Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-])=O)=[C:9]([F:14])[CH:8]=[C:7]([Cl:15])[C:5]=2[N:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:11][C:10]1[C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[C:7]([Cl:15])=[CH:8][C:9]=1[F:14]
Reactant: O=[N+]([O-])c1c(F)cc(Cl)c2nc(Cl)sc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1c(F)cc(Cl)c2nc(Cl)sc12

Procedure:
5 g Iron powder was added to 40 ml 5% aqueous acetic acid. The mixture was heated to reflux and a solution of 5 g 2,4-dichloro-6-fluoro-7-nitrobenzothiazole in 40 ml acetic acid and 40 ml ethyl acetate was added. The mixture was heated for 2 hours under reflux and after cooling the mixture was filtered over celite, the phases separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and water and dried with magnesium sulfate. Yield: 4.3 g=97% of theory m.p.: 173° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
In Ar atmosphere, (R)-5-(azidomethyl)-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (3 g, 8.3 mmol) was dissolved in THF (20 mL) solution, and was added with PPh3 (2.2 g, 8.3 mmol) and p-TsOH (3.2 g, 16.6 mmol). The mixture was agitated at a room temperature for 4 hours, and the solid was filtered and washed with THF, to obtain p-toluenenesulfonic acid salt of (S)-5-(aminomethyl)-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (1.5 g, 54%). The product was used for subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2Cl)cc1
Reactant: N#CCc1ccc(F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4Cl)cc23)cc1

Procedure:
The title compound, green solid (53 mg, 41%), MS (ISP) m/z=390.2 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 1 from 1-(2-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate L) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[C:14]([NH:21][CH2:22][CH2:23][NH2:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][CH2:23][NH:24][C:5](=[O:7])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[NH:2][CH3:8])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCN
Product: CNc1ccccc1C(=O)NCCNC(=O)OC(C)(C)C

Procedure:
Starting from N-methylisatoic anhydride and N-Boc-ethylenediamine and using Procedure S, the title compound was obtained as a slightly brown solid (903 mg; quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH:18]([OH:23])[C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(O)C(C)(C)C)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 1-(2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanone T9.6 (2.00 g, 6.3 mmol) in THF (63 mL, 6.3 mmol) at 0° C. was added LAH (1.0 M in THF, 13 mL, 13 mmol). Stirring was continued for 2 hours. 1N NaOH (aq) was added to the mixture, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the residue. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to afford 1-(2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanol T9.7 (1.50 g, 75% yield) as a white solid. MS ESI (pos.) m/e: 336.2 (M+H2O)+. Chiral separation of T9.7 was accomplished on Chiracel-OD (4% IPA in hexane) to provide T9.8 and T9.9. Analytical column (Chiracel-OD (4% IPA in hexane, 45 min run) peak 1—18.5 mins, peak 2—24.5 mins).1
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OC)=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH3:17])[C:6]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.C(O)(=O)C.Br.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.C(Cl)Cl.N1C=CC=CC=1>[CH3:39][C:29]1[CH:30]=[CH:31][C:32]([S:35]([O:38][C:11]2[CH:12]=[CH:13][C:14]3[C:9](=[CH:8][C:7]([CH3:17])=[C:6]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:5]=3[OH:4])[CH:10]=2)(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: COc1ccc2c(OC(C)=O)c(-c3ccccc3)c(C)cc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Oc2ccc3c(O)c(-c4ccccc4)c(C)cc3c2)cc1
Yield: 89 %

Procedure:
A round-bottomed flask was charged with 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl acetate (6) (5.00 g, 16.34 mmol), acetic acid (100 mL) and 48% aqueous HBr (50 mL). The resultant mixture was stirred between 90° C. and 100° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with sat. NaHCO3 (100 mL). The aqueous reaction mixture was extracted with CH2Cl2 (4×150 mL). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford ˜4.10 g (86%) the crude title product. To a solution of the above obtained crude product (˜1.00 g) in CHCl3 (50 mL) were added pyridine (1 mL), p-toluene sulfonic acid (2 equiv). The resultant mixture was stirred at RT for 36 h. Reaction mixture was diluted with CH2Cl2 (250 mL), washed with 10% aqueous HCl, brine (1×50 mL), and dried (Na2SO4). The organic layer was concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography to afford 850 mg (89%) of the title compound (239). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J=9.2 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.54 (dd, J1=7.6 Hz, 2H), 7.47 (d, J=7.2 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.30 (dd, J1=6.4 Hz, J2=6.4 Hz, 4H), 7.22 (br s, 1H), 6.98 and 6.96 (dd, J1=9.2 Hz, J2=2.0 Hz, 1H), 5.25 (s, 1H), 2.44 (s, 3H), 2.16 (s, 3H). LCMS (ESI) m/z 405.22 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:25]=[CH:24][C:11]2[N:12]([N:22]=O)[CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][O:15][C:10]=2[CH:9]=1>C(OCC)C.C1COCC1.CCCCCC>[CH3:7][C:8]1[CH:25]=[CH:24][C:11]2[N:12]([NH2:22])[CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)N2N=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)OCC(c1ccccc1)N2N
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A slurry of lithium aluminum hydride (6.9 g, 183 mmol) in ethyl ether (300 mL) is stirred in an ice bath under an argon atmosphere. A solution of 7-methyl4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (23.22 g, 91.3 mmol) in ethyl ether (250 mL) and dry THF (40 mL) is added dropwise over 1.5 h. The mixture is removed from the ice bath and allowed to stir for 18 h. Water (50 mL) is slowly added, forming solids. The solids are collected by filtration and washed with ethyl ether. The resulting filtrates are combined and washed three times with water (400 mL), dried over magnesium sulfate, and concentrated to dryness to give a solid. The solids are slurried in hexane, collected, and dried to give 16.5 g (69%) of 7-methyl-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([Cl:15])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1nc(O)cc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Nc1nc(O)c(Cl)c(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To 1.87 g. (10 mM) of 2-amino-6-phenyl-4-pyrimidinol is added 50 ml. of glacial acetic acid and 1.46 g. (11 mM) of N-chlorosuccinimide. The mixture is heated with magnetic stirring under nitrogen at 90° C. for 2 hours (solution was complete in less than 20 minutes). The heat is removed and the amber solution is allowed to cool to room temperature. The solution is evaporated to a volume of 10 ml under vacuum, cooled to 20° C. and filtered. The resulting solids are washed successively with CH3COOH (5 ml.), water (50 ml.), acetone (100 ml.) and diethyl ether (100 ml.). The solids are dried at 60° C. in a vacuum oven to yield 1.40 g. (63%) of title compound. The solids can be recrystallized from ethanol:DMF by adding DMF to a hot, ethanol slurry of the pyrimidine until solution is complete. Cooling the solution at 5° C. for 18 hours chloro-6-phenyl-4-pyrimidinol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:12]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])=[N:11]1.[C:45](Cl)(=[O:49])[CH2:46][CH2:47][CH3:48].C(OCC)(=O)C>C(#N)C>[C:45]([O:15][C:14]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[C:13]=1[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)(=[O:49])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cncn2)c1
Reactant: CCCC(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2nn(-c3c(Cl)cc(Cl)cc3Cl)c(OC(=O)CCC)c2-n2cncn2)c1
Temperature: 25 °C

Procedure:
20 g of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-tetradecanamidoanilino)-4-(1,2,4-triazol-1-yl)-5-oxo-2-pyrazoline (prepared by the method described in U.S. Pat. No. 4,076,533) was suspended in 100 ml of acetonitrile and 3.7 g of butanoyl chloride was added to the mixture, followed by refluxing for 3 hours. After cooling to room temperature, 500 ml of ethyl acetate was added to the reaction mixture and washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and benzene, 16 g of Coupler (1) was obtained. The melting point of the coupler was 89° to 95° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F-:15].[K+]>[Br-].C[N+](C)(C)C>[F:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: [F-]
Agent: C[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Temperature: 165 °C

Procedure:
A mixture of 22.6 parts of 4-chloro-3-nitrobenzotrifluoride, 9.3 parts of potassium fluoride, and 1.4 parts of tetramethylammonium bromide catalyst was heated and maintained at about 165.0° C. for about 9 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was distilled under reduced pressure to yield 161 parts of 4-fluoro-3-nitrobenzotrifluoride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: Nc1ccc(F)cc1Nc1ccc(F)cn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-N2-(5-fluoropyridin-2-yl)benzene-1,2-diamine (30 mg, 0.136 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (28 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) in DCM (5 mL) was stirred at 0° C. for 1 h. Additional (S)-2-tertbutoxycarbonylaminopropionic acid (5 mg), HOAt (4 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5 mg) were added and stirring continued for 30 min. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo to afford {(S)-1-[4-fluoro-2-(5-fluoropyridin-2-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester as an orange oil. LCMS (Method C): RT 3.51 min [M+H]+ 393.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[O:32][CH3:33]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[O:32][CH3:33])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1coc(-c2ccc(N)c(OC)c2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2OC)nc1Cl
Yield: 85.6 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (2 mL), methyl 2-(4-amino-3-methoxyphenyl)-1,3-oxazole-4-carboxylate obtained in Example (102d) (0.25 g, 1.01 mmol) and pyridine (5 mL), to obtain 0.26 g of the title compound as a colorless solid (86%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[H][H]>CO.[Pt](=O)=O>[NH2:24][C:3]1[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][CH2:6][NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
N-(3-Fluoro-2-nitrophenethyl)-1-benzylpiperidin-4-amine (800 mg, 2.238 mmol) was dissolved in methanol (30 mL). Platinum(IV) oxide (18.5 mg, 0.081 mmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 60 psi of hydrogen gas. Reaction shook at room temperature for 1 hour 20 minutes. Reaction was removed from the apparatus. Mixture was filtered through a 0.45 μm PVDF membrane. Filtrate was concentrated to dryness. Title compound was obtained as grey oil in 97% yield. MS (M+H)+=328.5.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]([C:16]3[CH:33]=[CH:32][C:19]([O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH2:23][CH2:24][CH2:25][C:26]5=[O:31])=[CH:18][CH:17]=3)=[C:14]3[C:9]([C:10]([C:34]([F:37])([F:36])[F:35])=[CH:11][CH:12]=[CH:13]3)=[N:8]2)=[C:4]([F:40])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]([C:16]3[CH:33]=[CH:32][C:19]([O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH2:23][CH2:24][CH2:25][CH:26]5[OH:31])=[CH:18][CH:17]=3)=[C:14]3[C:9]([C:10]([C:34]([F:36])([F:37])[F:35])=[CH:11][CH:12]=[CH:13]3)=[N:8]2)=[C:4]([F:40])[CH:3]=1
Reactant: O=C1CCCc2c(Oc3ccc(-c4c5cccc(C(F)(F)F)c5nn4Cc4ccc(Cl)cc4F)cc3)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2c(Oc3ccc(-c4c5cccc(C(F)(F)F)c5nn4Cc4ccc(Cl)cc4F)cc3)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-{4-[2-(4-chloro-2-fluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}-3,4-dihydronaphthalen-1(2H)-one (14 mg, 0.025 mmol) dissolved in 1.5 mL THF was added to a slurry of LiAlH4 in THF and stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O and stirred for 15 min. Filtration of the mixture was followed by extraction with CH2Cl2. The combined organic phases were dried, evaporated and the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 1.2 mg analytically pure product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:32][O:33]C(=O)C1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[N:18][C:17]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])=[N:18][C:17]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@]3(COC(=O)c4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of compound 14 (8.2 g, 14.7 mmol) in ethanol/pyridine (8:1, 450 mL) was added 2 M aqueous solution of NaOH (15.5 mL) and the mixture was stirred for 30 min at ambient temperature. Acetic acid (25 mL) was added to the reaction mixture and the solvents were removed under reduced pressure. The residue was crystallised from 20% aqueous ethanol to give 5.8 g (87%) of compound 15 as a white solid material. δH (DMSO-d6) 8.05 (1H, s, 8-H), 7.33-7.26 (5H, m, Bn), 5.85 (1H, s, 1′-H), 5.17 (1H, t, J 5.4, 5′-OH), 4.69 (1H, s, 2′-H), 4.64 (2H, s, Bn), 4.23 (1H, s, 3′-H), 3.95 (1H, d, J 7.9, 1″-H), 3.83 (2H, m, 5′-H), 3.80 (1H, d, J8.0, 1″-H), 2.78 (1H, m, CHCO), 1.12 (6H, m, CH3). δC (CDCl3) 180.2 (CHCO), 154.8, 148.2, 147.7 (guanine), 137.9, 136.3, (guanine, Bn), 128.3, 127.6, 127.5 (Bn), 120.5 (guanine), 88.2, 85.2, 76.9, 72.1, 71.3, 56.7 (ribose, Bn), 34.8 (CHCO), 18.9 (CH3CH).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O=[Si]=O.[F:15][C:16]1[CH:17]=[C:18]([CH:23]([OH:26])[CH2:24][CH3:25])[CH:19]=[CH:20][C:21]=1[F:22]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([C:23](=[O:26])[CH2:24][CH3:25])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCC(O)c1ccc(F)c(F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
In a round bottom flask containing pyridinium chlorochromate (12.5 g, 58.1 mmol) was added celite 545 (25 g) and with the help of a magnetic stirrer the solids were mixed together. 200 mL of CH2Cl2 was added followed by a solution of 1-(3,4-difluoro-phenyl) propan-1-ol (5.0 g, 29.1 mmol) in 10 mL of CH2Cl2 and the resulting brown suspension was stirred overnight at room temperature. The suspension was filtered through a sintered glass funnel and the solvent was removed in vacuo from the pale green colored filtrate. The green oil was then diluted with diethyl ether (200 mL) and it was filtered through a pad of celite to remove the metal impurities. The solvent was removed in vacuo to obtain 1-(3,4-difluorophenyl)propan-1-one as a pale yellow oil (3.4 g, 69% yield). It was used in the next step without purification.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:19]=[C:20]([NH:24][C@H:25]([C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:26]([CH3:28])[CH3:27])[CH:21]=[N:22][CH:23]=3)=[CH:16][N:15]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:12]2=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:19]=[C:20]([NH:24][C@H:25]([C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:26]([CH3:28])[CH3:27])[CH:21]=[N:22][CH:23]=3)=[CH:16][N:15]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:12]2=[N:13][CH:14]=1
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(NCc4ccccc4)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 22 h

Procedure:
To a solution of N2-{5-[5-(benzylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}-N-(2,2,2-trifluoroethyl)valinamide 5-1a (1.03 g, 1.643 mmol) in MeOH (4 mL) purged with nitrogen (3×) was added palladium hydroxide on carbon (0.540 mg, 0.769 μmol) added and mixture hydrogenated 1 atm for 22 h. The reaction was filtered over Celite and the residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water (0.1% TFA), to give product 5-1b. The combined product fractions were basified with NaHCO3, dried over MgSO4, filtered and concentrated. MS APCI: [M+H]+ m/z=537.0.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:6]=O.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][N:17]=[N+:18]=[N-:19])[CH3:13].[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:20])/[C:16](/[N:17]=[N+:18]=[N-:19])=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:3]([F:2])[CH:4]=1)[CH3:13]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1ccc(C=O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/c1ccc(C)c(F)c1)N=[N+]=[N-]
Yield: 54.6 %

Procedure:
To ethanol (200 ml) was added portionwise 6.7 g sodium metal in such a way that the temperature stayed below 50° C. After all sodium had dissolved, the temperature was brought to −5° C. and a solution of 3-fluoro-4-methylbenzaldehyde (10.0 g, 0.072 mol) and azido acetic acid ethyl ester (37.4 g, 0.29 mol) in 100 ml ethanol was added while maintaining the temperature below 5° C. After 3 h the orange-red solution was poured on saturated aqueous ammonium chloride solution and ethyl acetate (300 ml) and water (100 ml) was added. The phases were separated, the aqueous phase was reextracted three times with ethyl acetate (300 ml each) and the combined organic layers were washed with brine (400 ml) and dried over magnesium sulfate. The crude reaction product was purified by column chromatography over silical gel (0.030-0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent to yield the title product as a yellow oil (9.8 g, 54.2%). EI-MS: m/e=249.1 (M)