Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:7]=1[NH2:8].[F:14][B-:15]([F:18])([F:17])[F:16].[H+]>O>[F:14][B-:15]([F:18])([F:17])[F:16].[Br:13][C:10]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([N+:8]#[N:1])[CH:9]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(Br)cc1N
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1[N+]#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (0.56 g) in water(2.0 mL) was slowly added to a mixture of 2-methyl-5-bromoaniline (1.50g) in tetrafluoroboric acid (6.0 mL) and water (4.0 mL) at 0-5° C. After addition, the reaction was stirred at room temperature for 30 min. The mixture was cooled to 0° C., filtered, washed with cold water, cold methanol and ether. The mixture was then dried to provide the product 5-bromo-2-methylphenyldiazonium tetrafluroborate (1.90 g).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>ClCCl>[CH3:17][O:18][CH2:19][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCl
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC(=O)C(c1ccccc1)c1ccccc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Diphenylacetic acid methoxymethyl ester was prepared in the following manner: to a mixture of 10.0 g (47.1 mmol) diphenylacetic acid and 4.0 ml (4.16 g, 51.8 mmol) of chloromethyl methyl ether in 50 ml of dichloromethane cooled to -5° C. was added 7.2 ml (5.24 g, 51.8 mmol) of triethylamine in 50 ml dichloromethane. The mixture was allowed to warm to room temperature and stir overnight at which point the reaction mixture was washed with aqueous sodium bicarbonate, dried with MgO-MgSO4, and concentrated in vacuo. The residue was distilled to give 7.25 g (28.3 mmol, 60% yield) of the corresponding methoxymethyl ester, bp 135°-140° C./0.1 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:2][C:3]3[C:4]([CH3:9])=[N:5][O:6][C:7]=3[CH3:8])[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: Cc1noc(C)c1CCl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1noc(C)c1CN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chloromethyl-3,5-dimethylisoxazole (8 mL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 mL, 92 Amok) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=3[F:35])[C:21]([O:23]C)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=3[F:35])[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)C(Oc1ccc2c(N)nccc2c1)c1cc(OC)c(OC)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C(Oc2ccc3c(N)nccc3c2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
7C (80 mg, 0.21 mmol) was dissolved in THF (2 mL). 1M LiOH (0.4 mL) was added, and the reaction was stirred at rt for 0.5 h. Additional 1M LiOH was added (0.4 mL) and the reaction was stirred for 3 h. The solvent was removed under reduced pressure, and water (10 mL) was added. The solution was acidified with 1 N HCl, then purified via preparative HPLC (MeOH/water/TFA) to provide 7D (65 mg, 64%). LC-MS: 373.18 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-pyridyl) benzoic acid (100 mg, 0.2544 mmol) was dissolved in methylene chloride (30 ml), then p-anisidine (56 mg, 0.4552 mmol), triethylamine (75 mg, 0.7425 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (126 mg, 1.3663 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:4) to give the title compound (33 mg, 0.0963 mmol, 38%).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[C:11](OC)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>C1C=CC=CC=1.O>[O:18]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[O-:8]
Reactant: COC(=O)c1ccccc1
Reactant: Cc1cccc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: O=C(Cc1cccc[n+]1[O-])c1ccccc1
Yield: 82.1 %

Procedure:
A solution of 2-picoline N-oxide (4.4 g, 0.04 mol) in benzene (25 ml) was added to a suspension of sodium hydride (3.2 g of 60% oil dispersion) and methyl benzoate (9.94 ml, 0.08 mol) in dry benzene (100 ml). The reaction mixture was refluxed overnight. Methanol (15 ml) was added to the cooled reaction mixture, followed by water (150 ml). The aqueous layer was separated and extracted with chloroform (2×40 ml). The aqueous layer was acidified with 1N HCl and extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated to give the subtitle ketone as a solid (7 g), mp 146°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[N:33]=[CH:34][N:35]=[CH:36][C:27]2=1.CCN(C(C)C)C(C)C>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH3:16])=[C:18]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]3[N:33]=[CH:34][N:35]=[CH:36][C:27]4=3)[CH:19]=2)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccc(N)cc1-c1ccc2[nH]c3ncncc3c2c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc(C)c(-c3ccc4[nH]c5ncncc5c4c3)c2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To 4-methoxy-3-(trifluoromethyl)benzoyl chloride (11.0 μL, 0.070 mmol) was added a solution of 4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)aniline (17.5 mg, 0.064 mmol) and DIPEA (16 μL, 0.089 mmol) in tetrahydrofuran (THF) (0.4 mL). The reaction was stirred at ambient temperature until LCMS indicated complete reaction, typically 16 hours. The reaction mixture was diluted to a total of 2 mL with THF and MeOH and purified by preparative LCMS to recover the product as a TFA salt (18.6 mg, 49.4%). 1H NMR (300 MHz, DMSO): δ 13.0 (bs, 1H), 10.33 (s, 1H), 9.64 (s, 1H), 9.13 (s, 1H), 8.35 (s, 1H), 8.24 (m, 2H), 7.7-7.8 (m, 3H), 7.63 (dd, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 2.25 (s, 3H). MS (EI) m/z=477 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=C(C)C=C(C)[C:17]=1[S:24]([O:27][NH2:28])(=[O:26])=[O:25].CS(O)(=O)=O>CO.ClCCl>[CH3:17][S:24]([OH:27])(=[O:26])=[O:25].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][NH2:28])=[C:4]([I:9])[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Oc1ccc(Br)cc1I
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NOc1ccc(Br)cc1I
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a solution of product of step A (10.0 g, 33.4 mmol) in methanol (100 mL) at 0° C. was added potassium tert-butoxide (2.59 g, 23.1 mmol) portionwise and the mixture stirred for 40 min. The reaction mixture was concentrated in vacuo, and suspended in dichloromethane. To the suspension was added a solution of O-(mesitylsulfonyl)hydroxylamine (5.53 g, 33.4 mmol) in dichloromethane at 0° C. and the reaction stirred for 1 h. The mixture was then washed with cold 5% KOH solution and dried over anhydrous sodium sulfate. The organic layer was treated with methanesulfonic acid (1.75 mL, 26.72 mmol) then concentrated in vacuo to give crude O-(4-bromo-2-iodophenyl)hydroxylamine methanesulfonic acid salt (8.0 g, 58%) as a brown solid. CAUTION: This compound has potential to be shock sensitive and may be susceptible to decomposition. It should be handled with care and used directly without storage.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13](O)=[O:14])[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][CH:7]=2.Cl.CN.[CH3:25][N:26]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:26][CH3:25])=[O:14])[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:6][CH:7]=2
Reactant: Cn1c(=O)n(CC(=O)O)c2cnc(-c3ccccc3)nc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purin-7-acetic acid (9.1 g) obtained in Example 48-(2), methylamine hydrochloride (3.2 g), BOP reagent (21.2 g), triethylamine (9.7 g), and dimethylformamide (100 ml) is stirred at room temperature for two hours. Water is added to the reaction mixture, and the precipitates are collected by filtration, and washed with water to give crude 8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-7H-purin-7-acetamide (8.1 g).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[CH2:14][CH2:13]2)[N:3]=1.[CH2:22](Br)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([O:8][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[CH2:14][CH2:13]2)[C:5]=1[N+:9]([O-:11])=[O:10])[CH3:23]
Reactant: CCBr
Reactant: Cc1nc(N2CCc3ccsc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)nc(N2CCc3ccsc3CC2)c1[N+](=O)[O-]

Procedure:
In analogy to the procedure described in example 2 2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4-one (example 9) was treated with ethyl bromide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield 6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine as light yellow amorphous solid; MS: [M+H]+=335; and 3-ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4-one as yellow foam; MS: [M+H]+=335.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:18])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[Se](=O)=[O:20]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:18])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH:17]=[O:20])=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(-c2ccc(C)nc2)c(Cl)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
0.6 g of 3-chloro-6′-methyl-[2,3]bipyridyl-5-carboxylic acid methyl ester(12) (2.3 mmol) prepared in Example 8 was dissolved in 10 mL of 1,4-dioxane, and 0.75 g of selenium dioxide (6.9 mmol) was added thereto. The mixture was refluxed under heating and stirring for 18 hours, and cooled to room temperature. The mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate to be washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.51 g of yellow crystal, 3-chloro-6′-formyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (yield 81%)
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:17][CH2:16][C:15]3[N:14]=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=3[CH2:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:22][I:23]>CC#N>[I-:23].[CH3:22][N+:3]1[CH:4]=[CH:5][N:1]([C:6]([N:8]2[CH2:17][CH2:16][C:15]3[N:14]=[CH:13][C:12]([C:18]([F:20])([F:21])[F:19])=[CH:11][C:10]=3[CH2:9]2)=[O:7])[CH:2]=1
Reactant: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)n1ccnc1
Reactant: CI
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a suspension of imidazol-1-yl-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (preparation #1) (1.28 g, 4.32 mmol) in MeCN (10 mL) was added methyl iodide (1.1 mL, 17 mmol) and the reaction mixture was stirred at ambient temperature for about 2 h. Additional methyl iodide (0.5 mL, 8 mol) was added and stirring resumed for about 16 h. The reaction mixture was concentrated in vacuo to afford 1-methyl-3-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-3H-imidazol-1-ium iodide (1.89 g, 100%) as an orange solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 1.77 min; m/z: (M+H)+ 311.
Reaction SMILES: [CH3:1][OH:2].[N+:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)([O-:5])=[O:4].[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(O)C>[N+:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:17][CH2:16][CH2:15][N:18]=[CH:8][C:9]1[C:1](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:13][CH:12]=1)[OH:2])([O-:5])=[O:4]
Reactant: CO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1O
Reactant: NCCN
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NCCN=Cc2ccc([N+](=O)[O-])cc2O)c(O)c1
Temperature: 70 °C

Procedure:
4 ml of methanol are added to a solution of 500 mg (2.99 mmol) of 4-nitrosalicylaldehyde (for preparation see Beilstein E IV, Vol. 8, 232) in 2 ml of ethanol. 95.2 mg (106 μl, 1.58 mmol) of ethylenediamine are added dropwise to the resulting yellow suspension. The reaction suspension is heated for 4 hours at 70° C. After cooling to room temperature, the precipitate formed is filtered off, washed with 2 ml of ethanol and dried to constant weight under a high vacuum at 30° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.Cl([O-])=[O:24].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19]([OH:24])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1.4 gm (5.2 mmol) of methyl 4-benzyloxy-3-formylbenzoate (prepared by benzylation of methyl 3-formyl-4-hydroxybenzoate) in 25 mL of acetonitrile is added an aqueous solution of NaH2PO4.2H2O (268 mg, 1.68 mmol in 3 mL of water) and 2.8 mL (5 equiv) of 30% hydrogen peroxide. To this mixture is added dropwise an aqueous solution of 79% sodium chlorite (830 mg, 7.25 mmol of NaClO2 in 7 mL of water). After 2 hr at room temperature at room temperature, the reaction mixture is concentrated to remove most of the acetonitrile. The residue is taken up in water and acidified with aqueous HCl. The aqueous acidic solution is extracted with ethyl acetate several times. The combined extracts are washed with brine and dried over Na2SO4. Rotoevaporation of solvent gives 1.5 gm (5.2 mmol) of methyl 4-benzyloxy-3-carboxybenzoate.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([OH:22])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:37][CH2:38][CH2:39][C:40]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[C@@H:44]([CH3:46])[OH:45])=[O:41]>>[C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([NH:37][CH2:38][CH2:39][C:40]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[C@@H:44]([CH3:46])[OH:45])=[O:41])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](NC(=O)CCN)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 86 %

Procedure:
Starting from 2-hexadecanoyloxyhexadecanoic acid (200 mg) prepared by the method described in Preparation 7 and N-β-alanyl-L-threonine (190 mg), N-[N-(2-hexadecanoyloxyhexadecanoyl)-β-alanyl]-L-threonine (230 mg) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][C:23]([CH2:28]O)([CH2:26][OH:27])[CH2:24][OH:25]>>[C:1]([O:20][CH2:28][C:23]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][OH:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)CO
Temperature: 130 °C

Procedure:
A four-necked round-bottom flask equipped with a stirrer, a thermocouple, and a nitrogen inlet tube was charged with 4 moles of stearic acid per 1 mole of pentaerythritol. The ingredients in the flask were heated at 130° C. for 5 hours under a nitrogen atmosphere, to carry out an esterification reaction. The reaction product was purified with methyl ether, to give pentaerythritol stearate. Here, the resulting compound had an acid value of 0.3 mgKOH/g, and a hydroxyl value of 1.8 mgKOH/g.
Reaction SMILES: [CH2:1]([CH:5]([O:10][C:11]1[CH:28]=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:13](=[C:14]23)[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[Br:29]N1C(=O)CCC1=O.CN(C=O)C>C(Cl)(Cl)Cl>[Br:29][C:28]1[C:11]([O:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:12][C:13]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20](=[O:27])[C:19]3[C:14]=2[C:15]=1[CH:16]=[CH:17][CH:18]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 45 g (0.12 mole) of 2-(1-isobutyl-3-methylbutoxy)-7H-benzo[de]anthracene-7-one, 23.6 g (0.13 mole) N-bromosuccinimide and 265 g DMF. The mixture was agitated well, heated to 50° C. and held at 50° C. for two hours. Some of the DMF was stripped from the reaction using heat and vacuum and then 300 g chloroform were added to the flask. The resulting solution was washed three times with 250 g deionized water. The solvent was removed using a rotary evaporator; the yield was 52.5 g of a dark brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([O:7]CC#C)=[O:6].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([OH:7])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1c(F)cc(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To 40 ml of methanol were added 4.5 g of 2-propynyl 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoate and 20 ml of 15% aqueous sodium hydroxide solution, and the mixture obtained was stirred at room temperature for 8 hours. Then, the reaction mixture was concentrated. Hydrochloric acid was added to the residue for acidification. Solids precipitated were collected by filtration and dried to obtain 3.7 g of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoic acid represented by the formula:
Reaction SMILES: [Cl:1][S:2]([N:5]=C=O)(=[O:4])=[O:3].[S:8](Cl)(=[O:11])(=[O:10])[NH2:9].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][NH:18][CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1)[CH3:14].Cl>C(Cl)Cl.C(N(CC)CC)C.C(O)=O>[S:2]([Cl:1])(=[O:4])(=[O:3])[NH2:5].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][N:18]([CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1)[S:8](=[O:11])(=[O:10])[NH2:9])[CH3:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)CNCc1cc2ccccc2o1
Agent: Cl
Agent: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1cc2ccccc2o1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock of sulfamyl chloride was prepared by adding formic acid to chlorosulfonyl isocyanate. The sulfamyl chloride was added to a room temperature solution of 104 and triethyl amine in methylene chloride. The reaction was stirred at room temperature overnight. TLC (30% ethyl acetate/hexanes) showed a major spot and a minor product. The reaction was poured into 10% HCl, extracted with methylene chloride, dried over sodium sulfate, filtered, and concentrated to a thick yellow syrup. The crude syrup was adsorbed onto silica and purified by flash chromatography with 15-30% ethyl acetate/hexanes to obtain the final product 105 as a light yellow film.