1

Procedure:
The title compound was prepared in analogy to example 26 starting from 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid (-2-cyclopropyl-2-hydroxy-propyl)-amide and replacing ethylenglycolmonomethylether by cyclopentylmethanol. MS (ISP) (M+H+)=430.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([N:26]1[CH2:34][C:33]2([C:35]([O:37][CH3:38])=[O:36])[CH:28]([C:29](I)=[CH:30][CH2:31][CH:32]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([N:26]1[CH2:34][C:33]2([C:35]([O:37][CH3:38])=[O:36])[CH:28]([C:29]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[CH:30][CH2:31][CH:32]2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1cc3ccccc3s1)=CCC2c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 9.3 g (17.3 mmol) of benzothiophene-2-boronic acid trimeric anhydride in 100 cm3 of methanol and 400 cm3 of a 2N aqueous sodium carbonate solution are successively added to a solution of 22.36 g (47 mmol) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate and of 6.03 g (5.2 mmol) of tetrakis(triphenylphosphine)palladium in 250 cm3 of 1,2-dimethoxyethane, the reaction mixture is then brought to reflux for two hours and stirring is maintained overnight at room temperature. After returning to a temperature in the region of 20° C., the reaction mixture is extracted with 800 cm3 of ethyl acetate and then the organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The brown residue obtained is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture. 11.04 g (50%) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(2-benzothienyl)-1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate are thus obtained in the form of a yellow foam, the characteristics of which are as follows:
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6]1[NH:10][CH2:9][CH2:8][S:7]1)#[N:4].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([N:10]1[CH2:9][CH2:8][S:7][C:6]1=[N:5][C:3]#[N:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CN=C1NCCS1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=C1SCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a suspension of 0.24 g of sodium hydride in 40 ml of N,N-dimethylformamide was added dropwise a solution of 1.27 g of 2-cyanoiminothiazolidine in 10 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. After stirring, 1.27 g of benzyl chloride was added, and the mixture was stirred at temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure, water was added to the residue, and the resulting crystals were then collected by filtration to give 1.84 g of 3-benzyl-2-cyanoiminothiazolidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Solvent: CO
Product: NC(=O)c1ccc(Nc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
Combine 6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (200 mg, 0.78 mmol) (step 2, Example 16), benzaldehyde (83 mg, 0.78 mmol), 3 Å molecular sieves (0.2 g), and methanol (10 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (0.4 mg) to the reaction and stirred at room temperature for 4 hours. Add water (20 mL) then extract with dicholormethane (3×50 mL). Dry the dichloromethane extracts with sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 0.2 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield 6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide (24 mg): 1H NMR (MeOD, 300.00 MHz): 8.66 (d, 1H, J=1.8 Hz), 8.00 (dd, 1H, J=9.0, 2.4 Hz), 7.55-7.15 (m, 10H), 6.81 (d, 1H, J=8.8 Hz), 3.80 (s, 2H), 3.38 (m, 1H), 2.84 (m, 5H); m/z=347.01 (M+1); HPLC=95%@5.54 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:20][C:21]([O:23]CC)=O)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][NH:34][C:21](=[O:23])[CH2:20][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[N:10]1)[CH3:27]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 45.4 %

Procedure:
By a procedure substantially similar to that of Example 14, 8 g (0.023 mol) of ethyl 4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetate of Example 3 and 34.3 mL (0.22 mol) of diethylaminopropylamine were reacted to produce 4.45 g of N-[3-(diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetamide. The solid product after trituration in water collapsed to a non-crystalline, white, waxy solid upon drying.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:18]=3)[NH:13][N:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH2:1])[CH:18]=3)[NH:13][N:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
Over five different reactions, liquid ammonia (about 10 mL) was added to a −78° C. solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (1.72 g, 3.63 mmol) in THF (48 mL). This was usually allowed to warm to ambient temperature. This was heated in sealed tube for about 16-35 hours at 70-100° C. After cooling to about ambient temperature, the combined reaction mixtures were then poured into excess sodium bicarbonate solution and extracted with chloroform or methylene chloride. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chlormatography with 0.75% ammonium hydroxide/7.5% methanol in chloroform. The residue was further purified by HPLC using 30-80% (chloroform/methanol(8:2)/TEA) in heptane/TEA. Concentrating and drying yielded 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethylamine as a white solid to which was added methanol and ethereal hydrochloride. Concentration and drying for 30 hours in vacuo at 83° C. yielded the hydrochloride as a cream-colored solid (0.0951 g, 7.4%): MP: >300° C.; Mass Spectrum (−EI, [M−H]−) m/z 316. 1HNMR (500 MHz, DMSO-d6): δ14.24(s, 1H), 8.09 (br,s, 3H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.39 (d, 1H, J=2.20 Hz), 7.17 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.22-4.25 (m, 2H), 3.20-3.24 ppm (m, 2H). Elemental Analysis for C15H15N3O3S.1.00 mol HCl.0.85 mol H2O: Calcd: C, 48.81; H, 4.83; N, 11.38; Found: C, 48.65; H, 4.77; N, 11.00.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[C:32]([C:29]([OH:31])=[O:30])=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)c1ccccc1B(O)O
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2ccccc2C(=O)O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 2-carboxyphenylboronic acid to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]([OH:14])[CH3:13].C[N+]1([O-])CCOCC1.CC#N>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)ccc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
1-(2-Bromo-5-trifluoromethyl-phenyl)-ethanol (0.914 g, 3.40 mmol), N-methylmorpholine N-oxide (0331 g, 6.24 mmol), and tetrapropylammonium perruthenate (0.109 g, 0.31 mmol) were combined in CH2Cl2 (18 mL) and MeCN (0.9 mL) and stirred at room temperature for 30 minutes. Once no starting material was seen by analytical LCMS, the mixture was filtered through Celite and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N>>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:6]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: N
Product: CC1(C)CC(C(O)CNc2nc(NCc3ccccc3)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (5.0 g) was reacted with benzylamine (25.0 g) for 8 hours and 30 minutes at 150°-160° C. The reaction mixture was poured into an aqueous ammonia solution, extracted with chloroform and dried over anhydrous potassium carbonate and chloroform was distilled off. The resulting residue was treated with silica gel chromatography (eluent=ethyl acetate:triethylamine:ethanol=10:12:3) to yield crystals, which were recrystallized from cyclohexane to afford the desired product as white crystals melting at 88° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 54, but using 0.30 g of 5-(4-{2-[1-(4-hydroxyphenyl)ethylideneaminooxy]ethoxy}benzyl)thiazolidine-2,4-dione (prepared as described in Example 51), 0.092 ml of acetic anhydride and 15 ml of pyridine, 0.3 g of the title compound, melting at 133-135° C., was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][C:7]([C@H:9]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:13]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][S:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:10][OH:11])=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]([NH:33][C@H:34]([C:48](O)=[O:49])[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:22]1[C:18]2[CH:17]=[C:16]([S:13]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:9]([C:7]3[S:8][C:4]([CH2:3][NH:2][C:48](=[O:49])[C@H:34]([CH:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:33][C:31]([O:30][CH3:29])=[O:32])=[CH:5][CH:6]=3)[CH2:10][OH:11])(=[O:15])=[O:14])[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: CC(C)CN([C@H](CO)c1ccc(CN)s1)S(=O)(=O)c1ccc2ncsc2c1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO)N(CC(C)C)S(=O)(=O)c2ccc3ncsc3c2)s1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-{(1R)-1-[5-(aminomethyl)thiophen-2-yl]-2-hydroxyethyl}-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide hydrochloride (30 mg, 0.065 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (21 mg, 0.071 mmol) and DIPEA (45 μL, 0.26 mmol) in DMF (300 μL) at 0° C. was added BOP (32 mg, 0.071 mmol). The reaction mixture was stirred at 0° C. for 4 hours before being quenched with a saturated solution of sodium bicarbonate (3 mL). The quenched mixture was extracted with ether/ethyl acetate (1/1 3×3 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate. MS: m/z=729.1 (MNa+).