Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]=[N:10]1.C(=O)([O-])[O-:34].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:34])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C#N)cc2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64171.7 %

Procedure:
To a solution of 4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonitrile (0.150 mg) in dimethyl sulfoxide (1.2 mL) is added potassium carbonate (0.03 g) and 50% aqueous hydrogen peroxide (0.2 mL). The reaction mixture is allowed to stir at room temperature for 30 minutes. The reaction mixture is diluted with water (55 mL), cooled to 0° C., and filtered. The resulting solids are washed with cold (−78° C.) hexanes. The white solids are allowed to dry under reduced pressure to give the title compound (0.100 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.9 (d, 2H), 7.6 (d, 2H), 7.5 (m, 5H), 6.9 (d, 2H), 5.0 (s, 2H), 3.3 (p, 1H), 1.5 (d, 6H);′ APCI/MS m/e 481 (M+1), HPLC purity 98.5%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-(4-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=1.3 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.28-7.31 (m, 2H), 6.91-6.93 (m, 2H), 3.81-3.83 (m, 4H), 3.75 (s, 3H), 3.59 (s, 3H), 3.07-3.10 (m, 4H); MS (ESI+) M/Z 395 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][OH:14])=O)C1C=CC=CC=1>[Pd].CO.O1CCOCC1>[NH2:11][C@@H:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][OH:14]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@H](N)CO
Temperature: 25 °C
Yield: 105.8 %

Procedure:
10% Palladium on activated carbon (10 mg) was added to a solution of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanol (920 mg) in methanol (10 mL) and dioxane (1 mL). The mixture was stirred under hydrogen atmosphere (3.5 atm) for one and a half days at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo to give (S)-2-amino-3-(tert-butoxycarbonylamino)propanol (571 mg) as a white solid substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=[CH:17]1.Cl>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[N:16]([CH3:15])[C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Temperature: 21 °C
Reaction time: 1 h

Procedure:
An acylating solution is prepared by the slow addition of 278 g. (1.58 moles) of p-chlorobenzoyl chloride to 210 g. (1.58 moles) of aluminum chloride in 750 ml. of ethylene chloride. The resulting solution is added to a solution of 190 g. (1.58 moles) of N-methylpyrrole-2-acetonitrile in 750 ml. of ethylene chloride. The temperature is maintained at 20-22° C. during the addition; and the solution is further stirred at room temperature for one hour. The solution is then heated rapidly to 74-76° C. at which point there is a vigorous evolution of hydrogen chloride gas. This temperature is maintained about 5 minutes, and the solution is cooled rapidly and poured into ice water. The product is extracted with methylene chloride and washed with water. The organic solution is then shaken with an excess of an aqueous solution of N,N-dimethylaminopropylamine followed by dilute hydrochloric acid to remove any excess p-chlorobenzoyl chloride. After a final wash with brine, the solution is dried over anhydrous magnesium sulfate. Distillation of the solvent leaves a residue which crystallizes. Recrystallization from methyl alcohol yields the product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 120-124° C. After two additional recrystallizations from methanol, the m.p. is 127-131° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCCCCCc1ccc(CC(=O)OCC)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(C(=CN(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
0.50 g (2.0 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 7 mL of N,N-dimethylformamide, mixed with 0.31 mL (2.3 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 18 hours. After the stirring, the reaction mixture was further mixed with 0.65 mL (4.9 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product as a brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=C[C:5]2[C:6](=[O:10])[O:7][C:8](=O)[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[C:18]([O:21][CH2:22]C)(=[O:20])[CH3:19]>CO>[CH3:12][C:2]1[CH:1]=[C:19]([C:18]([O:21][CH3:22])=[O:20])[C:5](=[CH:4][CH:3]=1)[C:6]([O:7][CH3:8])=[O:10]
Reactant: CCOC(C)=O
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3.00 g of 5-methyl-2-benzofuran-1,3-dione was suspended in 30 mL of methanol, to which 0.2 mL of sulfuric acid was added at room temperature, and this suspension was stirred for 2.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and poured into ice water followed by addition of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled out under reduced pressure to yield 2.95 g of dimethyl 4-methylphthalate as light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[N:3]=1.CC1(C)OB([C:28]2[CH:32]=[CH:31][N:30]([Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:29]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:11]1[C:2]([C:28]2[CH:32]=[CH:31][N:30]([Si:33]([CH:37]([CH3:39])[CH3:38])([CH:40]([CH3:42])[CH3:41])[CH:34]([CH3:35])[CH3:36])[CH:29]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (180 mg, 0.59 mmol) in ethylene glycol dimethyl ether (6 ml) and water (2 ml) was added 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[tris(propan-2-yl)silyl]-1H-pyrrole (618 mg, 1.77 mmol), sodium carbonate (188 mg, 1.77 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) with stirring for 1 h at 95° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate as a light yellow solid (150 mg, 52%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]([Cl:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1CCCCC1.C(OCC)(=O)C>[CH:8]1([C:7]2[CH:2]=[CH:3][C:4]([CH:14]([Cl:16])[CH3:15])=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(Cl)c1ccc(C2CCCCC2)c(Cl)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
1-(3'-Chloro-4'-cyclohexyl-phenyl)-1-chloro-ethane, an oil, Rf -value 0.8 on carrier A with cyclohexane/ethyl acetate =4/1.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.[OH-].[Na+].Cl>O>[CH3:13][Si:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc([Si](C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[Si](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 130 mg (0.676 mmol) of 3'-trimethylsilylacetophenone and 127 mg (0.774 mmol) of methyl 4-formylbenzoate in 4.5 ml of tetrahydrofuran(THF) were added 128 mg (3.20 mmol) of NaOH and 3 ml of hot water, and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted with 7 ml of 0.5N-HCl to pH6, and then the aqueous solution was extracted with ethyl acetate. The extract was washed with 0.05N-HCl and H2O, dried and evaporated. The residue was purified by column chromatography affording 133 mg of pale yellow powder (yield 61%), which was recrystallized from a mixture of methylene chloride, methanol and n-hexane to give 98 mg of pale yellow needles, m.p.179°-180° C. (yield 45%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[S:5][C:6]=1I.C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[C:6]2[S:5][C:4]([C:8]#[N:9])=[CH:3][C:2]=2[I:1])=[CH:18][CH:17]=1
Reactant: N#Cc1cc(I)c(I)s1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1cc(I)c(C(O)c2ccc(Cl)cc2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
An oven-dried round-bottomed flask was charged with 4,5-diiodothiophene-2-carbonitrile (1.80 g, 5.0 mmol). After degassed, anhydrous THF (15 mL) was added through syringe. After cooled to −78° C., i-PrMgCl (3 mL, 2.0 M, 6.0 mmol) was added dropwise. The reaction was further stirred for 30 min at −78° C. after complete addition. 4-chlorobenzaldehyde (0.98 g, 7.0 mmol) in 5 mL THF was then added. After stirring for 10 min at −78° C. for 1 h, the reaction mixture was warmed to room temperature. 50 mL of saturated aqueous NH4Cl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:CH2CL2=30:3:10). 1.39 g (74%) of product was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:24]1([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:35][CH:36]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1ccc(N2CCCCCC2)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCCCCC5)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 6.1 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (37 mg, 0.11 mmol), prepared as described in Example 3a, was dissolved in anhydrous dioxane (2 mL) and to it was added 4-azepan-1-yl-phenylamine (19 mg, 0.1 mmol) followed by DIEA (20 uL, 0.11 mmol) and the mixture was stirred at 100° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 3 mg (6%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-azepan-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) 9.08 (s, 1H), 7.55-7.23 (m, 4H), 7.18 (d, 1H), 6.77 (d, 1H), 6.37 (s, 1H), 4.27 (m, 2H), 4.07 (s, 6H), 3.68-3.32 (m, 3H), 3.30-2.90 (m, 2H), 2.24-1.88 (m, 4H), 1.86-1.38 (m, 10H). LC/MS (ESI): 490.3 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH3:28]
Reactant: COc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Reactant: CC(=O)Cl
Product: COc1cc(C(C)NC(=O)c2ccnc(NC(C)=O)n2)cnc1OCC(F)(F)F

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.04 mmol, Step-1, single enantiomer) and acetyl chloride (10 mg, 0.12 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:10]([NH2:13])(=[O:11])=[O:12])=[C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)(=[O:26])=[O:25])[CH:7]=1)#[N:9]
Reactant: N#Cc1ccc(S(N)(=O)=O)c(N)c1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Product: N#Cc1ccc(S(N)(=O)=O)c(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)c1
Yield: 57 %

Procedure:
The title compound was synthesized as described for Example 178 in 57% yield, starting from 2-amino-4-cyanobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OC)=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][C:15]1[CH:56]=[CH:55][C:18]([C:19]([N:21]([CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)=[CH:36][CH:35]=4)[N:30]=3)=[CH:25][CH:24]=2)=[O:20])=[CH:17][CH:16]=1)=[O:13].[CH3:57][OH:58].[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:58][CH3:57])[C:4]=1[CH2:11][C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:21]([CH2:47][C:48]([OH:50])=[O:49])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)[N:30]=3)=[CH:25][CH:24]=2)=[O:20])=[CH:55][CH:56]=1)=[O:13]
Reactant: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CC(=O)Nc1ccc(C(=O)N(CC(=O)O)Cc2ccc(-c3nc(-c4ccc(-c5ccc(C)cc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
Prepared using General Procedure 9. To a stirring solution of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-66 (45 mg, 0.060 mmol) in THF (2 mL) and MeOH (0.25 mL) was added 1 M LiOH (120 μL, 0.120 mmol). The reaction mixture was stirred at room temperature for 20 h and a precipitate was formed. The mixture was filtered under vacuum and the captured solid washed with diethyl ether (5 mL). The captured solid was dried in a vacuum oven to provide 20 mg (48%) of 2-(4-(2-(2,6-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 458. LCMS-ESI (m/z) calculated for C41H36N4O7: 696; found 697 [M+H]+, tR=9.08 min (Method 9). 1H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.22-8.12 (m, 4H), 7.92-7.83 (m, 2H), 7.70-7.64 (m, 2H), 7.63-7.54 (m, 4H), 7.53-7.46 (m, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (t, J=8.3 Hz, 1H), 6.67 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 3.78 (s, 6H), 3.67 (s, 2H), 3.47 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].CO[C:13](=O)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:13]1[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:2]
Reactant: CCNc1ccncc1N
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnccc21

Procedure:
The title compound is prepared from N4-ethyl-pyridine-3,4-diamine and (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester following the procedure given in Example 8. 1H NMR (CDCl3) δ 9.08 (s, 1 H), 8.43 (d, 1 H), 7.85 (d, 1 H), 7.38 (d, 1 H), 7.38-7.26 (m, 1 H), 7.17 (s, 1 H), 7.14 (s, 1 H), 6.35 (s, 2 H), 4.25 (q, 2 H), 1.11 (t, 3 H). Electrospray MS: m/z 311 [M+1]
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH2:19][NH2:20])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@@H]2CNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@@H]2CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 100 %

Procedure:
Prepared from N-{(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-[(2R)-2-tert-butoxycarbonylaminomethylpyrrolidin-1-ylcarbonyl]propyl}-3-methyl-4-(pyrrolidin 1-ylcarbonyl)benzamide followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 100%; Rf value: <0.1 (silica gel; ethyl acetate); C29H35ClN6O5 (551.09); mass spectrum: (M+H)+=551/553 (chlorine isotope).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:20][C:19]3[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.8 %

Procedure:
A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil). The reaction mixture was then stirred for 45 minutes at ambient temperature under argon. 4-Bromobenzyl bromide (0.58 g) was added and the mixture heated slowly to 60° C. and then maintained at this temperature for 2 hours. The resulting mixture was then poured into water, basified with aq.NaHCO3 solution and then extracted with diethyl ether. The organic extracts were then washed with aq.NaHCO3, water, brine, dried (Na2SO4) and evaporated. The residue was recrystallised from acetonitrile to give 1-(4-pyridyl)-4-(4-bromobenzyl)piperazine (0.2 g) as a solid, m.p. 140-141° C.; microanalysis, found: C,55.3; H,5.2; N,12.0%; C16H18N3Br requires: C,55.4; H,5.7; N,12.1%; NMR: (CDCl3) 2.54(t,4H); 3.2(t,4H); 3.51(s,2H); 6.66(d,2H); 7.23(d,2H); 7.46(d,2H); 8.29(d,2H); MS: m/z 332 (MH)+.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=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][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1]([OH:24])=[O:23]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Yield: 82 %

Procedure:
Five-hundred grams molten erucic acid were slowly added to a mixture of 679 gms toluene and 723 gms concentrated sulfuric acid while maintaining the temperature below 10° C. Tolyldocosanoic acid (acid value 123) was obtained in 82% yield. Distilled tolyldocosanoic acid (108 gms), 400 mls acetic acid 9.8 gms Co(OAc)2.4H2O and 1.3 gms ZrO(OAc)2 were then heated at 105° C. and 350 psi O2 for six hours during which time the acid value increased from 127 to 207. The selectivity to the desired carboxyphenyldocosanoic acid was 64.4% at a tolyldocosanoic conversion of 53.7%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(O)c1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 20 mg (0.17 mmol, 1.1 eq.) of benzoic acid were reacted according to General Method 1. Yield: 35 mg (56% of theory)