Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)C>[CH2:33]([O:32][C:30]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)=[O:31])[CH3:34]
Reactant: N[C@@H]1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.6 %

Procedure:
To a solution of (±) cis 1-amino-2-(4-benzylphenoxymethyl)cyclopentane (0.9 g, 3.20 mmol) in dry diethyl ether (100 ml) containing triethylamine (0.89 ml, 6.4 mmol) was added ethyl chloroformate (0.40 ml, 4.16 mmol) under argon. After stirring at room temperature for 2.5 h the reaction was quenched with ice water and the pH of the aqueous layer was adjusted to 7 by addition of dilute hydrochloric acid. The organic layer was separated and the aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a pale yellow oil (1.16 g) which was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:8]([N:19]2[CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17][CH2:18]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4,5-dichloro-2-nitro-aniline (500 mg, 2.4 mmol), 4-trifluoromethyl-piperidine hydrochloride (550 mg, 2.9 mmol) and K2CO3 (830 mg, 6.0 mmol) in DMSO (10 mL) in analogy to example 3, step (a).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1>>[N+:11]([C:10]1[C:4]2[NH:3][C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[C:20]([C:19]([F:33])([F:18])[F:32])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:27][CH2:28]3)=[N:6][C:5]=2[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2[nH]c(Cl)nc12
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12

Procedure:
The benzoimidazole from step (c) above (1.5 g, 5.7 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (1.8 g, 7.8 mmol, Matrix) reacted under the conditions of Example 3c to give the title compound as a orange solid. M.p. 192° C. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:22](=[O:24])[CH3:23])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Commercial available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetic anhydride (2.22 g, 20.8 mmol) were added in drops. The mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, the mixture was filtered using dichloromethane and crystallized to give the title compound (4.50 g, 18.6 mmol)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:43])[CH:34]=[C:35]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:43][C:33]2[CH:34]=[C:35]([S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Yield: 69.4 %

Procedure:
A similar procedure as described in Example 40, step 6 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (632 mg, 1.34 mmol), 3-bromo-5-(propane-2-sulfonyl)-phenol (340 mg, 1.22 mmol), and potassium carbonate (337 mg, 2.44 mmol) to afford 4-[3-{6-[3-bromo-5-(propane-2-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (567 mg, 70%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C32H45BrO8S (M+Na)+ 691.1911, found 691.1908.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH:9]([OH:15])(O)[C:10]([F:13])([F:12])[F:11]>>[F:11][C:10]([F:13])([F:12])[CH:9]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[C:5]([CH:9]([OH:15])[C:10]([F:13])([F:12])[F:11])[C:6]=1[OH:7])[OH:15]
Reactant: Cc1ccc(O)cc1
Reactant: OC(O)C(F)(F)F
Product: Cc1cc(C(O)C(F)(F)F)c(O)c(C(O)C(F)(F)F)c1
Temperature: 105 °C

Procedure:
5.8 g (50 mmol) of p-cresol and 15.5 g (100 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 5 g of MgO are added. The mixture is heated at 105° C. for 8 hours. After treating according to the protocol described in Example 1, 70% of dihydroxyalkylated product are obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1[C:6]2([CH2:15][CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8][CH2:7]2)[CH2:5]1>CO>[CH3:1][O:2][CH2:5][C:6]1([OH:4])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1
Reactant: C1COC2(CCC3(CC2)CO3)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCC2(CC1)OCCO2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
75 ml of a 25% strength methanolic sodium methoxide solution were added to 4.56 g (26.8 mmol) of the compound from Example 6A in 150 ml of methanol, and the mixture was stirred at 60° C. overnight. After cooling, the reaction mixture was concentrated and the residue was taken up in saturated aqueous ammonium chloride solution and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 3.23 g (60% of theory) of the title compound.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:13]=[C:12]([O:26][C@@H:27]2[CH2:31][O:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]2)[CH:11]=1>>[N:1]1([S:5]([NH:8][C:10]2[N:15]=[C:14]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[N:13]=[C:12]([O:26][C@@H:27]3[CH2:31][O:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]3)[CH:11]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Reactant: NS(=O)(=O)N1CCC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)CO1

Procedure:
The subtitle compound was prepared from azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.22 g) and 1,1-Dimethylethyl (S)-4-[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]pyrimidin-4-yloxy]-isoxazolidine-2-carboxylate (the product of step i) (0.13 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.14 g
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]1(=[O:14])[O:13][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCCO
Reactant: O=C(O)CCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCCCCCCCC(=O)OCCCCCCO1
Temperature: 165 °C

Procedure:
Crystalline poly (hexamethylene sebacate) was prepared using a kettle equipped with a stirrer, nitrogen gas inlet tube, thermometer and condenser by reacting sebacic acid with 1,6hexamethylene glycol in the presence of a p-toluenesulfonic acid catalyst as follows: sebacic acid and hexamethylene glycol were added to the reaction kettle in a respective 1.0 to 1.1 molar ratio along with 0.5 wt % p-toluenesulfonic acid. The 10 mole % excess of glycol was used to ensure the predominant presence of hydroxyl end groups in the reaction product. The mixture was heated to 165°C while stirring. At 165°C, an amount of xylene was added to assist refluxing and this temperature was maintained until water evolution ceased (4 hrs.). Afterwards, the condensers were removed and the excess glycol and catalyst were removed by sparging with nitrogen for 0.5 hours at 165°C. On cooling to room temperature, the poly (hexamethylene sebacate) crystallized into an off-white solid. Next, the poly (HMS) from above was purified by precipitation from a benzene solution into methanol using techniques well known in the art. The precipitated poly (HMS) was collected by filtration and dried in vacuo. Analytical data on this purified material indicate an acid number of 1.06, an hydroxyl number of 34.4, an Mn of 3165 g/mole, an MWD (Mw /Mn) of 1.41 by GPC in chloroform, a glass transition temperature of about -62°C and a crystalline melting point of about 65°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].C(N(CC)CC)C>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1=c2cnc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 70.3 %

Procedure:
A mixture of Example 69e (0.04 g, 0.106 mmol), ethanesulfonyl chloride (0.054 g, 0.2423 mmol), and triethylamine (0.064 g, 0.635 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with dioxane (3 mL) and 2.0 N NaOH (2 mL). The reaction mixture was heated at 90° C. for 2 hours. The solvents were partially removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC(C18, CH3CN/water (0.1% TFA), 0-100%) to afford 0.035 g (56.6%) of the title compound as the TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (d, J=5.8, 1H), 10.15 (s, 1H), 8.17 (d, J=2.75 Hz, 1H), 8.00 (d, J=2.75 Hz, 1H), 7.82 (s, 1H), 7.09 (d, J=5.8 Hz, 1H), 7.03-7.07 (m, 2H), 6.58-6.62 (m, 2H), 4.62 (s, 2H), 4.07 (s, 3H), 3.26 (q, J=7.32 Hz, 2H), 1.29 (t, J=7.32 Hz, 3H). MS (DCI+) m/z 470.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[F:33][C:34]([F:42])([F:41])[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][S:37]([CH2:36][CH2:35][C:34]([F:42])([F:41])[F:33])(=[O:39])=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OS(=O)(=O)CCC(F)(F)F)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 21.3 mg, 0.0474 mmol) was dissolved in methylene dichloride (1 mL), 3,3,3-trifluoropropane-1-sulfonyl chloride (11.6 mg, 0.0590 mmol) and triethylamine (18 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.5 mg) as a colorless amorphous product. (Yield 80%)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15](Br)[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:19])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Zn]C
Reactant: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Temperature: 22 °C
Yield: 95 %

Procedure:
A solution of the product from step j) (284 mg, 0.86 mmol) in dioxane (4.3 ml) was treated with Pd(dppf)2Cl2 (42 mg, 0.051 mmol) and a 2M solution of dimethylzinc in toluene (0.86 ml, 1.72 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) passed through a plug of silica-gel eluting with 50:50 hexanes:EtOAc to provide the subtitle compound (216 mg, 95% over 3-steps). MS calculated for C14H19NO2S +H 266, observed 266.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[C:13]([I:25])[CH:12]=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:8][C:9]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:13]([I:25])[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NCCc1c(I)ccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1c(I)ccnc1F
Reaction time: 4 h

Procedure:
TFA (0.677 ml, 8.79 mmol) was added into a solution of tert-butyl 2-(2-fluoro-4-iodopyridin-3-yl)ethylcarbamate (1.61 g, 4.40 mmol) in DCM (6.28 ml, 4.40 mmol). After 4 h, LCMS showed mainly starting material. 1 mL of TFA was added. After 16 h, the reaction was diluted with DCM, neutralized with sat. NaHCO3. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and concentrated to afford a creamy colored solid, 2-(2-fluoro-4-iodopyridin-3-yl)ethanamine MS Calcd for C7H8FIN2: [M]+=266. Found: [M+H]+=267. HRMS Calcd for C7H8FIN2: [M+H]+=266.9789. Found: [M+H]+=266.9802.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.3 g, 0.858 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.355 g, 1.029 mmol) according to the general procedure VI. Obtained as a white solid (0.220 g, 48%). MS (ISP) 533.2 [(M+H)+]; mp 242° C. (dec.).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([S:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][N:28]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccc(S)c1
Reactant: CCCn1cc(-n2ccc3ccc(Cl)cc32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (372 mg, 2.03 mmol) in CH2Cl2 (20 mL) under inert atmosphere was added NCS (271 mg, 2.03 mmol) at 0° C.; warmed to RT and stirred for 45 min. To this, compound 2 (500 mg, 1.93 mmol) was added at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 3 (700 mg, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.76-7.74 (m, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.49-7.47 (m, 2H), 7.40 (s, 1H), 7.24-7.23 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.01-1.96 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H); LC-MS (ESI): 72.2%; m/z 440.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)c(F)c1

Procedure:
20.9 g (0.1 mol) of 3-fluoro-4-methylbenzenesulphonyl chloride are taken up in 200 ml of carbon tetrachloride and, after addition of 19.6 g (0.11 mol) of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide, the mixture is heated under reflux for 5 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography using petroleum ether/toluene (4:1), 50 μm particle size, gives 12.4 g (44% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[NH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[S:5])[CH3:2]
Reactant: CCN=C=S
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=S)Nc1nccs1
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of ethyl isothiocyanate (1.74 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.48 g (13%) of the title product:
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]3[S:25][C:23](=[O:24])[NH:22][C:20]3=[O:21])=[CH:16][CH:17]=2)=[N:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:29]>C(Cl)Cl>[CH2:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:29])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]3[S:25][C:23](=[O:24])[NH:22][C:20]3=[O:21])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:1]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
The N-oxide of racemic pioglitazone (935 mg, 2.54 mmol) was suspended in 12 mL CH2Cl2, then trifluoroacetic anhydride (TFAA, 1.49 mL, 12.69 mmol., 5 equiv.) was added and the reaction mixture was shaken at 50° C. After 24 h, an additional equivalent of TFAA was added and the vial was shaken for another 24 h. After the solvent and excess TFAA were evaporated, the resuting light yellow residue (1.922 g) was dissolved in 5 mL tetrahydrofuran (THF), and next a saturated NaHCO3 aqueous solution was added until gas evolution stopped (4 mL). The resulting solution was diluted with water (10 mL) and the mixture extracted with ethyl acetate (EtOAc, 3×20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to provide the alcohol in crude form. The crude alcohol was purified by preparative HPLC (0.1% TFA water/acetonitrile gradient). Fractions containing the pure product were neutralized by addition of triethylamine, combined, and evaporated to provide a residue. The residue was redissolved in EtOAc and the organic layer was washed with brine then dried over Na2SO4. Evaporation of the solvent gave pure 5-({p-[2-(5-ethylpyridin-2-yl)-2-hydroxyethoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione as a white foam (434.8 mg, 1.17 mmol, 46% yield). LC-MS: 373 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][NH:11][C:12]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)[CH:15]=[CH:14][C:13]=1[CH2:24][NH:25][C:26](=[O:38])[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([CH3:35])=[C:29]([O:36][CH3:37])[CH:28]=1)C1C=CC=CC=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:37][O:36][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([O:33][CH3:34])[C:30]=1[CH3:35])[C:26]([NH:25][CH2:24][C:13]1[CH:14]=[CH:15][C:16]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[CH:17][C:12]=1[NH:11][CH2:10][C:9]([OH:39])=[O:8])=[O:38]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)OCc2ccccc2)cc(OC)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
To a solution of compound 14a (110 mg, 0.29 mmol) in a mixture of THF (3 mL) and methanol (3 drops) was added 10% LiOH (1 mL). The reaction mixture was stirred for 5 h at rt and acidified with 1 N HCl. The resulting solid was filtered, washed with water, and dried to give compound 47a (57 mg, 52%).