Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([O:9]C(C1C=CC=CC=1)=O)=[O:8])=[O:4].[OH-].[K+]>O.C1COCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
The Boc-Gly-Pro-OBz (19.4 g, 0.054 mol.) was dissolved in a mixture of 100 ml H2O and 100 ml THF. After cooling the solution to 0° C., KOH (4.8 g, 0.085 mol.) in 50 ml H2O was added slowly. The solution was stirred for one hour. Then, the THF was removed under reduced pressure and the aqueous solution was extracted with ethyl acetate to remove the benzyl alcohol. The resulting aqueous phase was covered by 200 ml ethyl acetate and was acidified at 0° C. to about pH 2 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase with ethyl acetate 3×200 ml. The organic layers were combined and washed with brine 2×30 ml, and dried by Na2SO4. Removal of the ethyl acetate gave the product Boc-Gly-Pro-OH (white solid, 12.3 g, 85%) TLC Rf=0.25 (CMA, 85:15:3) FAB-MS, observed MH+=273. 1H-NMR (360 MHz, DMSO-d6, 20° C.) δ12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 4.50 (dd, 0.25H, Pro α-minor), 4.20 (dd, 0.71H, Pro-α-major), 3.81-3.62 (m, 1.7H, Gly-α-major) 3.47-3.33 (m, 2H, Pro-δ and Gly-α-minor), 2.25-2.00 (m, 1.2H, Pro-β), 1.96-1.60 (m, 2.7H, Pro-β and Pro-γ), 1.36 (s, 9H, Boc).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=2)[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:26][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[O:14][N:13]=2)[CH:20]=[CH:19][C:18]=1[O:21][C:22]([F:23])([F:24])[F:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(OC(F)(F)F)c(Cl)c2)no1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc(-c2ccc(OC(F)(F)F)c(Cl)c2)no1

Procedure:
(S)-tert-butyl(1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (2.0 g, 4.90 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 1.4 g waxy off-white solid. HRMS m/z 307.0335
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:24]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: c1ccc(COC2CCCNC2)cc1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC(OCc3ccccc3)C2)ccc1Br

Procedure:
2-Bromo-5-chlorosulfonylbenzoic acid is reacted with 3-benzyloxypiperidine by the method of Example 1. Recrystallization from ether-hexane, yields the product, m.p. 177°-178° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][CH2:39]O.N1C=CN=C1>ClCCl>[Br:20][CH2:39][CH2:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1
Reactant: OCCc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A solution of triphenylphosphine (0.57 g, 2.2 mmol) and N-bromosuccinimide (0.39 g, 2.2 mmol) in anhydrous dichloromethane (4 mL) was stirred for 10 minutes. 2-Naphthalenethanol (0.25 g, 1.45 mmol) was added, followed inmmediately by imidazole (0.25 g, 1.45 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between H2O and dichloromethane. The aqueous layer was extracted with diethyl ether (2×20 mL) and the combined organic extracts were dried over MgSO4 and evaporated to dryness. The crude residue was purified by column chromatography through a plug of silica gel eluting with 10% ethyl acetate in hexanes to afford a colorless solid 214 (0.29 g, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][S:9]([CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:2]=1.CO/[CH:20]=[CH:21]/[C:22]([O:24][Si](C)(C)C)=[CH2:23]>C1(C)C=CC=CC=1>[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][S:9]([N:8]1[CH:20]=[CH:21][C:22](=[O:24])[CH2:23][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:11])=[O:10]
Reactant: C[Si](C)(C)CCS(=O)(=O)N=Cc1cccnc1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)N1C=CC(=O)CC1c1cccnc1
Yield: 39.6 %

Procedure:
To a solution of 2-trimethylsilyl-ethanesulfonic acid pyridin-3-ylmethyleneamide (665 mg) in toluene (4.5 mL) was added Danishefsky's diene (0.46 mL, 2.4 mmol) under Ar atmosphere. The mixture was heated at reflux for 90 minutes. The toluene was removed in vacuo and the residue was dissolved in dichloromethane (ca. 10 mL) and treated with 2N HCl (ca. 10 mL) for 5 minutes. 10% Aqueous sodium bicarbonate was added carefully to adjust to pH 8. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure. Purification of the residue by flash chromatography (gradient hexane/ethyl acetate) gave 1-(2-trimethylsilyl-ethanesulfonyl)-2,3-dihydro-1H-[2,3′]bipyridinyl-4-one (322 mg, 40% overall).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:26](O)=[O:27])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:3]1[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:33]([CH3:34])([CH3:35])[CH3:36])[C:31]([OH:32])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCNC(=O)Nc1ncccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ncccc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 86.9 %

Procedure:
A mixture of 1-(3-amino-2-pyridyl)-3-heptylurea (0.80 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.80 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.67 g) was stirred in dichloromethane (35 ml) at room temperature for 3 hrs. After filtering off the insolubles and distilling off the solvent, the residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to give N-[2-(3-heptylureido)-3-pyridyl]-3,5-di-t-butyl-4-hydroxybenzamide (1.34 g, 87%) as a non-crystallizable solid.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:30])[NH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[S:21]3)=[CH:12][CH:11]=1>O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17](=[O:30])[NH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[S:21]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2c3c(c[nH]c2=O)Sc2ccccc2N3)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]cc2c(c1-c1ccc(O)cc1)Nc1ccccc1S2

Procedure:
To 10 parts pyridine hydrochloride heated to 170° under a stream of nitrogen is added 0.5 parts of 4-(4-methoxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one in one portion. The reaction mixture is refluxed for 45 minutes, cooled, water is added and the solid which forms is collected and dried to yield 4-(4-hydroxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, m.p. greater than 300°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][C:14](=O)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:20]1([NH2:24])[CH2:23][CH2:22][CH2:21]1.C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][CH:14]([NH:24][CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: NC1CCC1
Reactant: O=C1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1csc2ncnc(N3C4CCC3CC(NC3CCC3)C4)c12
Temperature: 30 °C
Yield: 89.6 %

Procedure:
8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (1.5 g, 4.43 mmol) in toluene (60 mL) was treated with cyclobutylamine (3.145 g, 44.3 mmol) and heated with stirring to reflux for 2 h. Ethanol (100 mL) and sodium triacetoxyborohydride (9.347 g, 44.3 mmol) were added and the reaction stirred and warmed at 30° C. over 3 days. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (50 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid (1.799 g, 3.97 mmol, 89%). 1H NMR (CDCl3) δ: 1.5 (3H, d, J=12 Hz), 1.65 (3H, br s), 1.93 (2H, br s), 2.1 (2H, d, J=6 Hz), 2.22 (2H, m), 2.4 (2H, m), 3.0 (1H, br s), 3.3 (1H, m), 4.63 (2H, br s), 7.3 (1H, s), 8.45 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([SH:10])[C:7]([OH:9])=[O:8].[Cl:11]N1C(=O)CCC1=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:11][C:5]1[S:1][C:2]([CH:6]([SH:10])[C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)C(S)c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(S)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of thiophen-2-yl-sulfanyl acetic acid ethy (0.52 g, 2.6 mmol) in 25 mL of CH2Cl2 is added N-chlorosuccinimide (0.35 g, 2.6 mmol). The solution is stirred for 10 minutes. After this time, 1 drop of TFA is added. The solution is stirred for 16 hours. The reaction mixture is then diluted with 25 mL of CH2Cl2. The resulting solution is washed with 1N NaOH and a saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated. The resulting product is obtained as an oil which is determined to contain 45% of the desired product. The oil is then dissolved in 60 mL of 1:1:1 THF:MeOH:H2O. To the solution is added lithium hydroxide monohydrate (1.26 g, 30 mmol). The solution is stirred for 16 hours. After this time, the solution is acidified to pH=3 with 1N HCl. The aqueous solution is washed with H2O and saturated NaCl solution. The solution is extracted with EtOAc/CH2Cl2 (2:1). The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude product is purified by column chromatography eluting with 20% MeOH:Et2O to give the product as a white solid (0.4 g, 1.9 mmol). MS (EI): m/z 208, 210 (M+), Cl pattern.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-:12].[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][OH:12])=[C:9]([CH:10]=1)[C:8]([OH:7])=[O:11]
Reactant: [OH-]
Reactant: O=C1OCc2ccc(F)cc21
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)ccc1CO
Yield: 78.1 %

Procedure:
To a solution of 6-fluoroisobenzofuran-1(3H)-one (0.549 g, 3.61 mmol) in methanol (12 mL) and water (3 mL) at room temperature was added potassium hydroxide (0.350 g, 6.24 mmol). The mixture was heated at reflux for 1.5 hr. The mixture was concentrated under vacuum to a volume of about 3 mL. The residue was acidified with 1 M KHSO4 solution to pH 3-4. The insoluble material (inorganic salt) was removed by suction filtration and the filtrate was extracted with ethyl acetate (5×30 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.479 g, 2.82 mmol, 78% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:3])=[O:2].[Br:18]Br.O>C(O)(=O)C>[Br:18][CH:11]([CH3:12])[C:10]([C:8]1[CH:7]=[CH:6][C:5]([NH:14][C:15](=[O:17])[CH3:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)=[O:13]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C(C)Br)cc1[N+](=O)[O-]
Temperature: 35 °C

Procedure:
To 1600 ml of acetic acid are added 46.7 g (198 mM) of N-(2-nitro-4-propanoylphenyl)acetamide. To the solution obtained, heated to 35° C., is added over 2 hours a solution of 10.13 ml (198 mM) of bromine in 200 ml of acetic acid. The reaction medium is then added gently to 5000 ml of water, and a solid crystallises out. After filtering off the solid and washing with water, 56.8 g of N-[4-(2-bromopropanoyl)-2-nitrophenyl]acetamide are obtained in the form of a pale yellow solid.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C1(S(O[CH2:18][CH:19]([CH3:21])[CH3:20])(=O)=O)C=CC=CC=1.[OH-].[K+]>>[CH:1]([N:4]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)COS(=O)(=O)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: [K+]
Agent: [OH-]
Product: CC(C)CN(C(C)C)C(C)C
Reaction time: 72 h
Yield: 68 %

Procedure:
A mixture of diisopropylamine (20.24 g, 0.2 mol) and isobutyl phenylsulfonate (29.83 g, 0.1 mol) was refluxed with stirring for 72 hours. Aqueous 5M potassium hydroxide (30 ml, 0.15 mol) was added. The organic phase was separated and the aqueous phase was extracted with n-pentane (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate and the produce was isolated by distillation to yield 10.70 g, 68% of the title product, bp 75-77° C./45 mm Hg. 1H NMR CDCl3 δ ppm, 0.83 (d, J=6.5 Hz, 6H, CH3), 0.95 (d, J=6.5 Hz, 12H, CH3), 1.59 (nonet, J=6.5 Hz, 1H, CH), 2.10 (d, J=6.5 Hz, 2H, CH2), 2.95 (sep, J=6.5 Hz, 2H, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:27]([C:34]([NH:36][OH:37])=O)C1C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:26])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1)=[O:27]
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCNCC1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a solution of (5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.263 g, 0.71 mmol) in dry THF (7 mL) was added N-(phenoxycarbonyl)hydroxylamine (0.216 g, 1.41 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 241 mg (64%) of COMPOUND 264 as a white solid. 1H NMR (CDCl3) δ 0.99 (d, 6H, J=6.9 Hz), 1.60-1.66 (m, 2H), 1.92 (d, 2H, J=11.1 Hz), 2.14 (s, 3H), 2.66-2.88 (m, 4H), 3.78 (s, 2H), 3.81 (s, 2H), 4.04 (d, 2H, J=12.9 Hz), 6.65 (br s, 1H), 6.81 (br s, 1H), 7.16 (dd, 1H, J=7.8, 4.8 Hz), 7.42 (d, 1H, J=1.5 Hz), 7.52 (dd, 1H, J=7.8, 1.5 Hz), 8.32-8.34 (m, 2H); 13C NMR (CDCl3) δ 19.64, 24.80, 28.47, 28.74, 45.43, 55.31, 58.83, 124.66, 132.29, 135.42, 136.61, 139.11, 145.69, 146.12, 147.20, 156.93, 162.45; ES-MS m/z 432 (35Cl) & 434 (37Cl) (M+H). Anal. Calcd. For C22H30N5O2Cl.0.2CH2Cl2.0.5H2O: C, 58.22; H, 6.91; N, 15.29; Cl, 10.84. Found: C, 58.51; H, 6.68; N, 15.29; Cl, 10.55.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[CH2:26]([O:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:40])=[O:2])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 73.1 %

Procedure:
A solution of 3,4-bis(tetradecyloxy)benzoic acid methyl ester (1.1 g, 2.0 mmol) and 1.6 ml (9.6 mmol) of 6N NaOH in 40 ml of methanol and 20 ml of dioxane was stirred at reflux for 17 hours. The solvents were removed at reduced pressure, the residue was acidified and the solid was filtered and recrystallized from methanol-THF-water to give 0.8 g (73% yield, mp 112°-113°) of 3,4-bis(tetradecyloxy)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:24](Cl)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>ClCCl>[Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])[CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]2
Reactant: COC(=O)CC1CCc2cc(Br)ccc2N1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1CC(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 6-bromo-2-methoxycarbonylmethyltetrahydroquinoline (43.8 g, 0.153 mol) and triethylamine (37.5 g, 0.371 mol) in dichloromethane (700 mL) was added slowly ethyl chlorooxalate (25.5 g, 0.187 mol) at 0° C. The mixture was stirred for 3 h at 0° C., poured into 0.3N hydrochloric acid (750 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 3:1 hexane/ethyl acetate to give 56.9 g of the title compound (97%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCc1cccc(O)c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccccn2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
3-Hydroxybenzyl alcohol (1.0 g, 8.2 mmol) was dissolved in pyridine (20 mL). 2-Bromopyridine (1.6 g, 9.8 mmol) and potassium carbonate (2.3 g, 16.4 mmol) were added thereto, and then the mixture was stirred at 90° C. for 10 minutes. Copper oxide(II) (1.6 g, 20.5 mmol) was further added thereto, and the reaction mixture was heated under reflux for 2 days. The reaction solution was filtered, and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (1.0 mg, yield 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11]Br.O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:11][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([F:1])=[CH:3][C:4]=1[OH:10]
Reactant: BrBr
Reactant: COc1ccc(O)cc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)c(O)cc1F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-methoxy-phenol (21.32 g; 0.15 mol) prepared according to literature [Freedman, J.; Stewart, K. T.; J. Heterocycl. Chem. 1989, 26, 1547-1554] is dissolved in dry dichloromethane (300 mL). The well stirred reaction mixture is cooled to −15° C. (ice/salt). A solution of bromine (23.97 g; 0.15 mol) in dry dichloromethane (75 mL) is dropped into the reaction mixture. After complete addition stirring is continued for one hour. Water (150 mL) containing sodium sulfite (3.0 g) is added to the reaction mixture. Stirring is continued at ambient temperature for 30 min. The organic layer is separated, washed with water (100 mL) and dried over MgSO4 in the presence of decolorizing charcoal. After filtration the solvent is completely removed under reduced pressure. The residue is crystallized from tert-butylmethylether/hexane to yield the title compound as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[NH4+:20].C(O)(=O)C>O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16]([NH2:20])(=[O:18])=[O:17])([O-:3])=[O:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ammonium hydroxyde is stirred at a temperature between 5° C. and 10° C. for 3 hours and then allowed to stand for 16 hours. To the mixture 6 ml of acetic acid and 40 ml of water are added, the separated crystals are filtered off, washed with water and acetone, dried and dissolved in a slight amount of hot dimethyl sulfoxide. The product is precipitated from this solution with 2-propanol. Thus 1.40 g (17%) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: >330° C.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[C:9]([C:12]1[CH:30]=[C:15]2[C:16]([C:22]3[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[N:14]2[N:13]=1)(=[O:11])[CH3:10]>C1COCC1>[OH:11][C:9]([C:12]1[CH:30]=[C:15]2[C:16]([C:22]3[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[N:14]2[N:13]=1)([CH3:5])[CH3:10]
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)=O)nn12
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)(C)O)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 0.90 mol/L methyl magnesium bromide-tetrahydrofuran solution (0.614 mL) was added dropwise to a solution of the compound of Example 241 (55.4 mg) in THF (5 mL) at −78° C. in an argon atmosphere. The mixture was allowed to gradually warm to room temperature and was stirred for 3 hours. Subsequently, a second portion of 0.90 mol/L methyl magnesium bromide-tetrahydrofuran solution (0.614 mL) was added dropwise at −78° C. and the mixture was stirred at room temperature for another 3 hours. The reaction was then quenched by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a pale yellow powder (14.0 mg).