Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[N:37]=[CH:38][N:39]([CH3:41])[CH:40]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[N:37]=[CH:38][N:39]([CH3:41])[CH:40]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)c1
Agent: Cl
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4[nH]cnc34)c2F)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-imidazole-4-sulfonamide (15 mg, 0.026 mmol) prepared at Step 8 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 11 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-1-methyl-1H-imidazole-4-sulfonamide (percentage yield: 88%), was obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]=[C:7]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:11]([CH:9]1[CH2:8][C:7](=[O:6])[CH2:10]1)=[O:13]
Reactant: CNOC
Reactant: O=C1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.054 mol), and 3-oxocyclobutanecarboxylic acid (4.0 g, 0.035 mol) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 0.052 mol), 1-hydroxybenzotriazole (7.1 g, 0.052 mol) followed by triethylamine (34 mL, 0.24 mol) at 0° C. The mixture was stirred at rt over night, then quenched with water. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex) to give the desired product (4.3 g, 78%) as light yellow oil. LCMS calculated for C7H12NO3(M+H)+: 158.1. Found: 158.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]([C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:14])[C:9](OCC)=[O:10].O.[OH-].[Na+]>C1COCC1>[NH2:7][C:8]([C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)([CH3:14])[CH2:9][OH:10]
Reactant: CCOC(=O)C(C)(N)c1ncccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(CO)c1ncccn1
Reaction time: 7 h
Yield: 44.6 %

Procedure:
To a mixture of 4 mg of lithium aluminum hydride and 0.2 ml of THF was added dropwise a solution of 20 mg of ethyl 2-amino-2-(pyrimidin-2-yl)propanoate in 0.2 ml of THF at 0° C. solution, followed by stirring at the same temperature for 7 hours. 2.5 mg of lithium aluminum hydride was added thereto, followed by stirring at 0° C. for 1 hour. 32 μl of water, 32 μl of a 15% aqueous sodium hydroxide solution, and 96 μl of water were sequentially added thereto at 0° C. The insoluble materials of the reaction mixture were filtered over Celite and washed with ethyl acetate, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7 mg of 2-amino-2-(pyrimidin-2-yl)propan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:55])[N:7]([C:20]1[N:21]([C:30]2[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([O:39]CC3C=CC=CC=3)=[CH:32][C:31]=2[O:47]CC2C=CC=CC=2)[N:22]=[N:23][C:24]=1[C:25](=[O:29])[NH:26][CH2:27][CH3:28])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:55])[N:7]([C:20]1[N:21]([C:30]2[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[C:33]([OH:39])=[CH:32][C:31]=2[OH:47])[N:22]=[N:23][C:24]=1[C:25](=[O:29])[NH:26][CH2:27][CH3:28])[C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1

Procedure:
Intermediate obtained from Step C was hydrogenated for 1 hour in EtOH (5 ml) in the presence of Pd(OH)2/C (0.015 mmol). The catalyst was filtered off through Celite® pad and ethanol was removed under reduced pressure. The crude reaction mixture was used in the next reaction without any purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[N:11][C:10]=1[C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:43]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:24]([C:10]1[N:11]=[C:12]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:25])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CN(C)C(=O)c1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carboxylic acid (210 mg, 0.6 mmol), NEt3 (175 μl, 1.25 mmol), and CH2Cl2 (12 ml) cooled with an ice bath was added ClCO2iBu (83 μl, 0.63 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (127 mg, 0.63 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a slightly yellowish gum (211 mg); MS-(+)-ion: M+1=498.1.
Reaction SMILES: [CH2:1]([N:3]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:18]([O-])=O)[CH:14]=2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2]>C(O)C.[Pd]>[NH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]([CH2:1][CH3:2])[C:16]2=[O:17]
Reactant: CCn1c(=O)c2cc([N+](=O)[O-])ccc2c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)c2cc(N)ccc2c2ccccc21
Reaction time: 3 h
Yield: 83.9 %

Procedure:
A solution of 5-ethyl-8-nitro-5H-phenanthridin-6-one I-16b (100 mg, 0.37 mmol) in ethyl alcohol (25 ml) was charged with 10% palladium on activated carbon (25 mg). The resultant suspension was placed on a Parr hydrogenation apparatus and shaken under 50 psi H2 for 3 hours. The catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuo to afford 8-amino-5-ethyl-5H-phenanthridin-6-one I-16c (74 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]#[N:22].[OH-:23].[Na+].OO>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: [OH-]
Reactant: Cc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: ClCCl
Product: Cc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.7 g (12.37 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-3methyl-1H-pyrazole-4-carbonitrile and 950 mg of tetrabutylammonium hydrogen sulphate are dissolved in 25 ml of CH2Cl2, 5.5 ml of 5M NaOH and 7 ml of 30% strength H2O2 are added, and the mixture is stirred for 15 hours at room temperature. The phases are separated, the organic phase is extracted twice with water, the organic phase is dried over Na2SO4, and the solvent is removed in vacuo. Yield: 3.24 g (83%), Rf=0.11 (petroleum ether/ethyl acetate=1:1)
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:47][N:48]([CH2:50][CH:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C@H:58]([NH:66][CH3:67])[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:53][CH2:52]1)[CH3:49].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[N:66]([C@H:58]([CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:57]([N:54]1[CH2:55][CH2:56][CH:51]([CH2:50][N:48]([CH3:49])[CH3:47])[CH2:52][CH2:53]1)=[O:68])[CH3:67])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (416 mg, 2.17 mmol) was added to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionic acid (715 mg, 2.17 mmol) and 1-hydroxy-7-azabenzotriazole (296 mg, 2.17 mmol) in dichloromethane (20 ml) and N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)-1-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(methylamino)-3-phenylpropan-1-one (659 mg, 2.17 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.56 ml, 3.26 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml). The aqueous solution was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane/triethylamine (1:1:0.08) as eluent, to give 1.05 g of N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]#[N:25])[CH:11]=1)[CH3:9])(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH:8]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[N:25])[CH3:9].[ClH:23]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(Oc2ccc(Cl)cc2C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1cccc(Oc2ccc(Cl)cc2C#N)c1
Reaction time: 2 h

Procedure:
The tert-butyl{1-[3-(4-chloro-2-cyanophenoxy)phenyl]ethyl}carbamate (0.040 g) was taken up in 4 M HCl in dioxane (3 mL) at r.t. and was stirred for 2 h. The reaction was concentrated under reduced pressure, taken up in acetonitrile and re-concentrated under reduced pressure two times to give crude 2-[3-(1-aminoethyl)phenoxy]-5-chlorobenzonitrile as HCl salt (0.045 g) as a semisolid residue. Analytical LCMS (M+H)+: m/z=272.9.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][C@H:38]1[CH2:40][O:39]1>C(O)(C)C.CO>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:37][C@@H:38]([OH:39])[CH3:40])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: C[C@H]1CO1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 29.3 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol) (Example 1, step 7, chiral intermediate from peak 1) and triethylamine (20 μL, 0.1 mmol) in isopropyl alcohol (0.10 mL) was added (S)-(−)-methyloxirane (3.2 μL, 0.046 mmol). The resulting mixture was stirred at 90° C. After 90 min, additional (S)-(−)-methyloxirane (6.4 uL) was added and stirred at 90° C. overnight. After cooling, the mixture was diluted with methanol and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6 mg (30%) of the product. The product was isolated as a single diastereomer. LCMS calculated for C22H30 ClN6O2 (M+H)+: m/z=445.2; Found: 445.2.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].[Cl:16]C1C=CC(O)=CC=1C>>[Cl:16][C:13]1[CH:14]=[CH:2][C:3]([O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])=[CH:11][C:12]=1[CH3:15]
Reactant: COC(=O)[C@H](C)Oc1cc(C)ccc1Cl
Reactant: Cc1cc(O)ccc1Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(C)c1

Procedure:
The title compound was prepared following the same general protocol as described for the synthesis of the (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate (Step 1, Example 55), using the 4-chloro-3-methylphenol instead of the 2-chloro-5-methylphenol.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[CH:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22]>C(O)C>[C:1]([O:9][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[CH:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC=C(C(=O)OC)c1ccccc1COC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
12.2 g (0.1 mole) of benzoic acid and 5.6 g (0.1 mole) of potassium hydroxide are dissolved in 150 ml of ethanol and the solution is stirred for 2 hours at room temperature (20° C.). The white precipitate which separates out is filtered off under suction, washed with diethyl ether and suspended in 300 ml of dimethylformamide. Thereafter, 28.5 g (0.1 mole) of methyl alpha-(2-bromomethylphenyl)-β-methoxyacrylate are added. The reaction mixture is then stirred for 24 hours at room temperature, after which it is evaporated down and the residue is taken up in methylene chloride. The organic phase is washed with water, dried over MgSO4 and evaporated down. The oil obtained is chromatographed over silica gel using 10:1 cyclohexane/ethyl acetate. 25.4 g (78%) of the title compound are obtained as a colorless, viscous oil (compound No. 83).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.BrC1C=CC(Cl)=NC=1.O>CS(C)=O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Clc1ccnc2ccccc12
Agent: Clc1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 0.25 h
Yield: 68 %

Procedure:
N-Boc-L-Tyrosine (0.844 g, 3 mmol) and KOBu-t (0.727 g, 6.5 mmol) are dissolved in dry DMSO (2.9 mL) under argon atmosphere in a tightly closed glass reaction tube and stirred for 15 min, then 4-chloroquinoline (0.491 g, 3 mmol) is added. The mixture is stirred for 6 days at 30° C. When only traces of 5-bromo-2-chloropyridine are detected (LC-MS control), the reaction mixture is poured into water (40 mL) and the aqueous phase is washed with diethyl ether (2×20 mL). The pH of aqueous phase is adjusted to ˜4 by adding 20% aqueous citric acid. The product precipitated is collected on filter and washed with water (50 mL) to give the title compound (0.833 g, 68%) as a grey solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20]B(O)O.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH3:20][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1Cl
Reactant: CB(O)O
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: O
Solvent: C1COCCO1
Product: Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
In a sealed tube, dissolve 6-chloro-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carbonitrile (242 mg, 0.853 mmol), CH3B(OH)2 (300 mg, 5.10 mmol), K2CO3 (1.6 g, 12 mmol), and Pd(PPh3)4 in a solution of dioxane (10 mL) and H2O (2 mL). Bubble argon through the mixture for 30 minutes and seal. Heat the mixture at 115° C. overnight. Cool the mixture to room temperature. Add H2O (20 mL) and extract with EtOAc (3×20 mL). Combine the organic extracts and wash with brine (60 mL). Dry the organic layer over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with EtOAc/hexane (1:1) to yield the title compound. MS 264.07 (M+1).
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH2:3][CH:2]1[OH:6].B(F)(F)F.CCOCC.[CH:17]12[O:22][CH:18]1[CH2:19][CH2:20][CH2:21]2.[OH-].[Na+]>>[OH:6][CH:2]1[CH2:3][CH2:4][CH2:5][CH:1]1[O:7][CH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[OH:22]
Reactant: C1CC2OC2C1
Reactant: OC1CCCC1O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OC1CCCC1OC1CCCC1O

Procedure:
A 1-liter, three neck, round bottom flask equipped with magnetic stirrer, internal thermometer, addition funnel, condenser, argon supply, and heating mantle, is flushed with argon. Then 1,2-cyclopentanediol (about 306 g, about 3 moles, Aldrich) is added and boron trifluoride diethyl etherate (about 0.14 g, about 0.01 moles, cis-trans isomer mixture, Aldrich) is added. Then the reaction mixture is held at about 10-40° C. as cyclopentene oxide (about 84 g. about 1 mole, Aldrich) is added dropwise with stirring until all the cyclopentene oxide has reacted. The reaction mixture is neutralized with sodium hydroxide, and the liquid is fractionally distilled under vacuum to recover the excess cyclopentanediol. The desired ether is obtained as a residue. Optionally, it is purified by further vacuum distillation.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:52]=[N:51][C:23]2[N:24](S(C3C=CC=CC=3)(=O)=O)[C:25]3[C:30]([C:22]=2[CH:21]=1)=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:27][CH:26]=3>C1COCC1>[Cl:19][C:20]1[CH:52]=[N:51][C:23]2[NH:24][C:25]3[C:30]([C:22]=2[CH:21]=1)=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:27][CH:26]=3
Reactant: O=C(NCCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCCc1ccc2[nH]c3ncc(Cl)cc3c2c1)c1ccccc1
Yield: 61 %

Procedure:
At room temperature and under inert atmosphere, 1.0 M TBAF in THF (310 μL, 5 equiv.) was added a solution of 17 (30 mg, 0.061 mmol) in anhydrous THF (2.5 mL). The solution was refluxed for 2 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×10 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to afford R265 in 61% yield. 1H-NMR (300 MHz, DMSO-d6): δ 11.91 (bs, 1H), 8.65 (d, 1H, J=2.3 Hz), 8.61 (bt, 1H, J=5.5 Hz), 8.39 (d, 1H, J=2.3 Hz), 8.07 (bs, 1H), 7.82 (d, 1H, J=7.5 Hz), 7.54-7.37 (m, 5H), 3.55 (q, 2H, J=7.7 Hz), 2.98 (t, 2H, J=7.7 Hz); MS (ESI) m/z 350.2 [M+H+], 698.9 [2M+H+], 721.0 [2M+Na+], HRMS (ESI): Calcd for C20H16ClN3O: 350.1060. Found: 350.10631.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:36]=[CH:35][C:27]([O:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[OH:34])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:36]=[CH:35][C:27]([O:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[OH:34])=[CH:26][CH:25]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@@H]4CCC[C@H]4O)cc3)cc12
Temperature: 90 °C
Yield: 90.7 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (92.6 mg, 0.288 mmol) and (±)-trans-2-(4-bromophenoxy)-cyclopentanol (37 mg, 0.14 mmol) in ethanol (0.2 mL), toluene (0.3 mL), and 2 M aqueous potassium carbonate (0.288 mL, 0.576 mmol) was sealed in a microwave vial and degassed with nitrogen for 10 minutes. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.2 mg, 0.014 mmol) was added, and the reaction mixture was resealed and heated to 90° C. in an oil bath for 1 hour. The reaction mixture was cooled to room temperature and poured into 0.5 N HCl (10 mL). The product was extracted with ethyl acetate (3×10 mL), and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using silica gel chromatography (4:1 to 1:4 heptane/ethyl acetate) to give the title compound (49 mg, 88%) as a white solid. MS (ES−) 384.2 (M−H)−. 1H NMR (500 MHz, CD3OD) δ 8.00 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H), 4.57 (br. s., 1H), 4.26 (br. s., 1H), 3.87 (s, 3H), 2.25-2.15 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 3H), 1.72-1.62 (m, 1H).