Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[F:11].[Cl-].[NH4+:13]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:13])=[CH:4][C:3]=1[F:11]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(F)c1
Temperature: 60 °C
Yield: 43 %

Procedure:
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ml) and heated to 60° C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture refluxed for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1,2-difluoro-4-aminobenzene (7 g, 43%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:3]1([CH2:2][NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:5][CH2:4]1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCC1CC1)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2 mL (23 mmol) of aminomethyl cyclopropane in 25 mL methylene chloride was added 4.8 mL (28 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 4.49 g (23 mmol) of 4-fluorobenzene sulfonyl chloride was added and the mixture was allowed to stir for 4 hours. The reaction mixture was quenched with water and the organic layer was washed twice with 1N HCl, twice with water, dried over magnesium sulfate and then concentrated in vacuo. Then the solid was dried under vacuum to give 4.65 g of the title compounds as an off white solid; 1H NMR (CDCl3) δ 0.08-0.13 (m, 2H), 0.45-0.51 (m, 2H), 0.83-0.94 (m, 1H), 2.86 (t, J=6.9 Hz, 2H), 4.66-4.71 (m, 1H), 7.12-7.23 (m, 2H), 7.85-7.92 (m, 2H); MS (ES) m/z 218.23 (MH+); HRMS for C10H12FNO2S: 218.0637
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: COc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1c(F)cnn1C
Yield: 48 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.69, providing 37 mg (48% yield) of Compound 90: LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.50 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.49 (m, 2H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −63.85 (s, 3F), −177.42 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]=3[N:26]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3Cl)nc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To 4-bromo-2-chlorobenzoic acid (2.48 g) in pyridine (12 mL) and DMF (12 mL) was added CDI (1.88 g). The solution was stirred at 45° C. for 2 hours, cooled, treated with 2,3-diaminobenzamide dihydrochloride (2.36 g), stirred at ambient temperature for 18 hours, and concentrated. The concentrate was partitioned between ethyl acetate (70 mL) and water (100 mL) and filtered. The filtrant was washed with water and ethyl acetate and dried. This solid was suspended in acetic acid (40 mL) and the mixture was heated at 125° C. for 4 hours and filtered. The filtrate was cooled to ambient temperature and filtered. The filtrant was washed with methanol and dried to give the first batch of product. The mother liquor was concentrated and the concentrate was treated with dichloromethane and filtered to provide a second batch of solid.
Reaction SMILES: [CH2:1]([NH:4][C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[NH2-].[Li+].[C:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:21]=[CH:22][CH:23]=[CH2:24]>O1CCCC1>[CH2:1]([N:4]([C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:22]([CH:23]=[CH2:24])[CH2:21][C:20]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:2]=[CH2:3]
Reactant: C=CC=CC(=O)OC(C)(C)C
Reactant: C=CCN[C@H](C)c1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: C1CCOC1
Product: C=CCN([C@H](C=C)CC(=O)OC(C)(C)C)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of (R)-N-allyl-α-methylbenzylamine (24) (1.78 g, 11.1 mmol) in anhydrous tetrahydrofuran (20 ml) was cooled to -78° C. and 1.6M butyllithium (6.00 ml, 9.5 mmol) was added dropwise via a syringe. The resulting orange lithium amide solution was stirred at -78° C. for 1 hour. A solution of t-butyl pentadienoate (25) (1.137 g, 7.4 mmol) in anhydrous tetrahydrofuran (15 ml) was then added via a cannula and the solution was stirred for a further 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and the solution was allowed to warm to room temperature. Ethyl acetate (50 ml) was added, followed by brine (10 ml). The organic layer was separated, dried (magnesium sulphate) and filtered and the solvent evaporated under reduced pressure to afford a pale yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] to afford the title compound (Rf 0.25) as a colourless oil (1.97 g, 85%). δH (300 MHz; CDCl3) 7.40-7.19 (5H, m, Ph), 5.94-5.74 (2H, m, CH2 =CHCH and NCH2CH=CH2), 5.16-5.00 (4H, m, CH2 =CHCH and NCH2CH=CH2), 4.02 (1H, q, J=6.8, PhCHCH3), 3.90 (1H, app. q, J=7.1, NCHCH2), 3.15 (2H, d, J=6.1, NCH2CH=CH2), 2.41 (1H, dd, J=6.4 and 14.5, CH2CO2), 2.31 (1H, dd, J=14.5 and 8.3, CH2CO2), 1.42 (9H, s, (CH3)3C), 1.39 (3H, d, J=6.8, PhCHCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH2:7][CH2:6]2.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH3:30]
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
To a solution of 3,4-dihydro-6-methoxy-1(2H)-isoquinolinone (852 mg, 4.81 mmol, prepared according to J. Chem. Soc., 1969, p 183) in THF (45 mL) at −78° C. was added 0.5M potassium hexamethyldisilazide (10.6 mL, 5.28 mmol) dropwise and the reaction mixture stirred at −78° C. for 5 minutes. The reaction mixture was warmed to 0° C. in a ice/water bath and ethyl bromoacetate (1.20 g, 7.21 mmol) was added dropwise and the mixture stirred at that temperature for 1 hour, and then at room temperature for 2 hours. The reaction mixture was quenched by addition of sat. NaHCO3, diluted with ethyl acetate, and the organic layer was washed with saturated NaHCO3 and then brine. It was dried (MgSO4) and concentrated in vacuo to afford the title compound (1.1 g, 86%) as a yellow solid. Molecular weight (MS): 263.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[NH:7][C:8]([O:10][C:4]2=[CH:3][CH:2]=1)=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][OH:15].CO>C(OCC)C>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:12]([CH3:11])[CH2:13][CH2:14][OH:15])=[O:9]
Reactant: CNCCO
Reactant: O=c1[nH]c2ccccc2o1
Solvent: CO
Solvent: CCOCC
Product: CN(CCO)C(=O)Nc1ccccc1O
Temperature: 75 °C

Procedure:
Benzoxalinone (202 g) and N-methylethanolamine (133 g) were stirred and heated at 75° C. for 3 hours, then cooled to 65° C. and methanol (50 ml) was added. The mixture was cooled to ambient temperature and diethyl ether (750 ml) was added. The precipitate was filtered off and recrystallised from methanol to give the desired urea which had a m.pt. of 128° C. (decomp.).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=4[Cl:39])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)=[O:8])(=[NH:5])[NH2:4].C1COCC1.[ClH:45]>CCO>[ClH:39].[ClH:45].[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=4[Cl:39])[CH2:27][CH2:28]3)=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)=[O:8])(=[NH:4])[NH2:5]
Reactant: COC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CNC(=O)NC(=N)N)c4)cn3)CC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N=C(N)NC(=O)NCc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 M aqueous NaOH solution was added to a mixture of methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg), THF (2 ml), and EtOH (2 ml), followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized with 1 M hydrochloric acid, and the precipitated solid was collected by filtration. A 4 M hydrogen chloride/dioxane solution (1 ml) was added to a mixture of the obtained solid and dioxane (3 ml), followed by stirring at room temperature overnight. The insoluble matter was collected by filtration to obtain 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoic acid dihydrochloride (112 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[CH:14][C:15]1[CH:24]=[CH:23][C:18](/[CH:19]=[CH:20]/[CH:21]=O)=[CH:17][CH:16]=1.[O:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:19]=[CH:20]/[CH:21]=[C:29]2\[C:28](=[O:30])[NH:27][C:26](=[O:31])[O:25]\2)=[CH:23][CH:24]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1C=Cc1ccc(/C=C/C=O)cc1
Product: Cc1oc(-c2ccccc2)nc1C=Cc1ccc(/C=C/C=C2/OC(=O)NC2=O)cc1

Procedure:
(E)-4-[2-(5-Methyl-2-phenyl-4-oxazolyl)vinyl]cinnamaldehyde and 2,4oxazolidinedione were reacted in the same manner as in Reference Example 28 to yield (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]cinnamylidene]2,4-oxazolidinedione, which was then recrystallized from chloroform-methanol to yield yellow needles having a melting point of 274°-275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(CCC(=O)O)c(Cl)c1
Temperature: 40 °C

Procedure:
A mixture of ethyl 3-(chloro-4-cyanophenyl)propanoate (33.0 g, 0.14 mol), KOH (6.27 g, 0.11 mol) and 95% ethanol (109 mL) was warmed at 40° C. for 1 h. The mixture was neutralized and evaporated to dryness. The residue was dissolved in 5% NaHCO3 and washed with EtOAc. Acidification and filtration gave crystalline 3-(2-chloro-4-cyanophenyl)propanoic acid: 18.4 g; mp 127°-219° C. ##STR30##
Reaction SMILES: C[O-].[Na+].CO.[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=1[C:14]([OH:16])=[O:15].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[O:30][CH:31]=1.[Cl-].[Na+]>CN1CCCC1=O>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:6][C:7]3[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=3)[O:10][CH2:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=3[C:14]([OH:16])=[O:15])[N:28]=2)=[CH:37][CH:36]=1
Reactant: Cc1cccc(COc2cccc(O)c2)c1C(=O)O
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cccc(COc2cccc(OCc3coc(-c4ccc(F)cc4)n3)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
18.6 g of 30% strength solution of sodium methoxide in methanol (104 mmol) are added to 15.9 g (51.6 mmol) of 2-(3-hydroxyphenoxymethyl)-6-methyl-benzoic acid (hemisolvate with N-methylpyrrolidone) in 70 ml of N-methylpyrrolidone while stirring at room temperature. After five minutes, 10.0 g (47.3 mmol) of 4-chloromethyl-2-(4-fluorophenyl)oxazole are added, and the mixture is stirred at room temperature for 23 h and finally heated at 50° C. for one hour. 500 ml of 19% strength sodium chloride solution are added to the reaction solution, and the resulting mixture is extracted twice with 225 ml of ethyl acetate. The combined ethyl acetate phases are extracted three times with 225 ml of water, and the combined aqueous phases are acidified to pH=3 with 2 M hydrochloric acid. The resulting crystals are filtered off with suction and washed with water. The product is purified further by crystallization from isopropanol. 2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]phenoxymethyl}-6-methylbenzoic acid is obtained as colorless crystals in a yield of 58.3%, melting point 168-173° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23]([OH:30])[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C(C)C>[N+:27]([C:26]1[CH:21]=[CH:22][C:23]([O:30][C:7]2[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(Oc2ccc([N+](=O)[O-])cc2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 54.5 %

Procedure:
A mixture of 7.0 g (0.022 mol) of product of Example 19, 3.03 g (0.022 mol) of p-nitrophenol and 3.31 g (0.024 mol) of K2CO3 in 75 ml of methyl isobutyl ketone was refluxed for 17 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in ether, washed with H2O, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized in hot hexane to give 5.09 g of tan solid. The solid was purified by HPLC using 3% ethyl acetate/cyclohexane as eluting solvent affording 3.88 g (41.6%) of product as a white solid; mp 111.5°-113.5° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1ccsc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccsc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.5 %

Procedure:
Methyl N-cyano-3-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.48 g, 1.89 mmol, yield: 95%) as colorless crystals.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15]Br)=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]([CH:18]([CH3:20])[CH3:19])[N:6]=1>C1COCC1>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][S:2][CH3:1])=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]([CH:18]([CH3:20])[CH3:19])[N:6]=1
Reactant: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
Sodium methanethiolate (0.23 g, 3.33 mmol) was dissolved in THF (1 ml) and added dropwise to a solution of 4-bromo-7-bromomethyl-2-isopropyl-2H-phthalazin-1-one (0.4 g, 1.11 mmol) in THF (10 ml). The mixture was stirred at RT for 3 hours whereupon LC-MS indicated complete consumption of starting material. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The residue was subjected to flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.29 g, 79% yield) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:6]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:1][CH:3]2[O:5][CH2:4]2)=[O:28])=[CH:30][CH:31]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: ClCC1CO1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC2CO2)cc1
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 89.0 g of epichlorohydrin, 92.0 g of sodium 4-(n-hexadecylamino)benzoate, and 350 ml of hexamethylphosphoramide is stirred at 105° C. for 5 hours, allowed to cool, and poured into 1.0 liter of water. The white solid is collected by filtration, recrystallized from acetonitrile and then from hexane-methylene chloride to yield 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate, mp 86°-89° C.
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=[O:3])[CH3:2].[C:13]1([NH:19][C:20](=[O:23])[NH:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:13]1([NH:19][C:20](=[O:23])[NH:21][N:22]=[C:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[N:12][C:4]=2[C:1](=[O:3])[CH3:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NNC(=O)Nc1ccccc1
Reactant: CC(=O)c1ncccc1C(=O)O
Solvent: CO
Product: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetylnicotinic acid (0.40 g, 2.4 mmol) in 7 ml of methanol is added a solution of 4-phenylsemicarbazide (0.37 g, 2.4 mmol) in 5 ml of methanol. The mixture is stirred at RT overnight, after which the solid precipitate is collected by filtration, washed with ethanol and dried to give 2-acetyl-nicotinic acid 4-phenylsemicarbazone, m.p. 174° (dec.) (compound 1, Table A).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]([CH2:18][N+:19]([O-])=O)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.[Zn]>[NH2:19][CH2:18][CH:12]([CH:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)CC(CN)C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of racemic 6-chloro-3-(3,3-dimethyl-1-nitromethyl-butyl)-1,3-dihydro-indol-2-one (3.8 g, 12 mmol) in methanol (80 mL) was added an aqueous solution (20 mL) of ammonium chloride (6.5 g, 122 mmol), followed by the addition of Zinc (Aldrich, activated) (8 g, 122 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated to give racemic 3-(1-aminomethyl-3,3-dimethyl-butyl)-6-chloro-1,3-dihydro-indol-2-one as a white foam (3.4 g, 99%)
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].C1CCC(N=C=NC2CCCCC2)CC1.ClCCl.[C:44](O)(=[O:46])[CH3:45]>CN(C)C1C=CN=CC=1.CCCCCC>[C:44]([O:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])(=[O:46])[CH3:45]
Reactant: CC(=O)O
Reactant: COc1ccc(OC)c2c(OC)c(C(O)CCC(C)C)cc(OC)c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(OC)c2c(OC)c(C(CCC(C)C)OC(C)=O)cc(OC)c12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a 25 ml two-neck flask 1 mmole of 2-(1-hydroxy-4-methylpentyl)-1,4,5,8-tetramethoxynaphthalene, 226 mg (1.1 mmole) of DCC and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were introduced and then 3 ml of dry dichloromethane was added thereto. After adding 1 mmole of acetic acid at 0° C. under nitrogen gas, the reaction mixture was stirred for 30 minutes and then subsequently stirred at normal temperature for further 3 hours. To the reaction mixture was added 20 ml of n-hexane. The mixture was stirred for further 10 minutes and then filtered to remove the insoluble materials. The filtrate was dried over anhydrous magnesium sulfate to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 2.5×20 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 20:1 to 5:1, to obtain the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1ccncc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according the general procedure for the synthesis of N-aryl-benzenesulfonamides using (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 4-oxazol-5-yl-benzenesulfonyl chloride and purified by HPLC. MS: m/z 485 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:14])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:13][C:12]1[O:11][C:10]([CH3:14])=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-chlorophenyl)-2,5-dimethyloxazole (6.21 g), N-bromosuccinimide (5.34 g) and azobisisobutyronitrile (0.25 g) in carbon tetrachloride (90 ml) was refluxed with stirring for 15 minutes, then washed with water, saturated aqueous sodium hydrogen carbonate and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was crystallized from cold ethanol to give 5-bromomethyl-4-(4-chlorophenyl)-2-methyloxazole, yield 6.73 g (78.4%). Recrystallization from ethanol gave needles, melting at 75°-76° C.