Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 1-methylpiperidin-4-amine (58 mg, 0.51 mmol). The title compound was obtained as a solid (95.0 mg, 50% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (1H, m), 8.65 (1H, m), 8.49 (1H, m), 3.60 91H, m), 2.78 (2H, m), 2.18 (3H, s), 1.98 (2H, m), 1.75 (2H, m), 1.53 (2H, m). MS m/z: 447.31, 449.29 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2/[N:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:17])[NH:14][C:15]/2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:39].[CH3:40][C:41]1[S:42][CH:43]=[C:44]([CH2:46][Cl:47])[N:45]=1>CN(C=O)C>[ClH:47].[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2/[N:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:17])[N:14]([CH2:46][C:44]3[N:45]=[C:41]([CH3:40])[S:42][CH:43]=3)[C:15]/2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2\C(=O)N(Cc3csc(C)n3)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl E-4-[[2-butyl-5-[[3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.66 g, 1.5 mmol) in DMF (10 mL) is added K2CO3 (3.0 g, 15 mmol). After stirring for 5 minutes 2-methyl-4-chloromethylthiazole hydrochloride (0.28 g, 1.5 mmol) is added. The mixture is stirred for 16 hours and then filtered. The filtrate is concentrated in vacuo and dissolved in ether (50 mL). This solution is washed with water and dried over K2CO3 and charcoal. The mixture is filtered and allowed to stand in which time the product crystallizes. Petroleum ether is added to complete crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:17])=[O:5].C([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH:8]1[C:28]2[CH2:19][C:18]3[CH:3]=[CH:2][CH:21]=[CH:20][C:31]=3[CH2:30][N:26]([C:11]([C:10]3[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=4[Cl:1])=[C:8]([CH3:17])[CH:9]=3)=[O:13])[C:27]=2[CH:29]=[CH:15][CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.8 %

Procedure:
A mixture of 1.69 g of 4-[(2,4-dichlorobenzoyl)amino]-3,5-dimethylbenzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under argon for i hour. The volatiles are evaporated and the residue evaporated in vacuo from toluene to give a residue. A solution of the residue in 25 ml of methylene chloride is treated with 0.75 g of N,N-di-isopropylethylamine and 0.98 g of 10,11-dihydro-5H-dibenz[b,e]azepine is stirred at room temperature for 18 hours. The reaction mixture is washed with saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a glass which is dissolved in methylene chloride dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated to give 1.89 g of the desired product as an amorphorous solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[C:39]([CH3:41])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M114) (0.50 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (274 mg, 68%).
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH2:14][CH3:15])=[C:12](Cl)[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH2:14][CH3:15])=[C:12]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1CC
Reactant: Cc1cc(C)c(N)c(C)c1
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CC
Yield: 209.4 %

Procedure:
A mixture of butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine (200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.963 g, 7.1 mmol) was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated potassium carbonate and brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of the dark oil which was then purified through silica gel column chromatography using chloroform as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.14 (t, 3H), 1.1–1.4 (m, 4H), 1.45–1.60 (m, 2H), 2.17 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2–3.4 (m, 4H), 6.90 (s, 2H) ppm.
Reaction SMILES: [OH:1][C:2]([CH:7]([F:9])[F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:14]1([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+].C>CC(N(C)C)=O>[C:14]1([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:27][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH:7]([F:9])[F:8])=[CH:28][CH:29]=2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)(C(=O)O)C(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-difluoromethylpropionic acid (0.9 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.3 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured into ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (Na2SO4) and decolorization (Charcoal) the solution was evaporated in vacuo. A foam was obtained which was triturated with toluene and crystallized from ethyl acetate/hexane to give the title tertiary carbinol (0.72 g, 47%) as white crystals; mp=168°-169° C. 1H-NMR (300 MHz, d6 -DMSO): 1.41 (s, 3H, CH3), 6.13 (t, J=54.9 Hz, 1H, CHF2), 6.76 (s, 1H, OH), 7.58-7.68 (m, 3H, ArH), 7.89-8.01 (m, 6H, ArH), 10.27 (s, 1H, NH). MS (CI, CH4): 356(M+1, 100). Analysis for C16H15F2NO4S: Calculated: C, 54.08; H, 4.25; N, 3.94 Found: C, 53.75; H, 4.40; N, 3.78
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[N:25]1([C:29]([O-:31])=[O:30])[CH2:28][CH2:27][CH2:26]1>>[C:7]([O:30][C:29]([N:25]1[CH2:28][CH:27]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:26]1)=[O:31])([CH3:8])([CH3:2])[CH3:6]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: O=C([O-])N1CCC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 9.170 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidinecarboxylate and 11.00 g of tertbutyl 3-toluenesulphonyloxy)azetidine-1-carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=023 (3:1 EtOAc-heptane); Rt=5.01.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH2:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.[OH-].[Na+:24]>O>[CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH-:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1.[Na+:24]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS([NH-])(=O)=O)OC(C)(C)O[C@@H]23)O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
10.09 g (29.73 mmoles) of topiramate (Cheminor Drugs Ltd., Hyderabad, India, Batch TP001 J00) was placed in a 250 mL beaker and 100.0 mL of HPLC grade water (JT Baker, Phillipsburg, N.J. USA, Lot V32E17) was added. 1.36 g (34.0 mmoles) of sodium hydroxide (Sigma, St. Louis, Mo. USA, Lot 99H0120) was added and the mixture was stirred with a TEFLON® coated magnetic stir bar using a hot plate/stir plate. The mixture was heated to 60° C. to dissolve. The solution was filtered and evaporated at 60° C. while blowing air over the surface using a TYGON tube attached to an air source to reduce the volume to 15 mL, and the flask was placed in a cold room (4° C.) overnight. Crystals grew overnight. The mixture was filtered and dried to yield 305 mg topiramate sodium as large, block-like crystals. Elemental analysis: calc. C, 34.70, H, 6.31, N, 3.37%; found C, 34.90; H, 6.04; N, 3.36%. mp 80-85° C., recrystallization from melted material 110-120° C., second mp 170-175° C. PXRD Cu-Kα radiation (1.5406 Å) first 8 peaks (peak number/2Θ value), #1/4.51°, #2/12.09°, #3/12.709°, #4/13.67°, #5/15.01°, #6/16.17°, #7/17.19°, #8/17.55°. The pH of a 400 mg/mL solution of the compound in distilled water was about 11.2, which was determined using a Thermo Orion pH meter, Model 525A+ (Orion Research, Inc., Beverly, Mass. USA).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:20][CH2:19][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:21]
Reactant: O=Cc1ccccc1Br
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CNCc1ccccc1Br)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirring solution of 2-bromobenzaldehyde in dichloromethane (0.2 M) was added glycine benzyl ester (1.2 eq), sodium triacetoxyborohydride (2 eq) and acetic acid (4 eq). After stirring overnight, the solution was washed with 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 30%-40% EtOAc/Hexanes) to afford a pale yellow oil. EI-MS m/z 334, 336 (M+H)+
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([NH:4][CH:5]([NH:30][NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: NNc1ccccc1
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Agent: BrB(Br)Br
Product: CC(=O)NC(NNc1ccccc1)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BBr3 (1M in CH2Cl2, 10.0 mL, 10.0 mmol), and phenylhydrazine (2.60 g, 24.0 mmol) gave a pale yellow oily residue which was purified by flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give the desired product. The product was recrystallized from chloroform/hexane as a light yellow solid.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([OH:17])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19].[H-].[Na+].IC>O>[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([O:17][CH3:2])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19]
Reactant: COc1cc(C(C)O)cc(OC)c1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(C(C)OC)cc(OC)c1Br
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (100 mL) solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (7.24 g, 27.7 mmol) was added sodium hydride (1.33 g, 33.2 mmol) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added dropwise iodomethane (1.90 mL, 30.5 mmol), and the mixture was stirred at room temperature for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 10/1 then 1/4) to obtain the title compound (7.39 g, 26.9 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](/[CH:10]=[C:11](\[C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)/[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(/C=C(/C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Yield: 81.5 %

Procedure:
To 5-[(E)-2-(4-tert-Butyl-phenyl)-2-carboxy-vinyl]-thiophene-2-carboxylic acid methyl ester (600 mg, 1.7 mmol) in 50 ml THF and 10 ml 1NHCl was added 10% palladium on carbon (1.5 g). The resulting mixture was stirred under 50 psi hydrogen gas for 2 hours. The catalyst was filtered off and the solvent was evaporated. The residue was sonicated in hexane for 30 seconds. The solvent was filtered to afford 5-[2-(4-tert-Butyl-phenyl)-2-carboxy-ethyl]-thiophene-2-carboxylic acid methyl ester as a yellow solid (480 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].[NH2:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]2[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:30][CH:29]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)OCc3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-1-propoxy)benzoate (361 mg, 1.27 mmol), EDC(hydrochloride) (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol), and 4-DMAP (31 mg, 0.25 mmol) in DMF (8 mL) was stirred at room temp. overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give 476 mg (58%) benzyl (S)-4-[2-[3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a brown solid. 1H-NMR (CDCl3) δ 1.25–1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95–3.97 (m, 2 H), 4.36–4.39 (m, 1 H), 5.33 (s, 2 H), 6.75–6.94 (m, 5 H), 7.26–7.70 (m, 8 H), 7.99–8.26 (m, 5 H).
Reaction SMILES: [C:1](O)(=O)[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]C.C(OC(=O)C)(=O)C>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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]=[CH: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][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Product: C=CCCCCCCCCCCCCCCC
Temperature: 90 °C
Yield: 188.6 %

Procedure:
A mixture of stearic acid (150 g, 0.527 mol), acetic anhydride (54 g, 0.53 mol), and triphenylphosphine (0.921 g, 3.51×10-3 mol) was heated to 220°-230° C. under reduced pressure (55 torr) in a 500 mL flask fitted with a distillation head for product removal. Into this solution was pumped a feed mixture composed of stearic acid (400 g, 1.41 mol), acetic anhydride (150 g, 1.47 mol), dichlorobis(triphenylphosphine)palladium (0.0492 g, 7.03×10-5 mol), and triphenylphosphine (0.921 g, 3.51×10-3 mol) This feed mixture was maintained at ca. 90° C. and introduced into the reactor via a stainless steel tube with the opening positioned below the solution level. As product distilled from the reactor it was continuously replaced with more feed mixture at a rate of introduction that was approximately equal to the rate of product removal in order to maintain a constant level of the reaction mixture. The reaction was continued in this manner until the supply of feed mixture was exhausted (ca. 3.5 hours). At the conclusion of the reaction the level of reactor contents was about the same as at the beginning of the reaction. The distillate product was fractionally distilled to afford 237 g of 1-heptadecene (bp 130°-135° C./0.4 torr) which was found by GC analysis to be 95.6% of the α-olefin. This amount of product corresponds to a catalyst TON of 13,515. Considering the amount of unreacted stearic acid-containing residue recovered in the distillation pot (94 g), the isolated yield of 1-heptadecene relative to the stearic acid in the feed mixture was at least 92%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:44]=[CH:43][C:31]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]3[NH:39][C:40](=[O:42])[NH:41][C:34]=23)=[CH:30][CH:29]=1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:39][C:40](=[O:42])[NH:41][C:34]=34)=[CH:43][CH:44]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(F)cc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)[nH]c34)cc2)n(-c2ccc(F)cc2)n1
Temperature: 50 °C
Yield: 86.4 %

Procedure:
Method I1. A mixture of phenyl 3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl-carbamate (66 mg, 0.18 mmol) and 7-(4-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (30 mg, 0.12 mmol) in anhydrous THF (1.5 mL) containing 4 Angstrom molecular sieves was heated at 50° C. for 14 hours. After dilution with EtOAc (10 mL) and filtration to remove the molecular sieves, the solution was washed with 0.5 M citric acid (aqueous), saturated NaHCO3 (aqueous) and brine. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The orange solid residue was washed with Et2O to afford the title compound (52 mg, 85%) as a slightly orange solid. 1H-NMR (6, ppm, DMSO-d6): 1.28 (s, 9H, t-Bu), 6.31 (d, 1H, HPy,5, J=6.0 Hz), 6.35 (s, 1H, HPyz,4), 7.09 (d, 2H, Harom,Ph,3+5, J=8.9 Hz), 7.37 (t, 2H, Harom,4-F-Ph,3+5 J=8.8 Hz), 7.47 (d, 2H, Harom,Ph,2+6, J=8.9 Hz), 7.57 (dd, 2H, Harom,4-F-Ph,2+6 J=8.8 Hz and J=5.0 Hz), 7.74 (d, 1H, HPy,6, J=6.0 Hz), 8.37 (bs, 1H, NHurea), 9.06 (bs, 1H, NHurea), 11.16 (bs, 1H, NHPy3) 11.34 (bs, 1H, NHPy2). LC-MS (m/z): 502 (M+H, 100).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=2[S:15][C:16]=1[NH2:17])=[O:11])[CH3:8].Cl>N1C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=2[S:15][C:16]=1[NH:17][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[O:11])[CH3:8]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(=O)C2CC2)sc2c1CCCC2
Reaction time: 1 h

Procedure:
11 millimol cyclopropanecarbonyl chloride was added dropwise to the solution of 10 millimol IV in 25 milliliter pyridine at 5° C. The reaction mixture was stirred at this temperature for 1 hour, poured onto icecold 1N aqueous HCl, the precipitated solid was filtered off, washed with water and n-hexane, then dried.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=O.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>C(O)C>[OH:19][N:18]=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: N#Cc1ccc(C=O)c(OCC(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(OCC(F)(F)F)c1

Procedure:
In analogy to example 106.2, 4-formyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile was reacted with hydroxylamine hydrochloride and sodium acetate in ethanol to give 4-(hydroxyimino-methyl)-3-(2,2,2-trifluoro-ethoxy)-benzonitrile as a yellow solid.