Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]3[N:14]([CH2:15][C:16]4([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:38][C:8]1[C:7]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCBPA (21 g of about 50% pure material, 61 mmol) was added to a solution of 1-{[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclopentanol (18.89 g, 46.6 mmol) in chloroform (190 mL), and the reaction was stirred for one hour at room temperature. Additional mCPBA (11 g) was added, and the reaction was stirred for an additional 30 minutes. Concentrated ammonium hydroxide (40 mL) was added slowly followed by p-toluenesulfonyl chloride (9.32 g, 48.9 mmol). The reaction was stirred for one hour at room temperature, and additional chloroform (600 mL) was added. The reaction was stirred for one additional hour, and additional p-toluenesulfonyl chloride (4.45 g, 23.3 mmol) and ammonium hydroxide (10 mL) were added. After the reaction mixture was stirred for an additional 1.5 hours, it was filtered to remove a precipitate. The filtrate layers were separated, and the organic phase was washed with saturated aqueous sodium bicarbonate (2×200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue (25.86 g) was triturated with acetonitrile at 98° C., and a solid impurity was removed by filtration. The acetonitrile was removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed with 1% aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 98.5:1.5 chloroform:methanol) and then triturated with acetonitrile at 98° C., isolated by filtration at room temperature, and dried in a vacuum oven at 110° C. over two nights to provide 4.83 g of 1-{[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclopentanol as a white solid, mp 166-167.5° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]([F:31])([C:20]([F:30])([F:29])[C:21]([F:28])([F:27])[C:22](OCC)=[O:23])[C:15](OCC)=[O:16].[H-].[Na+]>C(Cl)Cl.O.CCCCCC>[CH2:1]([N:8]1[C:22](=[O:23])[C:21]([F:27])([F:28])[C:20]([F:29])([F:30])[C:14]([F:31])([F:13])[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)C(=O)OCC
Reactant: NCc1ccccc1
Agent: C[Al](C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: O=C1N(Cc2ccccc2)C(=O)C(F)(F)C(F)(F)C1(F)F
Reaction time: 0.17 h

Procedure:
Dissolve 3.4 mmol of benzylamine in 12 mL of methylene chloride and cool in an ice/water bath under argon. Add 4.1 mmol of trimethylaluminum as a 2 M hexane solution dropwise during several minutes. Stir for 10 min, then add 3.4 mmol of the product of Example 7 as a solution in 4 mL of methylene chloride. Remove ice bath and stir for 2 h at room temperature, then heat under reflux for 3 h. Cool in an ice/water bath and cautiously decompose excess trimethylaluminum with water. Partition the reaction mixture between 30 mL each of ether and water and wash the organic layer with 1N HCl, saturated sodium bicarbonate, and brine, then dry over MgSO4 and concentrate in vacuo. Dissolve the residue in 2 mL of DMF and add to a slurry of 3.5 mmol of sodium hydride (washed with hexane twice to remove mineral oil) and 4 mL of DMF under argon. Stir for 16 h at room temperature. Cautiously decompose excess sodium hydride with several drops of water and partition the mixture between ethyl acetate and water. Extract the aqueous layer twice with more ethyl acetate, then wash the combined organic layers with 1N HCl, saturated sodium bicarbonate, and brine. Dry over MgSO4 and concentrate in vacuo. Purify the residue by silica gel chromatography using ethyl acetate/hexanes eluant to yield the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23](=[O:31])[C@@H:22]3[CH2:32][CH2:33][C@H:34]([O:42][Si](C(C)(C)C)(C)C)[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.F.[OH-].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:41][C:38]1[CH:37]=[CH:36][C:35]([C@@H:34]([OH:42])[CH2:33][CH2:32][C@@H:22]2[C@@H:21]([C:18]3[CH:19]=[CH:20][C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=4)=[CH:16][CH:17]=3)[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]2=[O:31])=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Agent: *CC(*)C
Agent: F
Agent: O=C([O-])O
Solvent: CC#N
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)cc2)N1c1ccccc1
Reaction time: 8 h

Procedure:
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one was synthesized in a manner similar to that described in Example 42. (3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.60 g, 0.86 mmol) was stirred at room temperature in acetonitrile (18 mL) in a 40 ml polypropylene vial fitted with a screw cap. Hydrogen fluoride (48% aqueous, 2.0 mL, 48 mmol) was dripped in and stirring was continued at room temperature overnight. The reaction mixture was poured into an aqueous solution of 1 N sodium hydroxide (45 mL) buffered with 1 M sodium phosphate (45 mL, pH 7.4), then the pH of the solution was brought to pH 8 with the addition of aqueous 10% sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the organic solution was washed successively with 10% sodium bicarbonate solution (2×), water (2×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one was obtained as a white foam (0.35 g, 87%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 10% ethyl acetate to 60%) 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.2, Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.0-7.3 (m, 12H), 6.80-6.86 (m, 1H), 5.00 (br s, 1H), 4.74 (t, J=6.2 Hz, 1H), 4.69 (d, J=2.2 Hz, 1H), 3.1-3.2 (m, 1H), 2.20 (br s, 1H), 1.8-2.1 (m, 4H) ppm; MS [M+HCO2−]− 512.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[BrH:12].N([O-])=O.[Na+].[OH-].[K+]>O.[Cu]>[Br:12][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Br
Reactant: Nc1cccc2cnccc12
Agent: [Cu]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Brc1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48% aqueous HBr (65 mL) at −78° C. for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 min at −78° C., the mixture was warmed to 0° C. Copper powder (0.3 g) was added very slowly to avoid excessive foaming. After addition was completed, the reaction vessel was fitted with a reflux condensor and the mixture was heated to 100° C. for 4 h. The mixture was poured onto ice (ca. 200 g) and was made basic (pH=10) with KOH. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, were dried (MgSO4), were filtered, and were concentrated in vacuo. Purification by silica gel chromatography (10:1 hexanes-ethyl acetate) afforded 3.8 g (53% yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 8.57 (d, J=6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/CI): 208.0, 210.0 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:48])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH2:25][CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C)[C:15]=3[Cl:47])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:49]>CO.O1CCOCC1>[ClH:47].[ClH:49].[C:1]12([CH2:11][NH:12][C:13](=[O:48])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:36][CH2:37][CH2:38][OH:39])[C:15]=3[Cl:47])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)[Si](C)(C)OCCCN(CCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl)CCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(NCCCN(CCCO)CCCO)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(1-adamantylmethyl)-2-({3-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)amino]-propyl}amino)3-chloroisonicotinamide (Example 36(iii)) in methanol (5 ml) was treated with HCl in 1,4-dioxane (3 ml). The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated. The product was purified by reverse phase HPLC, using NH3/H2O/CH3CN as eluant. The resulting oil in methanol was treated with ethereal HCl and the solvent was evaporated to yield the title compound as a white solid (0.14 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4](=[CH:7][CH2:8][CH:9]1[CH2:14][CH:13]2[C:11]([CH3:15])([CH2:12]2)[C:10]1([CH3:17])[CH3:16])[CH:5]=[O:6].CC(C)=O>O.C(O)C>[CH3:3][C:4](=[CH:7][CH2:8][CH:9]1[CH2:14][CH:13]2[C:11]([CH3:15])([CH2:12]2)[C:10]1([CH3:17])[CH3:16])[CH2:5][OH:6]
Reactant: CC(C=O)=CCC1CC2CC2(C)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: CC(=CCC1CC2CC2(C)C1(C)C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
0.5 g (10 mmol) of sodium borohydride dissolved in 5 ml of water was added portionwise to the solution of 5.0 g (24 mmol) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal in 20 ml of ethanol maintained at 0° C. Stirring was continued for 1 hour at 0-5° C., then acetone was added to destroy the excess of hydride. The reaction mixture was poured on 100 ml of water, extracted with 2×100 ml of ether, dried (MgSO4) and evaporated in vacuo. Kugelrohr distillation of the residue at 160° C./0.1 Torr gave 4.5 g (90% yield) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-en-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(O)cn1
Reactant: COc1ccc(CO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(OC)nc2)cc1

Procedure:
According to Scheme 32 Method B: To a mixture of 2-methoxy-5-hydroxypyridine (2.87 mmol, 0.36 g), 4-methoxybenzyl alcohol (5.75 mmol, 0.72 mL) and PPh3 (5.29 mmol, 1.4 g) in THF (3.75 mL) cooled with an ice-water bath, was added dropwise DEAD (5.47 mmol, 0.86 ml). The resulting mixture was irradiated under microwave conditions at 90° C. for 30 minutes. The resulting reaction mixture was cooled, washed with a 1 N NaOH solution and extracted with AcOEt. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue triturated with diisopropyl ether. The precipitated obtained (PPh3O) was filtered off. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge heptane/CH2Cl2 80/20 yielding 2-methoxy-5-(4-methoxybenzyloxy)pyridine (339 mg, 48%).
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][C:26]1[CH:30]=[C:29]([CH2:31][NH:32]C(OC(C)(C)C)=O)[O:28][N:27]=1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:29]1[O:28][N:27]=[C:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cc1cc(CN)on1)c1csc(N)n1)C(=O)O
Yield: 22.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert butoxycarbonyl)amino)methyl)isoxazol-3-yl)methyl)-4-oxoazetidine-1-sulfonic acid (10.9 mg, 14 μmol), TFA (70 μl, 0.91 mmol), and DCM (0.2 mL). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 19×100 mm, 5 μM, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min) to afford the title compound (1.7 mg, 17%). LCMS: Rt=0.48 min, m/z=532.1 (M+1). Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 6.85 (s, 1H), 6.52 (s, 1H), 5.38 (d, J=5.6 Hz, 1H), 4.26 (s, 2H), 3.22 (dd, J=16.2, 7.1 Hz, 2H), 3.10 (dd, J=16.2, 6.0 Hz, 1H), 1.33 (s, 3H), 1.29 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCOC(=O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCOC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.0 g) and ethyl N-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinate (1.55 g) in 2-propanol (20 mL) was added piperidinium acetate (0.86 g). The reaction mixture was stirred at 70° C. for 2 hr and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (2.62 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[S:32][C:31]([NH2:33])=[N:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.O.C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:33][C:31]3[S:32][C:28]([O:27][CH3:26])=[CH:29][N:30]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: COc1cnc(N)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cnc(NC(=O)C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a mixture of 2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (0.1 g, 0.27 mmol), 5-methoxy-thiazol-2-ylamine (0.042 g, 0.33 mmol), HOBt (0.044 g, 0.33 mmol), and EDCI (0.062 g, 0.33 mmol), in DMF (10 mL), was added N-methyl morpholine (0.034 g, 0.33 mmom). The resulting mixture was stirred at room temperature overnight followed by dilution with DCM. The reaction mixture was poured into water; organic layer was washed with water, brine, dried over sodium sulfate, and the organic solvent evaporated to get a residue which was purified by column chromatoghaphy using 40-50% ethylacetate in hexane as eluent to provide the title compound (0.045 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N+](C1C=C[C:46]([O:49]C=O)=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[F:15][C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH:27]=4)[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH:46]=[O:49])[CH2:36][CH2:35]4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1CN1CCN(C=O)CC1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-methyl-3-piperazin-1-ylmethyl-phenyl)-amine (Example 332) with formic acid 4-nitro-phenyl ester in presence of triethylamine in THF. HPLC: tR=6.84 min (Method B); MS-ES: (M+H)+=562
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[C:3]=1C(OC)=O.Cl>O1CCOCC1.CCOC(C)=O>[OH:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: COC(=O)c1c(O)c(C)nn(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(=O)cc1O
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of methyl 5-hydroxy-2,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carboxylate (3.00 g, 15.1 mmol) and 6 N aqueous HCl (25 mL, 150 mmol) in dioxane (25 mL) was refluxed for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.74 g (35%) of the desired product. The aqueous layer was concentrated under reduced pressure. The resulting solid was diluted with water and EtOAc-THF. The organic layer was separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.80 g (37%) of the additional desired product. A total of 1.54 g (72%) of the desired product was obtained, which was used directly without further purification.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@:9]2([CH2:18]O)[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11](O)[C@@H:10]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24](O)[C:25]([NH2:30])(CO)CO>>[NH2:30][CH2:25][CH2:24][C:10]1[CH:9]=[CH:18][C:14]([OH:15])=[C:12]([OH:13])[CH:11]=1
Reactant: NC(CO)(CO)CO
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: NCCc1ccc(O)c(O)c1
Reaction time: 1.33 h

Procedure:
The pooled supernatant was underlayed with 16 mL of a 36 % sucrose solution prepared in 10 mM Tris (pH 9.0). The supernatant was then ultracentrifuged at 18,000 rpm in a Beckman SW28 rotor for 80 min at 4° C. to pellet recombinant virus. After ultracentrifugation, the supernatant was removed from the visible virus pellet by aspiration, and the pellet resuspended in 1.0-1.5 mL 10 mm Tris (pH 9.0). This suspension was dounced about 7 times on ice to provide a suspension having a milky, even consistency. The recombinant virus suspension was then transferred in 20-40μL aliquots to 2 mL plastic screw-capped FALCON tubes, titred and stored at -70° C. Typical virus stocks prepared in this way were found to have viral titres of about 1010 pfu/mL.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1nc(-c2c(-c3ccccc3)noc2C)c[nH]1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(C)n1
Yield: 36 %

Procedure:
As described for Example 57, 5-methyl-4-(2-methyl-1H-imidazol-4-yl)-3-phenyl-isoxazole (70 mg, 0.3 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (38 mg, 36%) which was obtained as an off-white solid. MS: m/e=361.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=2)[CH:3]=1.[Br:18]Br.O>C(Cl)(Cl)Cl.CS(C)=O>[Br:18][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:15]([OH:17])=[O:16])=[CH:6][CH:5]=2)[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: BrBr
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc2c(Br)c(O)c(C(=O)O)cc2c1
Reaction time: 1 h
Yield: 97 %

Procedure:
2-Hydroxy-3,6-di-hydroxycarbonylnaphthalene (11.8 g) was dissolved in chloroform (300 g) and dimethyl sulfoxide (100 g), followed by ice-cooling. Then, a solution of bromine (8.0 g) and chloroform (50 g) was added dropwise at not more than 5° C. over 2 hours. After continuously stirring for 1 hour, this solution was poured into water (1500 g) dropwise. The deposit was filtered and then washed with water and dispersed in a small amount of methanol. The dispersion was concentrated under reduced pressure at room temperature and then dried under vacuum to obtain 15.1 g of 1-bromo-2-hydroxy-3,6-di-hydroxycarbonylnaphthalene as a whitish brown crystal (DSC analysis value: 145.2° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=O.Cl.[NH2:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1C=CC=CC=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]([NH:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])=[O:9]
Reactant: CCc1ccc(C=CC(=O)O)cc1Cl
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1ccc(C=CC(=O)NN2CC(=O)NC2=O)cc1Cl

Procedure:
3-Chloro-4-ethylcinnamic acid (50 g, 0.24 mole) in SOCl2 (100 ml) was heated under reflux for about 1 hour. The excess SOCl2 was removed in vacuo and the residue flushed with benzene. The acid chloride was treated with 1-aminohydantoin hydrochloride (40 g, 0.26 mole) and pyridine (300 ml) and the reaction mixture heated on a steam bath for 4 hours. The reaction mixture was poured onto HCl/ice to precipitate the product. (40 g, 55%). Several recrystallizations from CH3NO2 provided analytical material which melted at 231°-234°.