Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH2:11][CH2:10]2)(=[O:6])=[O:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:35]=[C:34]([N:12]3[C:13]4[C:9](=[CH:8][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=4)[CH2:10][CH2:11]3)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of NaH (0.62 g, 15.5 mmol, 60% NaH) in 40 mL of DMF, 5-methanesulfonyl-2,3-dihydro-1H-indole (1.9 g, 9.63 mmol) was added and the mixture was stirred at room temperature for 30 minutes. 17a (3.09 g, 9.88 mmol) was added in DMF and the mixture was heated at 85° C. for 17 h. After cooling to room temperature, brine was added (200 mL) and the mixture was extracted with DCM (200 mL then 3×500 mL). The combined extracts were washed with brine (3×100 mL), dried, filtered and evaporated. The residue was purified by flash chromatography (eluent: 25 to 100% EtOAc in hexane with 0.1% triethylamine) to afford 2.83 g (62%) of 17b.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCOC(=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Yield: 76.5 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of hydroquinone (polymerization inhibitor) were added. The mixture was heated to keep 120° C. for4 hours in nitrogen atmosphere with distilling 14 ml (0.25 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 88.1 g (yield 76.5%) of 2-ethoxalyloxyethyl methacrylate (colorless transparent liguid) (bp 98° C./0.3 mmHg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19]>C1(C)C=CC=CC=1.O>[Br:19][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]ethanol (500 mg, 1.94 mmol) in toluene (5 mL) was added phosphorus tribromide (550 mg, 2.03 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (258 mg, 41%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:29]3[CH:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
N,N'-carbonyldiimidazole (1 g) is added to a solution, cooled to +5° C., of 2-dimethylaminophenylacetic acid (1.1 g) in dry dichloromethane (30 cc). The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS, 7aRS)- 7,7-diphenylperhydro-4-isoindolone hydrochloride (2.03 g) and triethylamine (1.68 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 24 hours, then washed with water (3×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 3 cm, height 25 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40:60 by volume) and collecting 125-cc fractions. Fractions 8 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS, 7aRS)-7,7-Diphenyl-2-[2(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (0.9 g) is obtained in the form of white crystals, m.p. 150° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[F:6][CH:7]([F:17])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O)C>O>[F:6][CH:7]([F:17])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[N:2][OH:3]
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1cccc(OC(F)F)c1

Procedure:
A 2.0 g portion of hydroxylamine hydrochloride was dissolved in 12 ml of water and 8 ml of 5N sodium hydroxide was added. A 1.0 g portion of 3-(difluoromethoxy)benzaldehyde was added followed by enough ethanol to give a solution. After 10 minutes of reflux, the reaction mixture was concentrated in vacuo and the residue taken up in 10 ml of water. The pH was adjusted to 4 with hydrochloric acid, then the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate and concentrated, giving the desired compound as an oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:15][C:14]2=[CH:32][CH:33]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[CH:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:15][C:14]2=[CH:32][CH:33]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:2]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NS(C)(=O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(C)(=O)=O)Cc2ccc(cc2)OCCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 55 (40 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.46 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 7 mg, 19%. Rf=0.25 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[N:18](C)C=O>>[NH2:18][C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CN(C)C=O
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Product: CCc1nnc2c(N)nc3ccccc3n12
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Ammonia gas was bubbled through a solution of 1.2 g. (0.005 mole) of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 4) in N,N-dimethylformamide (20 ml.) at 0° C. for about 2 minutes. The solution was stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction mixture was then poured over ice and stirred for 20 minutes. The precipitate which formed was removed by filtration, washed with water and air dried. Recrystallization from ethanol afforded 220 mg. (22% yield) of pure 4-amino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 284°-8° C. Mass spectrum: m/e, 213 (P).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([OH:19])=O)[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:20].C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40]>C1COCC1>[F:35][C:36]([F:48])([F:49])[C:37]1[CH:38]=[C:39]([NH:40][C:17]([C:12]23[CH2:14][CH2:15][CH2:16][CH:11]2[C:10](=[O:20])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:13]3)=[O:19])[CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=1
Reactant: Cc1cccc(C)c1N1CC2(C(=O)O)CCCC2C1=O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1CC2(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2C1=O
Temperature: 75 °C
Yield: 55 %

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylic acid (86 mg, 0.3 mmol) and diisopropylethyl amine (104 μL, 0.6 mmol) in THF, methanesulfonyl chloride (32 μL, 0.4 mmol) was added. The mixture was treated with 3,5-bis(trifluoromethyl)aniline (137 mg, 0.6 mmol) and heated at 75° C. for 3 h. After evaporating the solvent, the crude product was applied on C18 preparative HPLC column and eluted with acetonitrile/water solvent system (5-80% acetonitrile gradient with 0.1% TFA). After neutralization and solvent evaporation of the combined product containing fractions, 80 mg of N-(3,5-bis(trifluoromethyl)phenyl)-2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxamide was obtained (53% yield). 1H NMR (400 MHz, CDCl3) δ□1.72-1.84 (m, 1H), 1.94-2.04 (m, 1H), 2.09 (s, 3H), 2.18 (s, 3H), 2.24-2.40 (m, 4H), 3.43 (d, 1H, J=11 Hz), 3.52-3.58 (m, 1H, 4.06 (d, 1H, J=11 Hz), 7.00-7.17 (m, 3H), 7.61 (s, 1H) 8.13 (s, 2H), 8.61 (s, 1H). LC-MS: Rt (retention time)=2.99 min, MS: (ES) m/z 485 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[C:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=O)(C)(C)C.CS(O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:10]12[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:14](=[O:23])[N:11]1[CH2:12][CH2:13][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(CC(F)(F)F)C(=O)C2(Cc3ccccn3)CNCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in Step 5, 1.89 g, 4.4 mmol) in CH2Cl2 (20 mL) was added MeSO3H (2.14 g, 22 mmol). The reaction mixture was stirred at room temperature for one hour. Triethylamine (2.45 g, 24.2 mmol) was added to the solution. The organic layer was washed with 100 mL of H2O, brine, dried over MgSO4, and concentrated to give a 1.4 g of the title compound as a yellow oil (97%). The oil solidified upon granulation in hexane or upon cooling.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1>[CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:10]([O:11][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 5-ethyl-5'-O-trityl-2'-deoxyuridine (7.5 g, 15 mmole) in dry pyridine (50 ml), methanesulfonyl chloride (4.0 g, 35 mmole) is added while cooling in an ice-water bath. The mixture is stirred for one hour at around 0° C. and followed by allowing the temperature to rise to room temperature. At this point, tlc indicates no remaining starting materials. The mixture is then poured into an ice-water mixture (1.5 liters) while stirring, the water is decanted, and the product is washed with cold water several times, dissolved in chloroform and dried (over MgSO4). Finally, the solvent is evacuated in vacuo to obtain a syrup (7.6 g, 90%). This material is sufficiently pure to carry out the next reaction without further purification. However, an analytical sample can be obtained by column chromatography or tlc using chloroform as an eluent.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[S:31])[C@@H:10]2[CH2:14][C@H:13]([C:15](=[O:17])[CH3:16])[CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:11]2[CH2:12][C@@H:13]([C:15](=[O:17])[CH3:16])[CH2:14][C@H:10]2[C:9]([OH:8])=[S:31])=[O:19])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: COc1ccc(COC(=S)[C@@H]2C[C@H](C(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)[C@H]1C[C@@H](C(O)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
9.76 g of cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline p-methoxybenzyl ester and 4.32 g of anisole were stirred together with 35 ml of trifluoroacetic acid at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:11][CH:10]=2)[O:15][CH:21]=1
Reactant: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.45 g (18.0 mmol) 3-(4-Trifluoromethylsulfanyl-phenyl)-acrylamide, 2.80 g (22.2 mmol) 1,3-dichloroacetone and 50.0 ml toluene were kept at reflux temperature for 40 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:1). All fractions containing the product were concentrated to a volume of 10 ml and the crystallized material isolated by filtration, washed with cold heptane and dried. Yield 2.02 g (35%) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: C([C:3]1[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:7][CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]=1[C:27]([OH:29])=[O:28])C.[OH-].[Na+].CO.Cl>O>[CH2:10]([O:9][C:8]1[CH:3]=[C:4]([C:27]([OH:29])=[O:28])[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of 6.46 g (16.4 mM) of ethyl p-(10-undecenyl)oxybiphenylcarboxylic acid and 2.18 g (54.6 mM) of sodium hydroxide in 4 ml of water was mixed with 30 ml of methanol, followed by 3 hours of refluxing at 50° C. After the reaction, 20 ml of distilled water was added to the reaction mixture, followed by distilling-off of methanol and acidification with 6M-HCl to obtain a crude product. The crude product was filtered and dried in a desiccator under reduced pressure to obtain 5.56 g (15.2 mM) of p-(10-undecenyl)oxybiphenylcarboxylic acid (Yield: 92.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([NH:1][C:20]2[C:15]([C:12]3[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=3)=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2-c2ccccc2)cc1
Temperature: 105 °C

Procedure:
Into a 250 mL round bottom flask was placed palladium acetate (120 mg) and Cytop-216 (120 mg) and was stirred in toluene (10 mL) for 1 hour at room temperature under argon. To this was added, in order, aniline (15 mL), 4-bromobiphenyl (12.5 g), sodium t-pentoxide (7 g), and a further 10 mL of toluene. The resulting mixture was heated at 100-110° C. for between 4 and 6 hours. The mixture was cooled to room temperature and diluted with 20 mL of toluene, filtered to remove insolubles, and 10-20 g of Al2O3 was added. The resulting slurry was heated to ˜80° C. and filtered while hot. The toluene was removed by rotary evaporation and the residue was recrystallized from 150 mL of isopropyl alcohol. The solid produced on cooling was filtered by suction, washed with a further 100 mL of isopropyl alcohol, and dried overnight. Yield was 8.9 g with a purity >99% which was determined by HPLC and NMR.
Reaction SMILES: [C:1]1([CH3:53])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:52])[CH2:14][O:15][C:16]2[CH:21]=[C:20](C)[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])=[C:18](C)[CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:1]1([CH3:53])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:52])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:48])[F:49])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:24])=[O:25])=[CH:20][CH:21]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)cc2)cc1
Yield: 60.1 %

Procedure:
A solution of (3,5-dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 14, 400 mg, 0.50 mmol) and NaHCO3 (51 mg, 0.60 mmol, 1.2 eq) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 3 h. Then volatile materials were removed, the residual gummy oil was dissolved in THF and the mixture was filtered to remove un-dissolved solid. The filtrate was dried, the solvent was removed by evaporation to give a yellow foam which was treated with ether-EtOAc (5:1) to precipitate a solid. The solid was treated with CH3CN, and then collected by filtration to give Compound 5 (230 mg, 72%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1.Cl.N>C(#N)C.CO>[S:15]1[CH2:16][CH2:17][N:18]2[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)=[CH:2][N:13]=[C:14]12
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC1=NCCS1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc(-c2cnc3n2CCS3)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
3.00 g (12.72 mmol) of 4-bromoacetylbenzonitrile is dissolved in 40 mL acetonitrile, and combined with 2.65 g (25.42 mmol) of 2-amino-4,5-dihydrothiazole and 2.00 g of molecular sieve 4 Å. Then the mixture is stirred for 2.5 days at ambient temperature. Then the solvent is eliminated in vacuo, and the residue is taken up with 100 mL of 1 molar hydrochloric acid solution and the insoluble matter is taken up with a little methanol and concentrated ammonia solution. After filtration, the filtrate is concentrated in vacuo and purified by chromatography on silica gel (gradient: initially ethyl acetate/ethanol=100:0 □40:60+0.5% ammonia, then dichloromethane/methanol=6:4+2% triethylamine). Yield: 2.4 g; Rf value: 0.65 (silica gel; ethyl acetate/ethanol=8:2+1% ammonia); C12H9N3S (227.29); mass spectrum: (M+H)+=228
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)=[C:4]([CH2:21][CH2:22][CH3:23])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)CCC>C1(C)C=CC=CC=1.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>[F:20][C:16]1[N:15]=[C:14]([C:10]2[N:9]([CH2:8][C:5]3[N:6]=[N:7][C:2]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:3][C:4]=3[CH2:21][CH2:22][CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nccs2)nnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6-chloro-3-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-4-propyl-pyridazine (268 mg, 0.81 mmol), 2-tributylstannanyl-thiazole (453 mg, 1.21 mmol), and Pd(PPh3)4 (0.08 mmol, 93 mg) in toluene (10 mL) is degassed. The mixture is then heated at 100° C. overnight. Saturated KF aqueous solution (8 mL) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is extracted with EtOAc (10 mL). The combined extracts are washed with brine (15 mL), dried (Na2SO4), and evaporated. Preparative TLC (5% methanol in DCM) purification of the residue provides the title product. 1H NMR (CDCl3) 8.14–8.18 (m, 2H), 7.97 (d, 1H0, 7.83 (q, 1H), 7.50 (d, 1H), 7.20 (d, 1H), 7.18 (d, 1H), 6.80 (dd, 1H), 6.28 (s, 2H), 2.80 (t, 2H), 1.62–1.73 (m, 2H), 0.97 (t, 3H).