Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)C1(c2ccc(C)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(c2ccc(CBr)cc2)CC1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a stirred solution of methyl 1-(p-tolyl)cyclopropanecarboxylate (3 g, 15.77 mmol) in acetonitrile (42 mL), was added N-bromosuccinimide (2.807 g, 15.77 mmol) followed by benzoyl peroxide (0.164 g, 0.473 mmol). The reaction was stirred at 80° C. for 2 hours 40 minutes and then allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with dichloromethane (×3). The combined organic extracts were washed with brine and dried (magnesium sulfate), filtered and concentrated under reduced pressure to afford a red oil. The crude material was purified by silica gel column chromatography eluting with 0-9% ethyl acetate in iso-hexane to afford the title compound (2.478 g, 58%).
Reaction SMILES: [CH2:1](P(CCCC)CCCC)CCC.[F:14][C:15]([F:52])([F:51])[C:16]1[CH:17]=[C:18]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:19][N:20]([C:39]1[N:40]=[N:41][NH:42][N:43]=1)[CH:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:34]=[CH:35][C:36]([Br:38])=[CH:37][C:22]1=2.CO>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:18]([CH:17]=[C:16]([C:15]([F:14])([F:51])[F:52])[CH:46]=1)[CH2:19][N:20]([C:39]1[N:40]=[N:41][N:42]([CH3:1])[N:43]=1)[CH:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:34]=[CH:35][C:36]([Br:38])=[CH:37][C:22]1=2
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc(Br)ccc21
Reactant: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(Br)ccc21
Temperature: 25 °C

Procedure:
Add tri-n-butylphosphine to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, methanol and 1,1′-(azocarbonyl)dipiperidine (ADDP) in toluene at 0° C. under nitrogen and warm to room temperature. Dilute the mixture with ethyl acetate, wash with 2 N HCl and brine and dry over sodium sulfate. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:9][C:10]=1[CH2:11][C:12]#[N:13].[N-:24]=[N+:25]=[N-:26].[Na+].[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C.O>[NH:24]1[C:12]([CH2:11][C:10]2[S:9][C:8]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:7][C:6]=2[CH2:5][C:4]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=2)=[N:13][N:26]=[N:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(Cc2nc(N3CCOCC3)sc2Cc2nnn[nH]2)cc1Cl
Yield: 5.2 %

Procedure:
To a solution of 2-(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)acetonitrile (87.0 mg, 0.236 mmol) in DMF (0.74 mL) was added sodium azide (21.6 mg, 0.332 mmol) and NH4Cl (17.8 mg, 9.53 mmol) and the resulting mixture was heated to 140 degrees overnight. More sodium azide (43 mg, 0.66 mmol) and NH4Cl (36 mg, 19 mmol) were added and the reaction was heated to 120 degrees overnight. The reaction was cooled and taken up in ethyl acetate (25 mL) and water (5 ml). The layers were separated and the organic layer was washed with water (3×5 mL).). The organic layer was dried and concentrated in vacuo. The residue was purified by preparative reverse phase chromatography to give 5 mg (5% yield) of the title compound as a white solid LC/MS (FA) ES+ 411. 413. 1H NMR (400 MHz, DMSO-d6) δ: 7.50 (d, 1H, J=8.0 Hz), 7.46 (d, 1H, J=2.0 Hz), 7.20 (dd, 1H, J=8.0, 2.0 Hz), 4.41 (s, 2H), 3.88 (s, 2H), 3.65-3.62 (m, 4H), 3.32 (bs, 1H), 3.26-3.24 (m, 4H).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH:14]=[C:13](F)[CH:12]=1.O>CN(C=O)C>[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])[CH:14]=[C:13]([S:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[CH:12]=1
Reactant: OC(c1cc(F)cc(F)c1)(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
2-Trimethylsilylethane thiol (2.9 g, 21.9 mmol) was added dropwise to a suspension of NaH (1.8 g, 43.8 mmol) in dry DMF (60 mL) and stirred for 20 min. Then 1,3-difluoro-5-(hexafluoro-2-hydroxyprop-2-yl)benzene (Step 1 ) was added in dry DMF and the resulting reaction mixture was heated at 70° C. for 16 h. The reaction mixture was then added carefully to H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a residue which was chromatographed on silica gel, eluting with 95:5 mixture of hexane:EtOAc to afford the title compound (3.2 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:17]I.[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:17])=[N:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccc(Cl)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Yield: 91.2 %

Procedure:
A solution of 5-(4-chlorobenzyl)-2-thiouracil (50.5 g), methyl iodide (28.4 g) and sodium hydroxide (8.2 g) in water (200 ml) and ethanol (400 ml) was stirred at 60° for 30 minutes then allowed to cool. The crystalline product was filtered and washed with water to give 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (48.6 g), m.p. 193°-194° (methanol/ethanol).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])(=[O:8])=[O:7])([CH3:4])[CH3:3].C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:25][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: COc1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A mixture of 27 g of N-(1,1-dimethylethyl)-2-methoxy-5-methylbenzenesulfonamide (E. H. Huntress and F. H. Carten, J. Am. Chem. Soc., 62 (1940), 603), 19.6 g NBS and 0.3 g azobisisobutyronitrile in 200 ml CH2Cl2 was refluxed and illuminated with an sun lamp. After 8 hours and the lamp was turned off and the reaction was refluxed for another 24 hr. The reaction was allowed to cool. The reaction mixture was washed with 200 ml of a 1:1:1:1 mixture of brine:sodium sulfite:sodium bicarbonate:water. The organic layer was dried (MgSO4), treated with charcoal and filtered through a 5 g plug of silica gel. The plug was washed with 100 ml of chloroform. The combined organic fractions were evaporated to give 34 g of solid, m.p. 137°-142° C.;
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:5](=[O:7])[CH3:6])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)cc(Cl)c1
Product: CC(=O)Nc1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Acetic anhydride (6.7 mL) and 3-chloro-5-methyl-phenylamine (5.0 g, 35 mmol) was mixed and stand for 2.0 h. The reaction mixture was cooled to room temperature to give N-(3-chloro-5-methyl-phenyl)acetamide (5.1 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1 H), 7.19 (s, 1 H), 7.12 (s, 1 H), 6.91 (s, 1 H), 2.31 (s, 3 H), 2.16 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:16])[CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:27][CH3:28])=[C:20]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[N:5]=[C:4]([NH2:16])[CH:3]=2)[CH:19]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)n1
Temperature: 95 °C
Yield: 29.5 %

Procedure:
A mixture of 6-chloro-N*2*-(4-chloro-phenyl)-pyrimidine-2,4-diamine (0.077 g, 0.30 mmol), 5-chloro-2-methoxy-phenyl boronic acid (0.112 g, 0.60 mmol), palladium (II) acetate (0.017 g, 0.075 mmol), 2-(dicyclohexylphosphino)biphenyl (0.105 g, 0.30 mmol) and potassium phosphate (0.254 g, 1.2 mmol) in dry toluene (3.5 ml) was heated at 90-100° C. under an argon atmosphere for 18 hours. After cooling to room temperature, ether (20 ml) was added and the mixture was washed with aqueous sodium hydroxide solution (1.0 M, 10 ml), with saturated aqueous sodium chloride solution (10 ml), and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (0.032 g, 30% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[O:12][CH3:13].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.O.C(OCC)(=O)C>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:13][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Reaction time: 3 h

Procedure:
2-Chloro-4-nitro-5-fluoroanisole (D42) (300 mg) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (0.3 ml), and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (330 mg) were added at room temperature. The mixture was stirred for 3 h, then water and ethyl acetate added. The organic layer was dried over MgSO4, filtered and evaporated, and the residue was crystallised from diethyl ether to afford the title compound, 400 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:31][C:32]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][C:35]([NH2:36])=[C:34]([O:42][CH3:43])[CH:33]=1>CC(O)CCC>[Cl:18][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[N:7][C:2]([NH:36][C:35]2[CH:37]=[C:38]([N+:39]([O-:41])=[O:40])[C:32]([F:31])=[CH:33][C:34]=2[O:42][CH3:43])=[N:3][CH:4]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 125 °C
Yield: 72.2 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1-methylindole (Intermediate 88, 1281 mg, 4.60 mmol), p-toluene sulphonic acid monohydrate (964 mg, 5.07 mmol) and 4-fluoro-2-s methoxy-5-nitroaniline (Intermediate 23, 900 mg, 4.84 mmol) in 2-pentanol (50 mL) was heated at 125° C. for 18 h. A precipitate formed from the solution upon cooling. The precipitate was collected by filtration, washed with CH3OH (10 mL) and diethyl ether (20 mL) and dried on the filter to give the title compound (1.42 g, 72%) as a tan solid, which was used without further purification; 1H NMR: 3.91 (3H, s), 3.96 (3H, s), 7.05 (1H, t), 7.23-7.3 (1H, m), 7.39 (1H, d), 7.53 (1H, d), 8.33 (1H, d), 8.47 (1H, s), 8.58 (1H, s), 8.65 (1H, d), 8.76 (1H, s); m/z: ES+ MH+ 428.10.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3]1.C(OCC)(=O)C.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl.O>[CH2:14]([N:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C1CCN(Cc2ccccc2)C1
Temperature: 70 °C
Yield: 93.9 %

Procedure:
To a solution of pyrrolidin-3-one hydrochloride (7.40 g, 60.9 mmol) in DCE (122 mL) was added ethyl acetate (23.9 mL, 137 mmol) followed by benzyl chloride (8.63 g, 68.2 mmol) at ambient temperature. The reaction was heated to 70° C. for 2 hours. The reaction was cooled, diluted with DCM (100 mL), water (100 mL), the layers were separated, and the organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give 1-benzylpyrrolidin-3-one (10.01 g, 57.2 mmol, 93.9% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]3[C:6](=[CH:7][N:8]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[N:9]=[C:10]2[C:6]=1[CH:5]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11]2
Reactant: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3cc([N+](=O)[O-])c(C4CC4)cc3c2Br)nc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (ii) (1.08 g, 3.67 mmol) in DMF (15 mL) was added N-bromosuccinimide (780 mg, 4.40 mmol) and the resulting mixture stirred at 80° C. for 1.5 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aq. saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and the volatiles removed in vacuo to give (iii) (1.37 g, >99%). ESI-MS: calculated [M+H]+ 373.01375.0. observed [M+H]+ 373.1/375.1.
Reaction SMILES: [OH:1][C:2]1[C:11]([C@H:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:26][CH2:27][CH3:28])=[CH:7][C:8](=[O:25])[O:9]2)=[C:4]2[O:29][C:30]([CH3:34])([CH3:33])[CH:31]=[CH:32][C:3]=12.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+]>C1COCC1.[Cl-].[Na+].O.[Hg](OC(C)=O)OC(C)=O>[Si:18]([O:17][C@H:12]1[C:11]2[C:10]3[O:9][C:8](=[O:25])[CH:7]=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=3[C:4]3[O:29][C:30]([CH3:33])([CH3:34])[CH:31]=[CH:32][C:3]=3[C:2]=2[O:1][C@H:14]([CH3:15])[C@H:13]1[CH3:16])([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20]
Reactant: C=C[C@@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)c1c(O)c2c(c3c(CCC)cc(=O)oc13)OC(C)(C)C=C2
Agent: CC(=O)O[Hg]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)[C@H]3O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a solution of 10 (812 mg, 1.68 mmol) in THF (80 mL) was added Hg(OAc)2 (534 mg, 1.68 mmol), and the mixture was stirred for 20 min at room temperature. K2CO3 (232 mg, 1.68 mmol) was then added, and the reaction mixture was stirred for 30 min, then cooled to -10° C. NaBH4 was added (420 g, 11.0 mmol), and the reaction was allowed to warm to room temperature and stir for an additional 15 min. Hexanes (20 mL) were then added, followed by brine (40 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried (MgSO4 ), concentrated under reduced pressure at room temperature, and then submitted to silica gel chromatography (solvent B) to give 11 (660 mg, 82%) as a glass: [α]D20 -41° (c 1.0, acetone); 1H NMR (CDCl3): δ -0.132, 0.256 (2s, 6H, --SiCH3), 0.792 [s, 9H, --C(CH3)3 ], 0.996 (t, 3H, J=7.3 Hz, CH2CH3), 1.05 (d, 3H, J=6.82 Hz, --CH3), 1.38 (d, 3H, J=6.35 Hz, --CH3 ), 1.45, 1.47 (2s, 6H, --C(CH3)2, 1.54-1.73 (m, 3H, H-11,-ch2 ch3), 2.87 (m, 2H, --CH2CH2CH3), 4.40 (m, 1H, H-10), 4.99 (d, H, J=2.1 Hz, H-12), 5.49 (d, 1H, J=10.0 Hz, H-7), 5.90 (s, 1H, H-3), 6.62 (d, 1H, J=10.0 Hz, H-8); 13C NMR (CDCl3): δ -0.91, -0.56, 13.89, 14.05, 18.46, 19.14, 23.10, 25.96, 27.75, 38.49, 39.02, 62.62, 72.91, 77.48, 102.77, 105.83, 106.75, 110.11, 116.63, 126.46, 151.18, 152.92, 153.05, 158.31, 160.54. Anal. Calcd for C28H40O5Si: C, 69.38; H, 8.32. Found C, 69.18; H, 8.25.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][C@H:20]1[C:25]([O:27][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])=[O:26])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a mixture of p-bromophenacyl bromide (242 mg, 0.87 mmol) in DCM (1.5 mL) and DMA (1.5 mL), under nitrogen, was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.87 mmol) and N,N-diisopropylethylamine (531.8 μL, 3.05 mmol) and the resulting mixture was stirred at 35° C. for 3 h, concentrated under vacuum, dissolved in DCM (30 mL), and washed with water (2×5 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title intermediate.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([O:27]CC)=[O:26])[C:4]=1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2].O.[OH-].[Li+].O>O1CCCC1.CO>[C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([OH:27])=[O:26])[C:4]=1[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1)#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c(C2CCCC2)n1CC(=O)O
Yield: 96.8 %

Procedure:
General procedure I was followed using ethyl 2-(3-cyano-2-cyclopentyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (747 mg, 1.55 mmol) and lithium hydroxide monohydrate (130 mg, 3.09 mmol) in tetrahydrofuran (9.3 mL), methanol (3.1 mL), and water (3.1 mL). The product 2-(3-cyano-2-cyclopentyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (685 mg, 1.50 mmol, 97% yield) was isolated as a tan solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.99 (dd, 1H), 7.42 (ddd, 1H), 7.31 (dd, 1H), 7.00 (d, 1H), 4.65 (s, 2H), 4.30 (s, 2H), 3.32-3.36 (m, 4H), 2.94 (m, 1H), 1.87-2.04 (m, 13H, composite of multiple shifts), 1.59-1.70 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:7]
Reactant: C1COCCN1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCOCC3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (49.0 mg, 0.105 mmol) synthesized in Example (44a) was dissolved in tetrahydrofuran (5 mL), and morpholine (22 pt, 0.26 mmol), HATU (64.5 mg, 0.170 mmol) and N,N-diisopropylethylamine (89 μL, 0.51 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. To the reaction solution, saturated brine (15 mL) was added, and extraction was carried out twice with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (39 mg, yield 70%) as a pale yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:17]=[C:16]([CH3:18])[C:6]([O:7][CH2:8][C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]2)=[C:5]([CH3:19])[CH:4]=1.CC[O:22]CC.[OH-].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[Br:2][C:3]1[CH:17]=[C:16]([CH3:18])[C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N@@+:11]([O-:22])([CH3:15])[CH2:10]2)=[C:5]([CH3:19])[CH:4]=1
Reactant: Cc1cc(Br)cc(C)c1OC[C@H]1CCCN(C)C1
Reactant: CCOCC
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1OCC1CCC[N@+](C)([O-])C1
Reaction time: 0.5 h

Procedure:
(S)-3-(4-Bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride (338 mg, 0.97 mmol) was partitioned between ether and aqueous sodium hydroxide. The ether was dried and concentrated to give an oil which was dissolved in dichloromethane (10 mL). To this solution was added m-chloroperbenzoic acid (327 mg, 50-60%). After 30 minutes, the reaction mixture was diluted with dichloromethane, then washed once with 10% aqueous sodium thiosulfate and three times with aqueous sodium bicarbonate. After drying, the dichloromethane solution was concentrated and the residue recrystallized from ethyl acetate to give (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine-N-oxide (90.1 mg), m.p. 210.0-211.0° C.