Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31].[Na+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH3:31])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ccc(Cl)cc3)cc2)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a stirred solution of (S)-2-[4-(4-chloro-phenylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (60 mg) in DMF (2 ml) was added sodium hydride (6.2 mg) and stirring was continued at room temperature for 15 min. Iodomethane (24.3 mg) was then added dropwise. The reaction mixture was stirred at room temperature for 1 h. TLC at t=1 h showed the reaction was incomplete with some starting material remaining A second portion of sodium hydride (6.2 mg) was added. After stirring at room temperature for 15 min, iodomethane (24.3 mg) was added. Stirring was continued for a further hour. TLC then showed the reaction was complete. The reaction mixture was poured into sat. aq. NaCl and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford (S)-2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (49 mg, 79%) as a colourless gum. MS (ISP): 405.4 ([{37Cl}M+H]+), 403.4 ([{35Cl}M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[C@H:3]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:4](=[O:30])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.[C:37]([O:41][C:42]([N:44]1[C@H:49]([C:50]2[NH:54][C:53]3[C:55]4[C:60]([CH:61]=[CH:62][C:52]=3[N:51]=2)=[CH:59][C:58](Br)=[CH:57][CH:56]=4)[C@@H:48]2[CH2:64][C@H:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:37]([O:41][C:42]([N:44]1[C@H:49]([C:50]2[NH:54][C:53]3[C:55]4[C:60]([CH:61]=[CH:62][C:52]=3[N:51]=2)=[CH:59][C:58]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([C@@H:6]5[CH2:7][CH2:8][CH2:9][N:5]5[C:4](=[O:30])[C@@H:3]([NH:31][C:32]([O:33][CH3:34])=[O:35])[CH:2]([CH3:36])[CH3:1])=[N:14][CH:13]=3)=[CH:16][CH:17]=2)=[CH:57][CH:56]=4)[C@@H:48]2[CH2:64][C@H:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 39.9 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (526 mg, 1.06 mmol) and (1R,3S,4S)-tert-butyl-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (427 mg, 0.96 mmol) were combined in DME (10 mL). Pd(PPh3)4 (111 mg, 0.096 mmol) and K2CO3 (2M H2O, 1.6 mL, 3.17 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (280 mg).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cccc(F)n1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (7.51 g, 35.6 mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide (7.60 g, 42.7 mmol) and 2,2′-azobis(isobutyronitrile) (290 mg, 1.78 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(6-fluoropyridin-2-yl)-3-oxopropionate (7.51 g, 35.6 mmol) in 1,2-dimethoxyethane (70 ml) was added sodium hydride (60% in oil, 1.42 g, 35.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(6-fluoropyridin-2-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (7.74 g, 52%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[C:29]([CH3:33])=[N:28]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH:11]3[CH2:15][NH:14][CH2:13][CH:12]3[CH2:23]2)=[N:7][C:2]([NH:32][C:30]2[C:29]([CH3:33])=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cc1nn(C)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole2(1H)-carboxylate (573.1 mg, 1.54 mmol) and 1,3-dimethylpyrazol-4-amine hydrochloride (458.8 mg, 3.11 mmol) in dioxane (10 mL) was added trifluoroacetic acid (856.4 mg, 7.51 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM=1/10) to give the title compound as a beige solid (256.8 mg, 48.1%).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1cccc(F)c1F
Product: COC(=O)c1cc(Cl)ccc1COc1cccc(F)c1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,3-difluorophenol:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:25]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
DIEA (137.5 mL, 0.766 mol) was added to a suspension of (S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900 mL), and the mixture was cooled to 0° C. (ice/water bath). Methyl chloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, the cooling bath was removed and the heterogeneous mixture was stirred at ambient temperature for 3 h. The solvent was removed under diminished pressure and the residue partitioned between EtOAc and water (1 L each). The organic layer was washed with H2O (1 L) and brine (1 L), dried (MgSO4), filtered and concentrated under diminished pressure. The crude material was passed through a plug of silica gel (1 kg), eluting with hexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl 2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99% yield). 1H NMR (500 MHz, DMSO-d6, δ=2.5 ppm) 7.34 (d, J=8.6, 1 H), 3.77 (dd, J=8.6, 6.1, 1 H), 3.53 (s, 3 H), 1.94-2.05 (m, 1 H), 1.39 (s, 9 H), 0.83-0.92 (m, 6 H). 13C-NMR (126 MHz, DMSO-d6, δ=39.2 ppm) 170.92, 156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC/MS: [M+Na]+254.17.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][CH2:41][N:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: ClCCN1CCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCC3)cc2)C(C)C)c1
Yield: 19 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-(2-chloroethyl)azepane (23 mg) according to an analogous synthetic method to Example 404 and purified by NH silica gel column chromatography (hexane-ethyl acetate system), the title compound (6.0 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31]([NH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[OH:15])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture of trans-tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (1.05 g, 4.86 mmol) in 80 mL of dichloromethane was added triethyl amine (5.89 g, 5.83 mmol), followed by the addition of N-(benzyloxycarbonyloxy)succinimide (1.27 g, 5.10 mmol) at 0° C. The reaction was stirred at room temperature for 16 hours and then diluted with 100 mL of dichloromethane. The solution mixture was washed with 5% citric acid solution (2×100 mL), 5% potassium carbonate solution (2×100 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:4˜1:2) to afford the title compound (1.7 g, ˜100%, crude) as a colorless oil. MS (ES+) C18H26N2O5 requires: 350, found: 251 [M+H−100]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.O[CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:8][CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(S(=O)(=O)CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)CCCBr)cc1
Reaction time: 1 h

Procedure:
7.3 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure R to yield 4-(3-hydroxypropylsulfonyl)benzonitrile. 1.9 g of NBS was added to a solution of 2 g of 4-(3-hydroxypropylsulfonyl)benzonitrile and 2.8 g of triphenylphosphine in 10 mL of dichloromethane at 0° C. The reaction mixture was stirred at 0˜5° C. for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (10-70% ethyl acetate/hexane) to afford 4-(3-bromopropylsulfonyl)benzonitrile. 300 mg of 4-(3-bromopropylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(allylsulfonyl)benzoic acid. 40 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(allylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 413.2 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[CH:11]=O.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([CH3:10])[CH:4]=[C:3]2[C:2]=1[O:1][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]2)=[O:9]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Temperature: 80 °C
Yield: 23 %

Procedure:
A mixture of 2-hydroxy-5-methyl-1,3-benzenedicarboxaldehyde (5.0 g, 30.46 mmole), K2CO3 (8.41 g, 60.92 mmole) and ethyl 4,4,4-trifluorocrotonate (7.68 g, 45.69 mmole) in anhydrous DMF (40.0 mL) was heated to 80° C. under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, poured into 1.2 N HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark red oil which was subject to flash chromatography (silica gel) and eluted with 50% CH2Cl2/hexane to give a light yellow solid (2.2 g, 23%): GCMS m/z 314.0 (M+). 1H NMR (CDCl3/400 MHz) 10.42 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.26 (s, 1H), 5.80 (q, 1H, J=7.0 Hz), 4.33 (m, 2H), 2.32 (s, 3H), 1.35 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:24])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(C(=O)OC(C)(C)C)c2)cc1
Yield: 78.2 %

Procedure:
A mixture of 4-methylphenylboronic acid (0.65 g, 4.3 mmol), t-butyl-3-iodobenzoate (0.87 g, 2.86 mmol), K2CO3 (0.59 g, 4.3 mmol), and (Ph3P)4 Pd (0.17 g, 0.14 mmol) in DME (15 mL) was degassed and flushed with N2 before being brought to reflux for 2 h. Following a standard aqueous/EtOAc work-up, the residue was triturated with 1:10 EtOAc/hexane. The excess boronic acid was removed by filtration, and the filtrate was concentrated to give an oil which was purified by flash chromatography (hexane) to give an oil (0.6 g). This material (≈60% pure) was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>C(COC)OC.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 43.8 %

Procedure:
A magnetically stirred suspension of 4-bromo-3-nitroanisole (64.41 g, 278 mmol), phenylboronic acid (36.15 g, 296 mmol), and tris(dibenzylideneacetone)dipalladium(0) in dimethoxyethane (375 mL)/2 N sodium carbonate solution (517 mL) was stirred for 3 d under nitrogen. Additional tris(dibenzylideneacetone)-dipalladium(0) (0.5 g) was added and the suspension was stirred for 12 h, treated with Et2O (200 mL) and brine (200 mL), and the layers were separated. The aqueous layer was further extracted with fresh Et2O (2×300 mL), the combined organic extracts were filtered through Celite with diethyl ether elution, washed with water (500 mL) and brine (500 mL), dried (K2CO3), filtered, and concentrated in vacuo to afford 27.89 g (44%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 7.12 (dd, J=8, 2 Hz, 1H), 7.23-7.29 (m, 2H), 7.32-7.42 (m, 5H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([CH3:28])[C:21]3[S:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18][C:17]=3[CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.[Br-:30].[Li+]>CC(C)=O>[Br:30][CH2:11][CH2:12][C:13]1([CH3:28])[C:21]2[S:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][C:17]=2[CH2:16][CH2:15][O:14]1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C)OCCc3nc(-c4ccccc4)sc32)cc1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(CCBr)OCCc2nc(-c3ccccc3)sc21

Procedure:
A mixture of 4-[2-(p-toluenesulfonyloxy)ethyl]-6,7-dihydro-4-methyl-2-phenyl-4H-pyrano[4,3-d]thiazole (16 g, 37.2 mmoles, described above), and lithium bromide (16 g) in dry acetone (100 ml) is heated at reflux temperature for two hr. The solvent is removed under reduced pressure, water is added and the aqueous solution is extracted with ether. The ether solution is washed with water, dried over sodium sulfate, treated with charcoal and evaporated under reduced pressure to give 4-(2-bromoethyl)-6,7-dihydro-4-methyl-2-phenyl-4H-pyrano[4,3-d]thiazole, γmaxCHCl3 1545, 1500, 1465 and 1090 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>O1CCCC1.O>[CH:20]1([CH:19]=[C:18]([C:16]2[NH:15][C:12]3=[N:13][CH:14]=[C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:35])=[O:3])[CH:10]=[C:11]3[CH:17]=2)[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1)C(=O)O
Reaction time: 12 h
Yield: 53.4 %

Procedure:
To a stirred solution of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (prepared as in Example 26, 120 mg, 0.24 mmol) in tetrahydrofuran (10 mL) and water (2.5 mL) was added lithium hydroxide (48 mg, 2 mmol) at room temperature and the mixture was stirred for 12 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid (60 mg, 92.3%) as a white solid: LC/MS m/e calcd for C25H30N2O5S [M+H]+ 471.59, observed 471.6; 1H NMR (400 MHz, CD3OD) δ ppm 1.24 (m, 2H), 1.51 (m, 2H), 1.57 (s, 6H), 1.60-1.88 (m, 5 H, H), 2.13 (m, 1H), 2.27 (m, 1H), 3.08 (s, 3H), 4.32 (t, J=7.8 Hz, 1H), 6.50 (s, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.85 (d, J=2.3 Hz, 1H), 7.89 (d, J=8.3 Hz, 2H), 7.97 (br. d., 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC2CCNCC2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4-(1-benzyl-piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.51 g) in 20 mL acetic acid was added 0.23 g 10% palladium on carbon, the resulting suspension was shaken under hydrogen (50 psi) in Parr shaker apparatus for 12 hours. The suspension was filtered through a layer of celite and the solvent was removed under vacuum. To the residue was added 10% aq. NaOH and extracted with dichloromethane (2×). The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The title compound was obtained as clear syrup (1.16 g). ESI MS m/z 284 (M+H+); 1H NMR (400 MHz, CDCl3) δ 4.00 (m, 2H), 3.06 (d, J=10.1 Hz, 2H), 2.74 (m, 4H), 2.57 (t, J=10.1 Hz, 2H), 1.81 (t, J=14.1 Hz, 1H), 1.42 (s, 9H), 1.17 (m, 4H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]=1[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(CO)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(C=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
To a solution of dimethyl sulfoxide (21.2 mL, 0.298 mol) in DCM (150 mL) was added oxalyl chloride (5.0 mL, 0.060 mol) at −78° C. under an atmosphere of nitrogen. The resulting mixture was stirred for 20 min. A solution of (4-bromo-3-methylphenyl)methanol (6.0 g, 0.030 mol) in methylene chloride (50 mL) was cannulated into the reaction flask. After stirring for 1.0 h, triethylamine (21 mL, 0.15 mol) was added. The reaction mixture was stirred at −78° C. for 1 h, warmed to room temperature for 1 h. The reaction was quenched with 1 N HCl solution, the aqueous phase was separated and extracted with methylene chloride once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (5.7 g, 96%). 1H NMR (400 MHz, CDCl3): δ 9.96 (s, 1H), 7.73 (m, 1H), 7.71 (s, 1H), 7.55 (m, 1H), 2.49 (s, 3H).