Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@:34]2([CH3:35])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)C(C)(C)N(Br)C1=O>CCCCCC>[C:1]([O:9][C@@H:10]1[C@@:34]2([CH3:35])[C:14](=[CH:15][CH:16]=[C:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](OC(=O)c5ccccc5)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCCCCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](OC(=O)c5ccccc5)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.75 h

Procedure:
A solution of the dibenzoate described in (a) (0.58 gms) in hexane (10 ml) was treated with dibromodimethylhydantoin (0.15 gms) and heated under reflux for 25 mins. After cooling the mixture was filtered and the filtrate concentrated to a pale oil. The oil was dissolved in dry xylene (3 mls) and added dropwise to a refluxing solution of trimethylphosphite (0.4 ml) in xylene (5 ml.). Heating under reflux continued for 1.75 hrs. after which time the solvents were removed under reduced pressure and the residue crystallized from acetone/methanol to give the title compound. Recrystallized from ethanol/acetone the product had melting point 161°-162°⟦alpha⟧sub.D -8°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=[CH:8]1)#[C:2][CH3:3].C(N(CC)CC)C.C(#N)C.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37]>ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[O:37]1[C:2]([CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)=[CH:3][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]1=2
Reactant: Oc1ccccc1I
Reactant: CC#COCCn1cnc2cnc3ccccc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: c1ccc2oc(COCCn3cnc4cnc5ccccc5c43)cc2c1
Temperature: 60 °C
Yield: 62.9 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(propynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (1.0 g, 4.21 mmol), triethylamine (1.53 mL, 10.96 mmol) and anhydrous acetonitrile (20 mL) were combined and then heated to 60° C. 2-Iodophenol (1.02 g, 4.63 mmol), copper (I) iodide (0.08 g) and dichlorobis(triphenylphosphine)palladium(II) (0.148 g) were added. After 4 hours analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalysts. The filtrate was concentrated under reduced pressure to provide an oil. This material was purified by flash chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 0.91 g of 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinoline as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([S:11][CH3:12])=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[Se:16][C:15]=1[C:23]([NH2:25])=[O:24].CN(C=O)C.[OH-].[Na+]>>[CH3:12][S:11][C:9]1[S:10][C:3]2[C:2]([NH:13][C:14]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[Se:16][C:15]=3[C:23]([NH2:25])=[O:24])=[N:7][CH:6]=[N:5][C:4]=2[N:8]=1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: CSc1nc2ncnc(Cl)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2s1

Procedure:
The reaction of 7-chloro-2-(methylthio)thiazolo[4,5-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale color solid, mp 280-282° C. 1H NMR (400 MHz, DMSO-d6): δ 12.16 (1H, br s, exchangeable with D2O), 8.77 (1H, s), 8.15 (1H, s), 7.61 (2H, br s, exchangeable with D2O), 2.69 (3H, s), 1.39 (9H, s); LC-MS (positive ion mode): m/z 426, 428 (M+H)+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(O)(=O)C.C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200.1 %

Procedure:
A solution of 4 N hydrochloric acid in acetic acid (2 mL) was added to a solution of tert-butyl N′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (300 mg) in ethyl acetate (2 mL), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 250 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Li+].Cl>O1CCCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C(F)(F)F)c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (4 mL) of the compound (7.4 g, 25 mmol) obtained in Example 64a in tetrahydrofuran was added lithium tetrahydroborate (2.6 g, 49 mmol), and the mixture was stirred at 80° C. for 5 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (5.4 g, 85%) as a colorless solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([CH2:44][C:45]([OH:47])=O)[C:35]1[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=1)#[N:24].[CH3:48][N:49]1[CH2:54][CH2:53][N:52]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:51][CH2:50]1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O.ClCCl.CO>[CH2:42]([O:41][C:36]1[C:35]([C:28]2([CH2:44][C:45]([N:58]3[CH2:57][CH2:56][CH:55]([N:52]4[CH2:51][CH2:50][N:49]([CH3:48])[CH2:54][CH2:53]4)[CH2:60][CH2:59]3)=[O:47])[C:27]3[C:31](=[CH:32][CH:33]=[C:25]([C:23]#[N:24])[CH:26]=3)[NH:30][C:29]2=[O:34])=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:43]
Reactant: CCOc1ncccc1C1(CC(=O)O)C(=O)Nc2ccc(C#N)cc21
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ncccc1C1(CC(=O)N2CCC(N3CCN(C)CC3)CC2)C(=O)Nc2ccc(C#N)cc21
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
200 mg (1.48 mmol) of 1-hydroxybenzotriazole and 284 mg (1.48 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added to a solution of 907 mg (1.48 mmol) of [5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid from example 1.6 in 10 ml of dimethylformamide. The mixture was stirred for 15 minutes and then 285 mg (1.56 mmol) of 1-methyl-4-piperidin-4-ylpiperazine and 1.03 ml (7.41 mmol) of triethylamine were added. The reaction mixture was stirred at room temperature overnight. The reaction was checked by TLC (silica gel, dichloromethane/methanol 15:5). The reaction mixture was mixed with water and diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (1×). The combined organic phase was washed with water (1×) and saturated sodium chloride solution (1×), dried over magnesium sulfate and filtered, and the solvent was evaporated in vacuo. The resulting residue was purified by preparative MPLC (ISCO Companion, 12 g NP cartridge) with dichloromethane/methanol (10-70%) as eluent. 497 mg (0.99 mmol, 66%) of the title compound were obtained as a colorless solid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[O:12][C:13]1[C:21]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[O:12][C:13]1[C:21]([S:22](=[O:24])(=[O:25])[NH2:23])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)Nc1ccc(C)cc1Oc1c(NCc2ccccc2)cc(C(=O)O)cc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N)c(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)c1

Procedure:
The mixture of 2.5 g of 4-(4-acetamido-3-tolyloxy)-3-benzylamino-5-sulfamoylbenzoic acid and 25 mlof 2N aqueous sodium hydroxide is refluxed for seven hours under nitrogen. After cooling it is filtered, the filtrate acidified to a pH of 4-5 with glacial acetic acid, the precipitate formed filtered off, washed with water and recrystallized from 50% aqueous ethanol, to yield the 4-(4-amino-3-tolyloxy)-3-benzylamino-5-sulfamoylbenzoic acid of the formula ##SPC13##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[C:10]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(C([Sn])=C(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[CH:10]=[CH2:11]
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccc(I)c(Cl)c1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(N)cc1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(O) (0.50 g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50° C. under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([N:27]2[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1>C(Cl)Cl>[NH2:32][CH:29]1[CH2:30][CH2:31][N:27]([C:10]2[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22])=[CH:19][CH:20]=3)[N:11]=2)[CH2:28]1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(NC(=O)OC(C)(C)C)C3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(N)C3)n2)cc1
Reaction time: 17 h
Yield: 47.7 %

Procedure:
TFA (200 μL, 2.596 mmol) was added to a stirred solution of tert-butyl 1-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)pyrrolidin-3-ylcarbamate (46 mg, 0.09966 mmol) in DCM (5 mL) at ambient temperature. The reaction was stirred at this temperature for 17 hours. A further portion of TFA (200 μL, 2.596 mmol) was added and the reaction stirred at ambient temperature for a further 2 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM/ether (×3). The residue was passed through a 2 g SCX-2 cartridge and washed with MeOH. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The residue was purified by column chromatography (ISCO Companion™, 12 g column, elueting with 0 to 10% MeOH+10% NH4OH/DCM) to give the title product as a yellow solid (17.2 mg, 45% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 1.61-1.70 (m, 1H), 1.97-2.06 (m, 1H), 3.01 (br s, 2H), 3.22 (dd, 1H), 3.38 (quin, 1H), 3.48-3.57 (m, 2H), 3.65-3.74 (m, 2H), 6.12 (br s, 2H), 7.84 (d, 2H), 8.13 (s, 1H) and 8.17 (d, 2H) ppm; (ES+) 362.3.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])[CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22][CH2:23][CH2:24]N>O>[CH3:21][O:22][CH2:23][CH2:24][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])=[C:7]([OH:13])[CH:8]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]
Solvent: O
Product: COCCNc1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]

Procedure:
A mixture prepared by adding 0.07 mol (20.2 g) of 4,5-dinitro-2-[β-(2-hydroxyethoxy)ethoxy]phenol, prepared according to Example 4, to 0.28 mol (21 g) of 2-methoxyethylamine and 15 ml of water is heated under reflux.
Reaction SMILES: CC1SC(C23CCC(CC[CH2:23][CH2:24][C:25]([OH:27])=[O:26])(CC2)CO3)=C(C2C=CC=CC=2)N=1.ICC12CCC(C3SC(C)=NC=3C3C=CC=CC=3)(CC1)OC2.I[CH2:51][C:52]12[CH2:59][CH2:58][C:55]([C:60]3[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH:67]4[CH2:72][CH2:71][CH2:70][CH2:69][O:68]4)[CH:61]=3)([CH2:56][CH2:57]1)[O:54][CH2:53]2>>[O:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[O:66][C:62]1[CH:61]=[C:60]([C:55]23[CH2:58][CH2:59][C:52]([CH2:51][CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:57][CH2:56]2)[CH2:53][O:54]3)[CH:65]=[CH:64][CH:63]=1
Reactant: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: Cc1nc(-c2ccccc2)c(C23CCC(CCCCC(=O)O)(CC2)CO3)s1
Agent: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Product: O=C(O)CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
4-(1-(3-(Tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanoic acid was prepared using a procedure analogous to 5-(1-(2-methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)pentanoic acid except that 5-(4-(iodomethyl)-2-oxabicyclo[2.2.2]octan-1-yl)-2-methyl-4-phenylthiazole was replaced with 4-(iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane. The title compound was obtained (0.88 g, 2.2 mmol, 95% yield) as a clear oil. LCMS, [M−H]+=373.1. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.17-7.10 (m, 1H), 7.05-6.99 (m, 1H), 6.95 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.9, 3.0 Hz, 1H), 3.84 (s, 2H), 3.67-3.58 (m, 1H), 2.36 (t, J=7.4 Hz, 2H), 2.11-1.99 (m, 5H), 1.91-1.82 (m, 2H), 1.77-1.54 (m, 9H), 1.26-1.16 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O>O.C(Cl)(Cl)Cl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[O:8][C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=3)=[N:14][C:15]=2[CH:20]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cc(Cl)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3cc(Cl)ccc3o2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (25.0 g, 135 mmol), 2-amino-4-chlorophenol (21.3 g, 149 mmol), CHCl3 (500 mL), and WSC (28.5 g, 149 mmol) were added together and stirred at room temperature for 2 hours. The reaction mass was concentrated, and then the residue was washed with water and ethanol. To a dioxane (500 mL) solution of the solid obtained was added methanesulfonic acid (81.9 g, 811 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (31.0 g, 78% yield) as reddish-brown crystals.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[C:19]1([OH:25])C=CC=CC=1.C(Cl)(Cl)Cl.S(=O)(=O)(O)O>C(O)C.O>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:19]=[O:25])[C:7]=1[OH:16])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCC(C)(C)c1cc(C(C)(C)C)ccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CCC(C)(C)c1cc(C(C)(C)C)cc(C=O)c1O
Reaction time: 1 h

Procedure:
2-t-amyl-4-t-butylphenol (53 g, 0.24 mole) is dissolved in 150 ml absolute ethanol in a 1 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (96 g, 2.4 moles) is dissolved in 100 ml water, and the hot solution is added to the solution of the phenol. Chloroform (57 g, 0.48 mole) is added in 1 ml portions over a 45-minute period. The resulting yellow-brown mixture is stirred 1 hour as it cools to ambient temperature. The mixture is diluted into 500 ml of 1M sulfuric acid and extracted with 200 ml hexanes. The organic layer is isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture is filtered and rotoevaporated to a thick syrup. A typical yield for this reaction is 30%. The product is used without further purification.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20]C)=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][CH3:25])[CH3:2].COCC(O)C.N.[Li].[Cl-].[NH4+]>O.COCCOC>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][CH3:25])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CCCO[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: COCCOC
Solvent: COCC(C)O
Solvent: O
Product: CCCO[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC
Reaction time: 0.5 h

Procedure:
Treat a suspension of 1.5 g. of dl-13-ethyl-3-methoxy-17β-propoxygona-1,3,5(10)-triene, 75 ml. of 1,2-dimethoxyethane, 75 ml. of 1-methoxy-2-propanol, and 300 ml. of liquid ammonia with 5.0 g. of lithium. When the reaction ends add 1.5 g. of ammonium chloride and water. Collect the precipitate of dl-13-ethyl-3-methoxy-17β-propoxygona-2,5(10)-diene, and add it to a solution of 50 ml. of methanol, 5 ml. of conc. hydrochloric acid, and 4 ml. of water. Stir for 0.5 hours. Filter off a small amount of insoluble material. Add water to clean solution and extract with ether. Recrystallize from etherpetroleum ether to obtain the title product, m.p. 88°-89°; ultraviolet peak at 242 mμ (ε16,600); infrared peaks at 6.00, 6.19μ.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:25]=[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([S:20][CH2:19][C:18]2[CH:30]=[CH:31][CH:32]=[C:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][C:9]=3[C:33]3[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:49])[F:50])[CH:43]=4)[CH:36]=[CH:35][N:34]=3)[CH:17]=2)[CH:22]=1)[NH:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reaction time: 1 h

Procedure:
A solution of 25 mg of 3-(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)-benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzylthio)benzoic acid 8.1, 12 mg of tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate, and 17.8 mg of diisopropylethylamine in 1 mL of DMF was treated with 15 mg of HATU. The mixture was stirred for 1 h and then the product was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[CH2:30][C:31]([O:33]CC)=[O:32])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[OH-].[Na+].O>[CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([NH:18][S:19]([C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:36])[CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:27]=4)(=[O:21])=[O:20])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(-c3ncccc3C)cc3cccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccnc1-c1cc2cccnc2c(NS(=O)(=O)c2ccc(NC(=O)CC(=O)O)cc2)n1
Temperature: 25 °C

Procedure:
Heat a stirred suspension of ethyl 3-[[4-[[[6-(3-methyl-2-pyridinyl)-1,7-naphthyridin-8-yl]amino]sulfonyl]-phenyl]amino]-3-oxopropanoate (387 mg, 0.765 mmol) in 0.125 N aqueous sodium hydroxide solution at 60° C. for 2 hours. Allow the reaction solution to cool to room temperature, and adjust the pH of the solution to 4-5 by the dropwise addition of glacial acetic acid. Dilute with water (50 mL) and filter. Triturate the isolate solid with methanol (1.5 mL), dilute with water (50 mL), filter and vacuum dry to obtain the title compound as a monohydrate, C23H19N5O5S.H2O, mp 163-164° C. (dec). FABMS: MH+ 478 (100%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([S:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][OH:28])(=[O:20])=[O:19])=[C:13]([CH3:29])[CH:12]=1.CCOC(C)=O.CCCCCC>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([S:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][O:28][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:19])=[O:20])=[C:13]([CH3:29])[CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(Br)cc(C)c1S(=O)(=O)N1CCCCC1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1S(=O)(=O)N1CCCCC1COCC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
180 ml of 50% sodium hydroxy solution and 180 ml of tert-butyl bromoacetate were added to a solution of 18 g of (1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol, and stirring was carried for 10 minutes. 1.815 g of tetra-n-butylammonium hydrogen sulfate were then added, and stirring was carried out for a further 45 minutes at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% EtOAc/hexane). When the reaction was complete, 400 ml of ethyl acetate were added, and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica; 5% EtOAc/hexane). tert-butyl 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate was obtained in a yield of 78.2% (18 g).