Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:15]=[C:16]3[CH:22]=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>[Pd].CO>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[C:16]3[CH:22]=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC=C(c2cnc3[nH]ccc3c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(c2cnc3[nH]ccc3c2)CC1
Reaction time: 20 h
Yield: 92.7 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohex-1-enyl ester (730 mg, 20 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (490 mg, 20 mmol), Pd(dppf)Cl2 (80 mg) and 2.0M Na2CO3 (3 ml, 6 mmol) in DMF (20 ml) was heated at 80° C. under N2 for 3 hours, and then concentrated. The residue was suspended in water, filtered and the solid was purified by FC to give [4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester (600 mg) in 96% yield. FIA-MS: m/e=314.05 (M+H). A suspension of the above cyclohexene (300 mg) and 10% Pd/C (200 mg) in a 1:1 mixed solvent of EtOAc and MeOH (30 ml) was shaken under 50 psi H2 for 20 h. Filtration gave [4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-cyclohexyl]-carbamic acid tert-butyl ester (280 mg). FIA-MS: m/e=316.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cccc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cccc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
7.61 g of 5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 40 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 4 hours. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 8.52 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xiv) of the present invention).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nnc(SCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
In a mixture of 40 ml of water and 45 ml of ethanol, 21.1 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 6.9 g of sodium hydroxide were dissolved. To this solution, 19.6 g of benzyl chloride was added, and the mixture was stirred at 50° C. for 1 hour. After cooling, water was added to the reaction mixture, the formed precipitate was separated by filtration and washed with water and an ethanol/n-hexane (1:1) mixture respectively. The thus treated precipitate was dried under reduced pressure, and thus 32.5 g of 2-amino-5-benzylthio-1,3,4-thiadiazole was obtained. m.p. 159°-161° C. Yield 94%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11]>C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(I)cc1
Solvent: CCO
Product: ON=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a stirred suspension of 4-iodobenzaldehyde (2000 mg, 8.620 mmol) in ethanol (9.000 mL) cooled in an ice bath, hydroxylamine (569.4 μL of 50% w/v, 8.620 mmol) was added and the reaction was removed from ice bath and stirred at rt for 1 h. After this time the reaction mixture was heated at 50° C. for 1 h and then cooled to rt and concentrated in vacuo to leave the title compound as a white solid (2.03 g, 95% yield); 1H NMR (400 MHz, DMSO) d 7.38 (m, 2H), 7.76 (m, 2H), 8.11 (s, 1H) and 11.37 (s, 1H) ppm; MS (ES+) 248.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:3]=1.C(=O)(O)[O-:25].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[Na+]>O.C(Cl)Cl.C(O)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:25])[C:13]2[NH:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 86.3 %

Procedure:
A mixture of pyrmetazOle (0.108 mole) and potassium bicarbonate (0.13 moles) in 115 mL of water and 180 mL of methylene chloride was cooled to 0° C. to 4° C. while being stirred. A solution of MCPBA (0.108 moles, 72% pure) in 51 mL of methylene chloride and 13.3 mL of ethanol was added dropwise over 3 hours while the temperature was maintained between 2° to 4° C. After the addition was complete the reaction mixture was stirred an additional 0.5 hour and analyzed by HPLC to ascertain the extent of conversion. The reaction mixture was then diluted with 115 mL of cold water, and the pH was adjusted to 13-13.5 with approximately 15 mL of 50% aqueous sodium hydroxide (NaOH) while the reaction temperature was maintained between 2° to 5° C. The reaction mixture was then stirred an additional 15 minutes and the layers were separated. The organic layer was extracted with pH 13.5 NaOH in water. The basic aqueous phases were combined and treated with approximately 12 mL of methyl formate which was added over a 4 hour period. When the reaction mixture pH reached approximately 10.8, the reaction mixture was seeded with omeprazole. When the methylformate addition was complete the product was collected by filtration and rinsed with water and methanol. Drying provided 32.2 g of crude omeprazole (86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:13][CH2:10][C:9]([C:5]1[C:4]([CH3:12])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH3:8])=[O:11]
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Cl)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27 mmol) in acetonitrile (54.8 mL) was added tetrabutylammoniumtribromide (TBABr3, 13.2 g, 27.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-chloro-2,6-dimethylphenyl)ethanone (7.2 g), which was used directly for the next step without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C>[OH:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(O)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
Nitric acid (95%, 42 g, 0.62 mol) was added dropwise (internal temperature kept below 5° C.) to a solution of methyl 3-hydroxy-4-methoxybenzoate (96.5%, 100 g, 0.53 mol) and acetic acid (250 mL) at 0° C. After 10 min at 0° C., a large amount of precipitate had formed and was collected by filtration. The filter cake was washed with water (100 mL×2), and then the crude product was recrystallized from methanol (40 mL) to give 33 g of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 7.49 (d, 1H), 7.22 (d, 1H), 3.93 (s, 3H), 3.76 (s, 3H); MS (ESI): 227.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([C:22]#[N:23])[CH:3]=1.C1COCC1>>[NH2:23][CH2:22][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2C#N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2CN)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyl 4-(4-bromo-2-cyanophenylamino)piperidine-1-carboxylate (1.00 g, 3 mmol) in THF (10 ml, 123 mmol) under argon was added borane-tetrahydrofuran complex (8 ml, 8 mmol) and stirred at RT for 20 h. The reaction was cooled to 0° C. and quenched with MeOH. The mixture was further diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4). Evaporation gave a relatively pure crop of the desired product, tert-butyl 4-(2-(aminomethyl)-4-bromophenylamino)piperidine-1-carboxylate, which was used directly in the next step without further purification. MS m/e 385.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]=[CH:22]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)=[O:27])[N:23]=[CH:22]1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)c1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
A mixture of N-[3-(trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (450 mg), 1-methyl-1H-imidazole-4-carboxylic acid (210 mg), EDC.HCl (320 mg), HOBt (250 mg) and acetonitrile (5 mL) was stirred at room temperature for an hour. Acetonitrile was distilled off under reduced pressure and an aqueous solution of 6 M sodium hydroxide was added. Extraction was conducted with ethyl acetate and the solvent was concentrated. The residue was purified by column chromatography (NH silica gel cartridge; ethyl acetate) to give the titled compound (90 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]4[CH2:29][O:28]4)[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5]>CO>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([OH:28])[CH2:29][N:2]([CH3:3])[CH3:1])[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C4CO4)n3)cs2)cc1OCC
Reactant: CNC
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)CN(C)C)n3)cs2)cc1OCC

Procedure:
2.4 g of a 50% aqueous dimethylamine solution was added to a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(6-oxiranyl-2-pyridyl)thiazole dissolved in 200 ml of methanol. The mixture was refluxed overnight. The resulting precipitate was removed by filtration. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (elutant: dichloromethane/methanol=20/1) and silica gel thin-layer chromatography and then recrystallized from diethyl ether-dichloromethane to obtain 140 mg of 2-(3,4-diethoxyphenyl)-4-[6-(1-hydroxy-2-dimethylaminoethyl)-2-pyridyl]thiazole (A). Further, recrystallization from diethyl ether-n-hexane was conducted to obtain 28 mg of 2-(3,4-diethoxyphenyl)-4-[6-(1-dimethylamino-2-hydroxyethyl)-2-pyridyl]thiazole (B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 104 was prepared from bis(4-fluoro phenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.33–8.14 (m, 1H), 7.89–7.67 (br, 1H), 7.51–6.60 (m, 10H), 4.98–4.79 (br, 1H), 4.75 (s, 1H), 3.46–3.29 (m, 2H), 3.29–3.08 (m, 2H), 2.79–2.63 (m, 2H), 2.63–2.46 (m, 1H), 2.46–2.21 (m, 4H), 1.97–1.60 (m, 8H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(c1ccccc1)n1c(C(=CC2CCCC2)c2ccc3c(c2)OCCO3)cc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: C(=C(c1ccc2c(c1)OCCO2)c1cc2cccnc2[nH]1)C1CCCC1
Yield: 85.5 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.27 mmol) in ethanol (6 mL) and tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was stirred at 40° C. for 48 h. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (80 mg, 87%) as a white solid: LC/MS m/e calcd for C22H22N2O2 [M+H]+ 347.43, observed 347.1.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C@H:6]1[NH:16]C(=O)C(F)(F)F)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C@H:6]1[NH2:16])[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1Cc2ccc(OC)cc2[C@H]1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCO[C@H]1Cc2ccc(OC)cc2[C@H]1N
Temperature: 73 °C

Procedure:
Step AE (3): N-((1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (650 mg) in methanol (15 mL) was added saturated potassium carbonate (570 mg), and the resulting solution was heated at 73° C. for 12 h. The reaction mixture was filtered through a pad of Celite to give, and the filtrate was evaporated in vacuo to give (1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine as a solid. HPLC Retention time: 1.34 min (method B). MS (ESI) (M+H)+ 220.27.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1COCC1.CCCCCC>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:22])[OH:18])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCOCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 25 g of the compound obtained in Step A (70.8 mmol) and 26 ml of triisopropyl borate in 400 ml of THF cooled to −60° C. there are added, dropwise, over 45 minutes and under a gentle current of nitrogen, 53 ml of a 1.6M solution of BuLi (84.9 mmol) in hexane. The reaction solution is then stirred for 1 hour 30 minutes at −60° C. and is subsequently returned to ambient temperature over 2 hours. The reaction mixture is treated with about 100 ml of 1N HCl and is extracted 3 times with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained is chromatographed on an SiO2 column, eluting with CH2Cl2 and then with a mixture of CH2Cl2/MeOH 98/2 and then 95/5. After evaporation of the fractions, the residue is triturated in ethyl ether to yield the title product after filtration.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][N:2]=[C:3]([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=2)[CH2:4][CH3:5])=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)COc1ccc(C(CC)=NO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(CC)=NOCc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of the product of step 2 (18 g, 0.0723 moles) in DMF (54 mL), cesium carbonate (47 gm, 0.1446 moles) and 4-(trifluoromethyl)benzyl bromide (19 gm, 0.0795 moles) were added and the reaction mixture was srirred at 25° C. for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 28 gm (95%) of product as thick liquid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[C:5]([C:23]2[CH:40]=[CH:39][C:26]([O:27][C@H:28]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:31])=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+:42].C(O)C>C(O)C>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[C:5]([C:23]2[CH:40]=[CH:39][C:26]([O:27][C@H:28]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[Na+:42]
Reactant: CCCCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 80 %

Procedure:
To a solution of (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid (969 mg, 1.74 mmol) in ethanol (10 ml) was added 1N sodium hydroxide-ethanol solution (1.71 ml, 1.71 mmol) and the mixture was concentrated. To the residue was added hexane to give the object compound as a solid. 740 mg, (yield 80%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl.CCCCCCC.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:11])([F:10])[F:12]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)Oc1ccccc1Br
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=S(=O)(Cl)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound.
Reaction SMILES: [CH2:1]([N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[O:8][C:7]1=[O:20])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH3:21][C:12]1([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:14][CH2:15][C:9]2([O:8][C:7](=[O:20])[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:10]2)[CH2:11]1
Reactant: COC(=O)C1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a 78° C. solution of methyl 3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (15.0 g, 52.9 mmol) in THF (41.0 mL) under N2 was added sodium bis(trimethylsilyl)amide, 1 M in THF (238 mL, 238 mmol) over 1 h using an addition funnel. The reaction mixture was stirred at −78° C. for 3 h. Iodomethane (14.9 mL, 238 mmol) was added, and the reaction was stirred at −78° C. for an additional 2 h. The reaction was quenched at −78° C. with water (5 mL) and diluted with brine (200 mL). The product was extracted into EtOAc (3×200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to a light yellow solid. The solid was suspended in Et2O (75 mL) and collected in a frit. The collected solids were washed with cold Et2O (4×10 mL) and dried to afford the title compound (13.4 g, 81% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.40 (d, J=8.78 Hz, 1H), 3.29 (d, J=8.78 Hz, 1H), 3.06 (d, J=14.05 Hz, 1H), 2.92 (d, J=14.05 Hz, 1H), 2.16 (d, J=14.05 Hz, 1H), 1.77-1.93 (m, 4H), 1.43-1.69 (m, 3H), 1.35 (s, 3H), 0.96 (s, 9H). MS (m/z) 298.1 (M+H+).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14].I[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.CNCCNC>[Cu]I.CN(C=O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NCCN1
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cccc(N2CCNC2=O)c1
Temperature: 130 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
A microwave test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), K3PO4 (425 mg, 2.0 mmol, 2.0 equiv), 2-imidazolidone (1.29 g, 15.0 mmol, 15.0 equiv), 3-iodoanisole (119 μL, 1.0 mmol, 1.0 equiv), N,N′-dimethylethylenediamine (22 μL, 0.20 mmol, 0.20 equiv) and dry DMF (2.0 mL), filled with argon. The test tube was sealed and the reaction mixture was stirred at 130° C. for 15 h in the microwave. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with ethyl acetate. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane:ethyl acetate 1:2) provided 128 mg (67% yield) of the title compound as a white solid.