Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:8]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:3][CH2:4][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:8]1
Reactant: CCOC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reaction time: 6 h
Yield: 45.5 %

Procedure:
A suspension of 1-ethoxycarbonylmethyl-3-(1-imidazolylmethyl)indole (1.42 g) in dry tetrahydrofuran (30 ml) was added portionwise to a stirred suspension of lithium aluminium hydride (0.19 g) in dry nitrogen. The mixture was heated under reflux with stirring for 6 hours, and then cooled and a further 0.19 g of lithium aluminium hydride was added. The mixture was heated under reflux with stirring for a further period of 3 hours and then cooled. Water (0.4 ml) was added cautiously with stirring and cooling followed by 5 N sodium hydroxide solution (0.4 ml) and a further 1.2 ml of water. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel, eluting with a mixture of chloroform and methanol (20:1) to give a solid. Crystallisation from ethyl acetate/petrol (b.p. 60°-80° C.) gave 1-(2-hydroxyethyl)-3-(1-imidazolylmethyl)indole, (0.55 g), m.p. 134°-135° C. Found: C, 69.75; H, 6.25; N, 17.46. C14H15N3O requires: C, 69.69; H, 6.27; N, 17.42%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[C:27]1(C)C=CC=CC=1.C(OC(OCC)OCC)C>C(O)(C)C.[Pt]>[N:14]1([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:27]1
Reactant: O=C(NCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Reactant: Cc1ccccc1
Agent: [Pt]
Solvent: CCOC(OCC)OCC
Solvent: CC(C)O
Product: O=C(NCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of N1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (1.0 g, 2.8 mmol) in isopropyl alcohol (120 mL) was warmed to dissolve some of the material. A catalytic amount of platinum on carbon was added and the reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After 3 hours the reaction mixture was filtered to remove catalyst. The filtrate was concentrated under vacuum to provide crude N1-{3-[(3-aminoquinolin-4-yl)amino]propyl}benzamide as an oil. Toluene (100 mL) was added to the oil followed by the addition of triethylorthoformate (0.8 g, 5.6 mmol). The reaction mixture was heated on a steam bath overnight. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 0.53 g of N1-[3-(1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as an off white solid, m.p. 188-190° C. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (t, J=5.5 Hz, 1H), 8.50 (s, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.17 (dd, J=8.0, 1.5 Hz, 11H), 7.87 (d, J=7.0 Hz, 2H), 7.71 (dt, J=7.5, 1.5 Hz, 11H), 7.56 (dt, J=7.5, 1.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.0 Hz, 2H), 4.78 (t, J=7.0 Hz, 2H), 3.38 (q, J=6.0 Hz, 2H), 2.18 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1.[K].[CH2:17](Br)[CH:18]=[CH2:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH2:19][CH:18]=[CH2:17])[C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)F
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: C=CCn1c(C(F)(F)F)c(C(=O)OCC)sc1=O
Reaction time: 2 h

Procedure:
10 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-5-thiazolcarboxylate (CA Vol. 92 110 998P), 200 ml of toluene, 2.6 g of potassium in pastilles, 6 ml of allyl bromide and 2.8 g of tetrabutylammonium bromide were heated at 90° C. for 3 hours and the mixture was allowed to return to ambient temperature followed by stirring for 2 hours. The mixture was washed with a N sodium hydroxide solution, with a N hydrochloric acid solution, with water and with a saturated sodium chloride solution. Drying, filtering and concentrating were carried out and the residue was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (9-1) to obtain 8.65 g of the expected product with a Rf=0.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:18][Si](C)(C)C)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[OH:18][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(C(O[Si](C)(C)C)C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C(O)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
30 g (0.091 mol) of 2-(4-methoxyphenyl)-1-phenyl-2-trimethylsilanyloxy-ethanone prepared in Step 2 was added to 50 mL of an aqueous 90% trifluoroacetic acid solution and the resulting reaction solution was stirred at room temperature for 2 hours. An ice bath was placed and the resulting reaction solution was neutralized with addition of sodium carbonate. Then, 200 mL of ethyl acetate and 100 mL of water were added to dilute the solution, followed by separation of layers. The obtained organic layer was washed twice with 100 mL of a saturated sodium bicarbonate solution and then successively washed twice with 100 mL of a brine solution. The organic layer thus obtained was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 17.25 g of a final product which was then recrystallized from ethyl acetate and hexane, to give 14.38 g (yield: 65%) of pure 2-hydroxy-2-(4-methoxyphenyl)-1-phenyl-ethanone.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20].C(=O)([O-])[O-].[K+].[K+].[O:28]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:36]=2)=[CH:10][C:5]=1[CH2:4][C:3]([OH:2])=[O:21]
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)Cc1cc(O)ccc1Nc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C(O)Cc1cc(OCc2cccc(Oc3ccccc3)c2)ccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A mixture of 2-[(2,6-dichlorophenyl)amino]-5-hydroxy benzene acetic acid methyl ester (2.5 g, 7.67 mmol) of Example 2F, powdered anhydrous potassium carbonate (0.55 g, 4 mmol), tetrabutylammonium iodide (0.050 g) and dry acetonitrile (50 mL) is stirred at room temperature under nitrogen for 30 min. To the slurry is then added 3-phenoxybenzylchloride (2 g, 9.17 mmol) and the mixture is placed in an oil bath maintained at 65°-70° C. overnight. The solvent is removed and the residue partitioned between water and ethyl acetate (50 mL each). The organic phase is washed with brine and dried (Na2SO4). The solvent is evaporated and the residue (brown oil, 4.2 g) is purified by flash chromatography (on silica Merck 60, hexane-ethyl acetate 85:15) to give the title product (yellow oil, 2.83 g, 73%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:6]=1.O>C(O)C>[Cl:4][C:5]1[N:10]=[C:9]([NH:3][CH2:1][CH3:2])[N:8]=[C:7]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:6]=1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCNc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 12 h

Procedure:
15 g of a 70% aqueous ethylamine solution is added to 28.9 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (prepared according to Example 1) in 250 ml of ethanol at room temperature. The temperature climbs rapidly to about 35°. The mixture is subsequently stirred at 55° for 12 hours, 25 ml of water are added and the mixture is cooled to 5°. The resulting precipitate is filtered off, washed with 200 ml of water and dried. 2-Chloro-4-ethylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained by crystallization from acetonitrile as colorless crystals having a melting point of 148°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O>O1CCOCC1.[Cu]I.O>[CH3:29][O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A suspension of 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3, 50 mg), methyl-4-hydroxyphenylacetate (26 mg), cesium carbonate (68 mg), copper(I)iodide (2 mg) and N,N-dimethylglycine hydrochloride (4.5 mg) in dioxane (0.5 ml) was heated to 120° C. for 10 min under microwave conditions. The reaction was not finished. The reaction mixture was placed in a heating bath and stirred at 70° C. for 16 h and at 90° C. for 4 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic phase was washed with water, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (23 mg) as an off-white solid. MS (m/e)=564 [M+H+].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:33][C:31]1([CH3:34])[C:30]([CH3:35])([CH3:36])[O:29][B:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][O:13][C:11]3[C:10]4[C:5](=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:12]=3)=[CH:27][CH:26]=2)[O:32]1
Reactant: Oc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Step 2A [Intermediate 4, G9591-157-1]: To a solution of 2,8-Bis-trifluoromethyl-quinolin-4-ol (3.85 g, 13.7 mmol, 1.1 equiv.) in DMF (40 mL) was added 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.7 g, 12.5 mmol, 1.0 equiv.) and K2CO3 (3.45 g, 24.92 mmol, 2.2 equiv.) under N2 atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction was complete as determined by TLC. The reaction mixture was poured into cold water, the white precipitate formed was collected by filtration, washed with water, dried under vacuum to yield 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-2,8-bis-trifluoromethyl-quinoline in 73% yield (4.95 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]#N)=N[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Br.O.S(=O)(=O)(O)O.[O:26]1CC[CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:15][C:10]=1[C:27](=[O:26])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncccc1OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 3-benzyloxypicolinonitrile (2.50 g, 11.9 mmmol) in tetrahydrofuran (100 mL) was added dropwise 0.92M methyl magnesium bromide in tetrahydrofuran (150 mL, 138 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hrs. The reaction mixture was poured into water (2000 mL) and acidified with 10% sulfuric acid (500 mL). After being stirred for 30 min, the reaction mixture was poured into saturate aqueous NaHCO3 solution slowly and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtrated, and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/3) to give 1-(2-benzyloxy-phenyl)-ethanone as a colorless oil (2.49 g, yield; 92%).
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([O:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:14]([O:21][CH3:22])[CH:15]=1)(=[O:18])[CH3:5]
Reactant: COc1cc(C=O)ccc1OC1CCCC1
Reactant: CI
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of methyl magnesium iodide, which is prepared from magnesium (2.9 g) and methyl iodide (7.5 ml), in diethyl ether (150 ml) is added dropwise a solution of 4-cyclopentyloxy-3-methoxybenzaldehyde (17.6 g) in tetrahydrofuran (40 ml) at 0° C., and the mixture is stirred at room temperature for one hour. To the reaction mixture is added a saturated aqueous ammonium chloride solution (20 ml) at 0° C., and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure, and the residue is dissolved in acetonitrile (300 ml), and thereto is added manganese dioxide (55 g) at 0° C. The mixture is warmed to room temperature, and the mixture is stirred for three days. To the reaction mixture is added cerite (20 g), and the mixture is stirred for 30 minutes. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from chilled hexane to give 4-acetyl-1-cyclopentyloxy-2-methoxybenzene (13.8 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[F:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([F:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 78.1 %

Procedure:
To a solution of [(S)-2-methyl-1-((2S,4S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (170 mg, 0.33 mmol) and (R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (192 mg, 0.33 mmol, Preparation 24) dissolved in toluene (2.1 mL) and water (0.8 mL) was added potassium carbonate (230 mg, 1.67 mmol). The reaction mixture was sparged with nitrogen, Pd(dppf)Cl2CH2Cl2 (25 mg, 0.03 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to RT, filtered through a pad of Celite® and silica gel and washed with EtOAc. The filtrate was washed with water and brine to produce a brownish colored oil. The residue was purified by silica gel chromatography (24 g, 40% to 100% EtOAc/hexanes) to produce the title intermediate as a yellowish solid (227 mg, 78% yield). (m/z): [M+H]+ calcd for C44H52F4N8O7 881.39. found 881.4.
Reaction SMILES: C([C:3]1[C:4]([F:17])=[C:5]([CH:9]=[C:10]([O:15][CH3:16])[C:11]=1[N+:12]([O-])=O)[C:6]([OH:8])=[O:7])C.CC(O)=O>CO>[NH2:12][C:11]1[C:10]([O:15][CH3:16])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:17])[CH:3]=1
Reactant: CCc1c(F)c(C(=O)O)cc(OC)c1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(F)cc1N

Procedure:
A solution of ethyl 2-fluoro-5-methoxy-4-nitrobenzoic acid (217 mg, 1 mmol), HOAc (cat.) and MeOH (10 mL) was hydrogenated using H-cube hydrogenator. The solution was then concentrated and dried to give the product which can be used for next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 5.88 (br s, 2H) 6.36 (d, J=16 Hz, 1H) 7.13 (d, J=8 Hz, 1H) 12.32 (br s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C2C(=CC=C([C:32]([F:35])([F:34])[F:33])C=2)N=CC=1C(OCC)=O.C1(NN)C=CC=CC=1>>[C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:32]([F:35])([F:34])[F:33])=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Cl
Solvent: NNc1ccccc1
Product: O=c1c2c[nH]c3ccc(C(F)(F)F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 of the synthesis of 4a, using 3h and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm):7.21 (1H, m), 7.42 (2H, t, J=7.56 Hz), 7.97 (1H, d, J=2.20 Hz), 8.00 (1H, d, J=2.20 Hz), 8.20 (1H, ddd, J=7.41, 1.10, 0.83 Hz), 8.43 (2H, dd, J=1.33, 0.83 Hz), 8.82 (1H, s). m/z 330.2 (MH+).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([CH3:45])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:21]1[N:22]=[CH:23][N:24]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]=1)=[O:20])[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:45][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:19]([C:21]3[N:22]=[CH:23][N:24]([C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:25]=3)=[O:20])=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[OH:8]
Reactant: Cc1c(O[Si](C)(C)C(C)(C)C)ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(O)ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
(6-tert-Butyldimethylsilyloxy-5-methyl-2-naphthyl)(1-trityl-1H-imidazol-4-yl)methanone (30.0 g) was dissolved in THF (200 mL) and tetrabutylammonium fluoride (14.9 g) was added. The mixture was stirred at room temperature for 18 hrs. and the solvent was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with diisopropyl ether and dried to give the title compound (22.4 g) as pale-orange crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH2:30][C:31]#[N:32])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Method A, Step 5 of Example 1, the title compound was prepared from 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (0.600 g, 1.74 mmol), sodium hydride (0.106 g, 2.65 mmol of a 60% dispersion on mineral oil) and bromoacetonitrile (0.18 mL, 2.6 mmol) in DMF (10 mL). Purification by flash chromatography using 60-80% chloroform in hexane as an eluant afforded a thick yellow oil (0.359 g). 1HNMR (200 MHz, DMSO-d6): δ8.45 (s, 1H), 8.0-8.2 (m, 3H), 7.85-7.95 (m, 1H), 7.7-7.8 (m, 1H), 7.65 (d, 1H, J=2.0 Hz), 7.35-7.5 (m, 1H), 5.35 (s, 2H), 2.75 (t, 2H, J=7.4 Hz), 1.45-1.65 (m, 2H), 1.05-1.25 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH:1]1([CH2:4]O)[CH2:3][CH2:2]1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[CH:1]1([CH2:4][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OCC1CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 354.4 %

Procedure:
To a mixture of cyclopropylmethanol (7.15 mL, 90 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (6.30 g, 27.1 mmol) and triphenylphosphine (28.5 g, 109 mmol) in THF (100 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (25 g, 109 mmol) in portions at ambient temperature. The reaction mixture was concentrated and allowed to stand overnight. The white solid (PPh3O) precipitated was filtered off and the filtrate was purified by flash chromatography (silica gel, EtOAc in Hexane in 5-25% gradient) to yield 27.5 g (96%) of the title compound.