Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[CH:14][C:15]([NH2:17])=[O:16])=[CH:5][CH:4]=1.C1COCC1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C=CC(N)=O)c2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cccc(CCC(N)=O)c2c1
Temperature: 50 °C

Procedure:
0.12 g of 5% Pd/C (50% wet) is added to a solution of the compound obtained in Step A (0.5 g) in a mixture of MeOH (6.5 mL)/THF (6.5 mL). The mixture is purged with nitrogen and then with hydrogen before being heated at 50° C. under atmospheric pressure during 1 hour. The suspension is then filtered over Celite and the filter is washed with a mixture of MeOH (5 mL)/THF (5 mL). The liquors are concentrated under reduced pressure to yield the title product in the form of a solid which is directly engaged in the following step without further purification.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1>>[NH:13]1[C:17]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:16][CH:15]=[N:14]1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1ccn[nH]1
Agent: OBO
Product: O=Cc1cccnc1-c1ccn[nH]1

Procedure:
2-(1H-pyrazol-5-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (1H-pyrazol-5-yl)boronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:1][C@H:2]2[CH2:3][C@@H:4]([NH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:5]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(N[C@H]1C[C@@H](O)C1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](NC(=O)OCc3ccccc3)C2)cc1

Procedure:
A solution of benzyl (cis-3-hydroxycyclobutyl)carbamate (intermediate 47, 0.3 g, 1.356 mmol), p-toluenesulfonyl chloride (0.284 g, 1.492 mmol), and triethylamine (0.567 ml, 4.07 mmol) in dichloromethane (2.71 ml) was stirred at room temperature for 14 hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, rotovapped, and advanced to next step directly.
Reaction SMILES: [CH2:1]([O:13][C@H:14]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:15][S:16][CH2:17][C@@H:18]([C:37]([O:39]C(C)(C)C)=[O:38])[NH:19][C:20](=[O:36])[O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:20]([NH:19][C@@H:18]([CH2:17][S:16][CH2:15][C@H:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:37]([OH:39])=[O:38])=[O:36])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCC
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC

Procedure:
A solution of (5R,9R)-tert-butyl 9-(dodecyloxy)-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylate in 50% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (30 minutes). The reaction mixture was diluted in MTBE, washed three times with 1M citric acid (adjusted to pH3), and once with 1:2 1N HCl/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used for the next step without further purification.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:37][C:38](=[O:45])/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])[C:30]([O:32]C(C)(C)C)=[O:31])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].Cl>O1CCOCC1>[C:1]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:37][C:38](=[O:45])/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])[C:30]([OH:32])=[O:31])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)/C=C/C(=O)OC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)/C=C/C(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
(S)-tert-butyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (500 mg) was taken up in 6 mL of a 4 N HCl solution in dioxane and stirred at room temperature under an inert atmosphere of argon for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between 30 mL of EtOAc and 30 mL of water. The organic layer was further washed with brine until the pH of the water layer was close to neutral, dried over Na2SO4 and concentrated under reduced pressure. Purification by preparative HPLC using a mixture of aqueous acetonitrile that has been buffered with 0.1% TFA afforded (S)-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoic acid (160 mg; 35%). MS (EI) calcd for C33H48N2O6: 568.35. found 569 (M+1).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[CH:4]=[CH:3]1.[CH2:14](O)[CH3:15]>>[CH2:14]([O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[S:2][CH:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13])[CH3:15]
Reactant: CCO
Reactant: O=C(O)c1ccc2sccc2c1
Agent: Cl
Product: CCOC(=O)c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A saturated solution of HCl in ethanol (15 mL) is added to benzothiophene-5-carboxylic acid (1 g, 5.44 mmol) and the reaction mixture is stirred at 80° C. overnight. The solvent is removed under reduced pressure and diethyl ether and saturated sodium bicarbonate are added to the residue. The layers are separated. The organic layer is washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (1.0 g, 89%) as a pale brown oil. 1H NMR (CDCl3): δ 8.54 (s, 1H), 8.01 (d, 1H, J=8.1 Hz), 7.92 (d, 1H, J=8.1 Hz), 7.51 (d, 1H, J=5.4 Hz), 7.42 (d, 1H, J=5.4 Hz), 4.42 (c, 2H, J=6.8 Hz), 1.43 (t, 3H, J=6.8 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]([C@H:24]1[CH2:27][C@@H:26]([C:28]([O:30]C)=[O:29])[CH2:25]1)([CH2:9][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)C(O)=O)=[O:4].C([N:34](CC)CC)C.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1>C1(C)C=CC=CC=1>[NH2:34][C:5]([C@H:24]1[CH2:27][C@@H:26]([C:28]([OH:30])=[O:29])[CH2:25]1)([CH2:9][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([OH:2])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(Cc1c2ccccc2cc2ccccc12)(C(=O)O)[C@H]1C[C@@H](C(=O)OC)C1
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: NC(Cc1c2ccccc2cc2ccccc12)(C(=O)O)[C@H]1C[C@@H](C(=O)O)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of cis-2-methoxycarbonyl-2-(3-methoxycarbonylcyclobutyl)-3-(9-anthracenyl)propanoic acid (0.15 g, 0.36 mmol), dry triethylamine (37 mg, 0.37 mmol) and diphenylphosphonic azide (103 mg, 0.37 mmol) in dry toluene (5 ml) was heated with stirring at 100° C. under a nitrogen atmosphere for 5 hours. Work up and chromatography eluting with hexane-diethyl ether (17:8) as described in Example 16 (v) gave the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1([C:9]2[C:10](F)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:33]>CN1C(=O)CCC1>[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][C:10]2[C:9]([C:3]3([CH:2]([F:16])[F:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Fc1ncccc1C1(C(F)F)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2ncccc2C2(C(F)F)CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 175 °C

Procedure:
To a solution of 3-(4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)-2-fluoropyridine (0.1 g, 0.432 mmol) in NMP was added cesium carbonate (0.282 g, 0.865 mmol) and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.155 g, 0.649 mmol). The resulting mixture was heated to 175° C. overnight. Purification by prep-plate TLC (5% MeOH/DCM & 75% EtOAc/hexane) produced product. MS (ESI, pos. ion) m/z: 450 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].[CH3:22][Mg]Br>C(Cl)Cl>[CH3:4][C:2]([S:5]([NH:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)=[CH:13][CH:14]=1)[CH3:22])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Oc2cncnc2)cc1
Solvent: ClCCl
Product: C[C@H](NS(=O)C(C)(C)C)c1ccc(Oc2cncnc2)cc1
Temperature: -20 °C

Procedure:
A solution of (R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide (830 mg, 2.74 mmol) in DCM (6.72 mL) was cooled to −40° C. To the solution was added methylmagnesium bromide (3M in diethylether; 1.81 mL) dropwise over 10 min. Additional DCM (5 mL) were added to retain stirring. The yellow suspension was stirred at −40° C. for ˜30 min while warming to −20° C. The mixture was cooled to −40° C. and additional methylmagnesium bromide (3M in diethylether; 1.8 mL) was added. The suspension was stirred for ˜3 hour while slowly warming to −20° C. The mixture was cooled to ˜−40° C., and additional methylmagnesium bromide (3M in diethylether; 0.4 mL) was added. The suspension was stirred for 30 min and allowed to warm to −10° C. The mixture was quenched slowly over 10 min with saturated aqueous NH4Cl solution (10 mL). The mixture was diluted with saturated aqueous NH4Cl solution (30 mL) and water (15 mL). The separated aqueous phase was extract with DCM (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified by column chouromatography [SiO2, 40 g, heptane/ethyl acetate followed by 5% MeOH in EtOAc] providing 2-methyl-N—((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)propane-2-sulfinamide (55 mg; purity ˜87%) as an off-white solid. LCMS m/z 320.0 (M+H)+, Rt 0.69 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([NH:15][C@H:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C1CCCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:15]([CH:12]([CH3:13])[CH3:14])[C@H:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC[C@@H](NC(C)C)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
2,4-Dichloro-5-nitro-pyrimidine (19.90 g, 103 mmol) was dissolved in 300 mL of cyclohexane followed by the addition of methyl (2R)-2-(isopropylamino)butanoate 22a (16.40 g, 103 mmol) and sodium bicarbonate (36.61 g, 412 mmol). The reaction solution was heated to 80° C., stirred for 4 hours and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 22b (20.50 g, yield: 62.8%) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[NH:11]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:12]([C:30](N(OC)C)=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[Li]C1SC=CN=1.Cl.C1C[O:53]CC1>>[NH:11]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[C@H:12]([C:30]([OH:53])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:20])=[O:21].[S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Agent: [Li]c1nccs1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) at −78° C. is added n-BuLi (1.6 M in hexane, 19 mL) dropwise. The mixture is stirred for 30 minutes. Then a solution of Boc-Arg(Tos)-N(Me)OMe, from Example 1, (1.7 g, 3.6 mmol) in THF (50 mL) is added to the lithiothiazole mixture at —78° C. The solution is stirred for 2 hours. 1M HCl (30 mL) is added to the reaction mixture and warmed to room temperature. The mixture is extracted with EtOAc (100 mL). The organic layer is washed with sat. NaCl (30 mL), dried over MgSO4, filtered and evaporated. The crude oily residue is purified by flash column over SiO2 (50% EtOAc in CH2Cl2) to give Boc-Arg(Tos)-Thiazole, shown above, (1.5 g, 84% yield) as a powder. DCI-MS (M+H)+=496
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH2:15][S:16][CH3:17])=[C:13]([CH3:18])[N:12]=[C:7]12.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH2:15][S:16]([CH3:17])=[O:27])=[C:13]([CH3:18])[N:12]=[C:7]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1c(C)nc2c3cccc(Cl)c3ccn12
Solvent: ClC(Cl)Cl
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CS(C)=O
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of 7-chloro-2-methyl-3-methylthiomethylimidazo[2,1-a]isoquinoline (2 g) in chloroform (20 ml) was added portionwise 70% m-chloroperbenzoic acid (1.78 g). After being stirred under ice cooling for 30 minutes, the mixture was washed successively with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, treated with activated charcoal and evaporated in vacuo. The residue was purified by column chromatography on silica gel (25 g) with a mixture of chloroform and methanol (50:1) as an eluent to afford a solid. This solid was recrystallized from ethanol to give 7-chloro-2-methyl-3-methylsulfinylmethylimidazo[2,1-a]isoquinoline (1.36 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:12][C:11]2=[O:21])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:22](OCC)(OCC)OCC>>[CH3:9][C:6]1[C:7]2[NH:8][CH:22]=[N:1][C:2]=2[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:12][C:11]2=[O:21])[CH:5]=1
Reactant: Cc1cc(N2C(=O)OC[C@@H]2c2ccccc2)cc(N)c1N
Reactant: CCOC(OCC)OCC
Product: Cc1cc(N2C(=O)OC[C@@H]2c2ccccc2)cc2nc[nH]c12

Procedure:
The (S)-3-(3,4-diamino-5-methylphenyl)-4-phenyloxazolidin-2-one was dissolved in triethyl orthoformate and was refluxed for 30 minutes. After cooling the excess of triethyl orthoformate was removed under reduced pressure. The final product was purified via FPLC using a chloroform-methanol gradient (0→10%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: Fc1ccccc1Br
Reactant: Nc1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Fc1ccccc1Nc1ccccc1F

Procedure:
A Schlenk flask was charged with 2-fluoroaniline (5.55 g, 50 mmol), 1-bromo-2-fluorobenzene (8.75 g, 50 mmol), Pd(OAc)2 (0.020 g, 0.089 mmol, 0.5% equiv), DPEPhos (0.216 g, 0.401 mmol, 0.75% equiv), NaOtBu (7.185 g, 74.84 mmol, 1.4 equiv), and toluene (45 mL) under nitrogen. The reaction mixture was heated to reflux with stirring. The reaction was monitored by GC, which showed complete formation of the desired product in 1 d. After being cooled to room temperature, the reaction was quenched with deionized water (45 mL). The organic portion was separated from the aqueous layer, which was further extracted with toluene (10 mL×2). The combined organic solution was dried over MgSO4 and filtered. All volatiles were removed in vacuo to yield red oil, which was directly used for the subsequent reaction; yield 9.38 g (91.4%). 1H NMR (CDCl3, 500 MHz) δ 7.42 (m, 2, Ar), 7.25 (m, 2, Ar), 7.20 (m, 2, Ar), 7.04 (m, 2, Ar), 6.03 (br s, 1, NH). 19F NMR (CDCl3, 470.5 MHz) δ-133.07. 13C NMR (CDCl3, 125 MHz) δ 153.45 (JCF=241, CF), 130.45 (JCF=11.75, CN), 124.14 (JCF=3.63, CH), 121.38 (JCF=7.25, CH), 117.98 (CH), 115.45 (JCF=19.00, CH). LR-MS (EI): calcd. for C12H9F2N m/z 205, found m/z 205. Anal. Calcd. for C12H9F2N: C, 70.24; H, 4.42; N, 6.83. Found: C, 70.13; H, 4.52; N, 6.69.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16](OCC)=[O:17])=[CH:14][CH:13]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(OCc2cc3ccccc3o2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
Compound 93 (400 mg, 1.29 mmol) was dissolved in THF (15 mL) and LiAlH4 (49 mg, 1.29 mmol) was added portionwise, with vigorous stirring. The suspension was stirred at room temperature for 1 h. THF was evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). EtOAc was evaporated off in-vacuo to obtain (4-(benzofuran-2-ylmethoxy)phenyl)methanol (220 mg, 67%) as a crude product. This was dissolved in toluene (10 mL). The solution was cooled to 0° C. PBr3 (98 μL, 1.04 mmol) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 1 h. It was then washed with saturated K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain 2-((4-(bromomethyl)phenoxy)methyl)benzofuran as a colourless oil, (132 mg). This intermediate was used in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[S:32](Cl)(=[O:34])=[O:33])[CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:32]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[N:22]=[CH:23][CH:24]=[CH:25]4)(=[O:33])=[O:34])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(-c2c[nH]c3ccccc23)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(-c2cn(S(=O)(=O)c3cccc4cccnc34)c3ccccc23)cc1OC
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-indole 22 (70 mg, 0.28 mmol) was dissolved in methylene chloride (5.0 mL). Tetra-N-butylammonium bromide (3 mg, 0.01 mmol) and aqueous potassium hydroxide (50% wt/vol, 500 μL) were added. The reaction mixture was stirred for 5 minutes. 8-quinoline-sulfonyl chloride (89.5 mg, 0.39 mmol) was added and the reaction mixture was stirred for 2 hours. The product was extracted with 2 N lithium hydroxide and methylene chloride. The organic portion was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by flash chromatography (ethyl acetate:hexanes 0%-50%). The appropriate fractions were combined and concentrated to provide 21, (76.1 mg, 90%). MS(ESI) [M+H+]+=445.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][CH:10]([C:11](OC)=[O:12])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>O1CCCC1.O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:11][OH:12])[CH2:15][CH2:16]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCN(c2ccncc2)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
1-(4-Pyridyl)piperidine-4-methanol was prepared using a procedure similar to the following: A solution of methyl N-(4-pyridyl)isonipecotate (600 mg, 2.72 mmol) in tetrahydrofuran was added to a solution of lithium aluminum hydride (100 mg) in tetrahydrofuran (14 mL) cooled to 0° C. upon consumption of the starting material (0.5-2 h), the mixture was treated with water (0.10 mL), 15% aqueous sodium hydroxide (0.10 mL), and water (0.30 mL). After 0.25 h, the mixture was sonicated for 0.25 h, then poured into a mixture of ethyl acetate, water, sodium tartrate, and potassium tartrate. The aqueous layer was extracted twice with ethyl acetate and the combined extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo to yield 357 mg (68%) of 1-(4-pyridyl)piperidine-4-methanol, which was used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@H:2]1[C:11]([N:13]1[CH2:20][CH2:19][C@:18]2([CH3:23])[C@@H:21]([CH3:22])[C@H:14]1[CH2:15][C:16]1[CH:27]=[CH:26][C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][C:17]=12)=[O:12]>CO.C(OCC)(=O)C.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@H:2]1[C:11]([N:13]1[CH2:20][CH2:19][C@:18]2([CH3:23])[C@@H:21]([CH3:22])[C@H:14]1[CH2:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=12)=[O:12]
Reactant: C[C@H]1[C@H]2Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3[C@]1(C)CCN2C(=O)[C@@H]1COc2ccccc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1[C@H]2Cc3ccccc3[C@]1(C)CCN2C(=O)[C@@H]1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Pd/C (0.10 g) is added to a solution of (2R,6R,11R)-trifluoro-methanesulfonic acid 3-[(S)-2,3-dihydro-benzo[1,4]dioxine-2-carbonyl]-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester (0.50 g) in methanol (15 mL) and ethyl acetate (25 mL). The resulting mixture is shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst is separated by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O) to give the product as a colorless gum-like solid.