Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]OS([O-])=O.[K+].CO.[CH3:9][S:10]([C:12]1[CH:13]=[C:14]([N:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21](=[O:30])[C:20]([CH3:31])=[C:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=[CH:16][CH:17]=1)=[O:11]>O>[CH3:9][S:10]([C:12]1[CH:13]=[C:14]([N:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21](=[O:30])[C:20]([CH3:31])=[C:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:1])=[O:11]
Reactant: O=S([O-])OO
Reactant: Cc1c(-c2ccccc2)n(-c2cccc(S(C)=O)c2)c(-c2ccccc2)cc1=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccccc2)n(-c2cccc(S(C)(=O)=O)c2)c(-c2ccccc2)cc1=O
Reaction time: 2 h
Yield: 74.1 %

Procedure:
In 5 ml of water was dissolved 1.2 g (0.0019 mole) of Oxone. The resulting solution was then added dropwise to 5 ml of a methanol solution of 0.5 g (0.0013 mole) of 1-(3-methanesulfinylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone. After stirring the reaction mixture for 2 hours, it was poured into water, followed by extraction with chloroform. The organic layer was washed with water and was thereafter dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was crystallized form a 2:1 mixed solvent of acetone and hexane, affording 0.4 g of 1-(3-methanesulfonylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 246°-248° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c2ccc3ccccc3c2N1
Yield: 40.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), and 4-(trifluoromethyl)benzoyl chloride (16 mg, 0.077 mmol), the title compound (10 mg, yield 41%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C@@H:14]1([OH:20])[CH2:18][CH2:17][CH2:16][C@H:15]1[OH:19]>CN(C=O)C>[O:19]([C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[OH:20])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@@H]1CCC[C@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of t-butyldimethylsilyl chloride (5.08 g, 33.7 mmol) and imidazole (2.30 g, 33.7 mmol) in DMF (10 mL), a solution of trans-1,2-cyclopentanediol in DMF (4 mL) was added. The reaction mixture was stirred overnight at 25° C. The reaction mixture was diluted with ice water and extracted with ether. The ether extract was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 9:1 hexane:ethyl acetate) to the title compound as an oil (3.44 g, 49%).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzophenone imine (100 g, 0.54 mol), and 78.4 g, 0.56 mol) ethyl glycinate hydrochloride are combined in 2 L of dichloromethane and stirred overnight at room temperature. A precipitate (ammonium chloride) is filtered and the solution washed with water, dried over magnesium sulfate, and concentrated. The residual oil is dissolved in 200 mL of boiling diethyl ether, cooled to room temperature, and diluted with 600 mL of hexane. Some seed crystals from a previous experiment are added and the mixture cooled at +2° C. overnight. A white crystalline precipitate is collected and the mother liquor is concentrated to one-half of the volume, cooled overnight as above. This affords a second crop of product. The total yield is 133.0 g of the title compound; mp 52°-54° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]([NH2:22])=O)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]#[N:22])=[CH:18][N:19]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cnc(C(=O)CCCCCCc2ccccc2)o1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cnc(C(=O)CCCCCCc2ccccc2)o1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-(7-Phenylheptanoyl)oxazole-5-carboxamide (35 mg, 0.117 mmol) was dissolved in 1,4-dioxane (3 mL) and pyridine (2.5 equiv) and trifluoroacetic anhydride (1.3 equiv) were added. The reaction mixture stirred for 2 h at 23° C. The mixture was diluted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude nitrile, which was purified by flash chromatography (2-20% EtOAc/hexanes) to afford the title compound as a clear oil: 1H NMR (CDCl3, 600 MHz) δ 7.84 (s, 1H), 7.28-7.25 (m, 2H), 7.18-7.16 (m, 3H), 3.07 (t, 2H, J=7.8 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.77-1.72 (m, 2H), 1.65-1.60 (m, 2H), 1.41-1.37 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 188.1, 159.5, 143.4, 139.0, 129.3, 129.1, 127.3, 126.5, 109.1, 40.5, 36.7, 32.1, 29.8, 29.7, 24.3; MALDI-FTMS m/z 281.1293 (M+H−, C17H17N2O2, requires 281.1295).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(F)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.120 g, 0.30 mmol) and EtOH (5 mL), was added p-anisaldehyde (0.045 g, 0.33 mmol) in EtOH (1.8 mL), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.9 mL, 0.9 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.010 g, 7%); 1H-NMR (500 Mz, DMSO-d6): δ 2.60 (m, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2), 3.65 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 7.10 (d, J=7.0 Hz, 2H, ArH, C6H4—OMe), 7.17 (br t, J=9.0 Hz, 2H, ArH, C6H4—F), 7.40 (br dd, J=8.5, 6.0 Hz, 2H, ArH, C6H4—F), 8.13 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.58 min—496/498 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 496.1144, calculated for C24H24BrFN5O (M+H)+: 496.1148.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@:9]3([CH3:49])[O:12][CH:13]=[CH:14][C@H:15]([O:47][CH3:48])[C@@H:16]([CH3:46])[C@@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:18]([CH3:41])[C@H:19]([OH:40])[C@H:20]([CH3:39])[C@@H:21]([OH:38])[C@@H:22]([CH3:37])[CH:23]=[CH:24][CH:25]=[C:26]([CH3:36])[C:27]([NH:29][C:30]4[C:34](=[O:35])[C:4](=[C:5]([C:32](=[O:33])[CH:31]=4)[C:6]=2[C:10]3=[O:11])[C:3]=1[OH:50])=[O:28].[CH3:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>O1CCOCC1.O>[CH3:37][C@@H:22]1[C@H:21]([OH:38])[C@@H:20]([CH3:39])[C@@H:19]([OH:40])[C@@H:18]([CH3:41])[C@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:16]([CH3:46])[C@@H:15]([O:47][CH3:48])[CH:14]=[CH:13][O:12][C@:9]2([CH3:49])[C:10](=[O:11])[C:6]3=[C:7]([O:8]2)[C:2]([CH3:1])=[C:3]([OH:50])[C:4]2=[C:5]3[C:32]([OH:33])=[C:31]([N:55]3[CH2:56][CH2:57][CH:52]([CH3:51])[CH2:53][CH2:54]3)[C:30](=[C:34]2[OH:35])[NH:29][C:27](=[O:28])[C:26]([CH3:36])=[CH:25][CH:24]=[CH:23]1
Reactant: CC1CCNCC1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(N5CCC(C)CC5)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(N5CCC(C)CC5)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Procedure:
A solution of 25 g (0.036 mol) of rifamycin S in 50 ml of dioxane is mixed with 20 ml (0.2 mol) of 4-methylpiperidine and left to stand at 20° C until the reaction mixture, which is initially deep violet in colour has assumed an orange-yellow colour. The reaction mixture is now diluted with water, acidified to pH 5 and extracted with chloroform. After drying and evaporating the chloroform extract, the evaporation residue is dissolved in methanol and mixed dropwise with concentrated ascorbic acid solution. After standing for some time yellow crystals separate out and are filtered off and twice recrystallised from 80 % strength aqueous methanol. 3-(4-methylpiperidino)-rifamycin SV is thus obtained in crystals of melting point 185°-186° C.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[C:27]([F:33])[CH:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:11][CH:12]=2)[CH2:4][O:3]1.C([O-])(=O)C.[NH4+:41].Cl>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[F:33][C:27]1[CH:26]=[C:25]([CH:17]([C:16]2[NH:41][C:13]([C:10]3[N:11]=[CH:12][C:7]([CH:5]([OH:6])[CH2:4][OH:3])=[CH:8][CH:9]=3)=[CH:14][CH:15]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:30]=[CH:29][C:28]=1[S:31][CH3:32]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C3COC(C)(C)O3)cn2)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-2-yl]-5-[3-fluoro-4-(methylsulfanyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (500 mg) in acetic acid (5 mL) was added ammonium acetate (1.20 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (400 mg). To a solution of the obtained crude product (400 mg) in tetrahydrofuran (5 mL) was added 1M hydrochloric acid (5 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (367 mg, quantitatively) as a pale-brown amorphous solid. MS: 457 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:16][CH2:15][CH2:14][C@@:11]3([O:13][CH2:12]3)[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][S:19][Na]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:16][CH2:15][CH2:14][C@@:11]([CH2:12][S:19][CH3:18])([OH:13])[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: CS[Na]
Reactant: Fc1cnc(Cl)nc1N[C@H]1CCC[C@]2(CO2)C1
Solvent: C1CCOC1
Product: CSC[C@@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-chloro-5-fluoro-N-((3R,5S)-1-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine, 49b, (0.10 g, 0.38 mmol) was dissolved in THF (2 mL). Methylsulfanylsodium (0.08 g, 1.15 mmol) was added to the reaction and the mixture was allowed to stir at room temperature for 3 hrs. An additional 36 mg portion of methylsulfanylsodium in THF (2 mL) was added and the reaction mixture was stirred overnight at room temperature. After LCMS showed starting material was still present, the reaction was warmed to 50° C. and stirred for 1 hr. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% Etoac/hexanes gradient). The product (contaminated with small amount of staring material) was carried on to the next step without further purification. LCMS RT=3.56 (M+1) 306.2.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21](Br)=[CH:20][N:19]=1.O>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[NH2:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[CH:20][N:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1

Procedure:
0.19 g of dichlorobis(tricyclohexylphosphine)palladium, 0.754 g of 4-tolyl-boronic acid and 12.5 ml of a 2N sodium carbonate solution are added to a solution of 0.93 g of 2-amino-5-bromo-3-nitropyridine in 20 ml of degassed dioxane. The mixture is heated to reflux under N2 for 2.5 hours and, after cooling and addition of water, extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated until a solid begins to precipitate. After addition of petroleum ether, the orange solid is isolated by suction, washed with petroleum ether and dried in vacuo. This gives 0.73 g of the title compound of m.p. 183–184° C. The mass spectrum shows the molecular peak MH+ at 230.1 Da.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)=[N:9][O:10][C:11]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:32][O:33][C:34](=[O:40])[C@@H:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>>[CH3:32][O:33][C:34](=[O:40])[C@@H:35]([NH:39][C:12]([C:11]1[O:10][N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])=[CH:17][CH:16]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14])[CH:36]([CH3:38])[CH3:37]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2noc(C(=O)O)c2-c2ccccc2)cc1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1onc(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1-c1ccccc1)C(C)C
Yield: 76.5 %

Procedure:
The title compound was prepared from 4-phenyl-3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 76.5% yield. 1H NMR (DMSO-d6) δ: 0.79 (m, 6H), 2.01 (m, 1H), 4.30 (m, 1H), 6.96 (t, 1H), 7.27 (t, 2H), 7.44 (d, 2H), 7.53 (m, 3H), 7.56 (d, 2H), 7.67 (d, 2H), 7:81 (m, 2H), 8.72 (s, 1H), 8.93 (s, 1H), 9.25 (d, 1H); Mass (ES+), 513 (M++1).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:3](=[O:10])[CH2:26][C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][CH:21]=1)=[O:27])[CH3:9]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 69.6 %

Procedure:
To a refluxing mixture of 7.0 g (175 mmol) of sodium hydride (NaH 60% dispersion in mineral oil) and 10.45 g (88.5 mmol) of diethyl carbonate (CO(OEt)2) in 100 mL of toluene was added dropwise via an addition funnel a mixture of 10 g (44.3 mmol) of 1-(4-benzyloxy-phenyl)-ethanone in 20 mL of toluene, and the resulting mixture was heated at reflux under argon for 1 h. The reaction mixture was then cooled to 0° C., quenched by the addition of 40 mL of acetic acid, during which time a yellow precipitate formed, and it dissolved upon subsequent addition of water. The separated organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated to give a residue which was chromatographed on silica gel (10% hexane in dichloromethane) to afford 9.2 g (70% yield) of desired 3-(4-benzyloxy-phenyl)-3-oxo-propionic acid ethyl ester as indicated by 1H NMR.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=O)C1C=CC=CC=1.CO>N>[CH:33]1([NH:32][C:28]2[N:27]=[CH:26][N:25]=[C:24]3[C:29]=2[N:30]=[CH:31][N:23]3[CH:13]2[O:12][C@H:11]([CH2:10][OH:9])[C:15]([CH3:16])([OH:17])[C@:14]2([F:22])[CH3:21])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCC4)ncnc32)[C@]1(C)F
Agent: N
Solvent: CO
Product: CC1(O)[C@@H](CO)OC(n2cnc3c(NC4CCCCC4)ncnc32)[C@]1(C)F
Yield: 86 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-5-(6-(cyclohexylamino)-9H-purin-9-yl)-4-fluoro-3,4-dimethyltetrahydrofuran-2-yl)methyl benzoate (about 0.32 g, 0.60 mmol) in methanolic ammonia (25% w/w 15 ml) was stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography and methanol was removed under reduced pressure then water added to the crude and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by silica gel column chromatography using 5% Methanol in dichloromethane to elude title compound (0.2 g) as a colorless solid. Yield: 86%; 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 7.93 (d, 1H, J=3.3 Hz), 6.60 (d, 1H, J=22.5 Hz), 5.79 (bs, 1H), 5.51 (s, 1H), 5.23 (bs, 1H), 4.25-4.13 (m, 3H), 2.17-2.04 (m, 1H), 1.76-1.52 (m, 16H); ES Mass: [M+1]+ 380 (100%), 381 (45%); IR cm−: 3338, 2928, 2854, 1624, 1475, 1226, 1062, 938, 740; HPLC: 97.8%.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:27].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][S:24]([CH3:23])(=[O:26])=[O:25])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 53.9 mg (470 μmol) methanesulfonic acid chloride are dissolved in 5 ml DMF under argon and while cooling with ice, 152 mg (1.18 mmol) N,N-diisopropylethylamine are added and the mixture is stirred overnight at RT. The reaction mixture is then purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6]C)=[O:5].[CH3:8][O:9][CH:10]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([O:13]C)=[O:12]>FC(F)(F)C(O)=O>[CH3:8][O:9][CH:10]([CH:15]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reactant: COC(=O)CCS
Solvent: O=C(O)C(F)(F)F
Product: COC(C(=O)O)C(SCCC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.17 h

Procedure:
To trifluoroacetic acid (100 ml) under argon and cooled to 0° C., was added methyl 3-mercaptopropanoate (0.5 ml, 4.5 mmoles). The mixture was stirred for 10 minutes, after which the ice bath was removed. Methyl 2-methoxy-3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (1.5 g, 4 mmoles) was added and the mixture stirred for 18 hours. The reaction mixture was evaporated and diluted in methylene chloride. The organic layer was washed with 10% sodium hydroxide (ice cold) followed by ice water. The organic layer was dried over magnesium sulfate, filtered and evaporated. Flash chromatography on silica gel provided the desired product.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].O[C:45]1[CH:46]=[N:47][C:48]2[C:53]([C:54]=1[CH:55]=O)=[CH:52][C:51]([O:57][CH3:58])=[CH:50][CH:49]=2.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>CN(C)C=O.C(OCC)(=O)C>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([CH2:39][C:40]2[C:41](=[O:43])[O:42][C:45]3[CH:46]=[N:47][C:48]4[C:53]([C:54]=3[CH:55]=2)=[CH:52][C:51]([O:57][CH3:58])=[CH:50][CH:49]=4)[CH2:37][CH2:38]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1ccc2ncc(O)c(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC(=O)O)CC1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc3oc(=O)c(C[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)cc3c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.04 g, 2.73 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-propionic acid (494 mg, 1.82 mmol, 1.0 eq) and 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde (370 mg, 1.82 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by 1,8-diazabicycloundec-7-ene (817 μL, 5.46 mmol, 3.0 eq). After 4 hours stirring at 50° C., solvent is evaporated and the residue is extracted with ethyl acetate (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1 to 2:1, v/v) to afford [trans-4-(6-methoxy-2-oxo-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester as a yellow solid (270 mg, 34% yield).