Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH2:15][N:16]2[CH2:21][CH:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[C:24]([O:31][CH3:32])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:33])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([O:31][CH3:32])[CH:23]=3)[CH2:20][CH2:21]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C2=CCN(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1N
Reaction time: 8 h

Procedure:
To a solution of 4-{2-[4-(3-Methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.54 mmol) in methanol (20 mL) was added 10% Palladium on Carbon (50% Wet, 58 mg, 0.027 mmol). The mixture was shaken in a Parr apparatus under an atmosphere of Hydrogen (50 PSI) overnight. Filtration through Celite and evaporation of the solvent provided crude 4-{2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Br:5].II>C1COCC1>[Br:5][CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: BrCc1ccccc1Br
Agent: II
Solvent: C1CCOC1
Product: Brc1ccccc1C(Br)Cc1ccccc1
Reaction time: 20 h
Yield: 38.2 %

Procedure:
200 g (0.8 mol) of 2-bromobenzylbromide and 800 ml of dry THF were placed in a 2 L round bottom flask equipped with mechanical stirrer. Keeping this mixture at 20° C., 9.8 g of Mg (0.4 mol) was added in small portions. The reaction was started with a trace of iodine and stirred for 20 h. Workup was done by decanting the organic layer from the salts and washing the salts with 4 portions of 50 ml THF. The organic layers were combined and concentrated in vacuo. The resulting solid was dissolved in 400 ml dichloromethane and washed with 400 ml 5% HCl and twice with 200 ml water. The organic layer was separated from the aqueous layer, dried with MgSO4, and concentrated in vacuo. Crystallization was done from ethanol. The product was isolated as white crystals (52 g). The remaining supernatant liquor was distilled to remove the starting material and by-products. The distilled product was crystallized from pentane and afforded an additional 12.6 g of product. Total product 64.6 g. Yield 48%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)[CH:8]=2)[N:3]1[C:21](=[O:23])[CH3:22].C(N(CC)C(C)C)(C)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>O1CCOCC1>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38]([N:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:12]3[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]3)[CH:8]=2)[N:3]([C:21](=[O:23])[CH3:22])[C@@H:2]([CH3:1])[CH2:11]1)=[O:39]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2NC[C@@H]1C
Reactant: O=C(Cl)c1ccco1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 50 °C
Yield: 66.5 %

Procedure:
A 100 mL round bottom flask fitted with a nitrogen inlet, and stir bar was charged with (S)-1-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.8 g, 2.53 mmol), 1,4-dioxane (30 ml), N,N-diisopropylethylamine (2.65 mL, 15.18 mmol) and furan-2-carbonyl chloride (0.991 g, 7.59 mmol). The reaction mixture was purged with nitrogen and heated to 50° C. for 2 h. The mixture was cooled to rt and diluted with ethyl acetate (100 mL). The mixture was then washed with brine (50 mL), and the organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 9:1 hexanes-ethyl acetate) to afford (S)-1-(4-(furan-2-carbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.69 g, 66% yield) as a colorless foam. MS (ESI, pos. ion) m/z 411 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[CH2:3]1.[CH3:15][C:16](OC(C)=O)=[O:17]>CCO.[Pd]>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:16](=[O:17])[CH3:15])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)CN(C)CC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A solution of isoquinoline 252 (2.5 g, 13.0 mmol) in EtOH (200 mL) was stirred with Pd/C (5%, 200 mg) under H2 (35 psi) for 4 h. The solution was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated. The residue was dissolved in dioxane (50 mL), Ac2O (2.7 mL, 28.6 mmol) was added and the solution stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×125 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give acetamide 253 (2.1 g, 77%) as a brown solid: mp 157-159° C.; 1H NMR δ 7.29 (br s, 1H, H-8), 7.27 (br s, 1H, H-6), 7.22 (br s, 1H, NH), 7.12 (br d, J=8.1 Hz, 1H, H-5), 4.18 (d, J=16.2 Hz, 1H, H-1), 3.82 (d, J=16.1 Hz, 1H, H-1), 3.11-3.25 (m, 2H, H-3), 2.91-3.00 (m, 2H, H-4), 2.61 (s, 3H, NCH3), 2.16 (s, 3H, COCH3); 13C NMR δ 168.3, 136.6, 131.0, 129.2, 126.6, 119.2, 118.1, 61.5, 56.6, 47.3, 24.5, 24.0; MS (APCI) m/z 205 (MH+, 100%). Anal. calcd for C12H16N2O.½CH3OH.½H2O: C, 65.5; H, 8.4; N, 12.2. Found: C, 65.8; H, 8.8; N, 12.6%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][N:7]=1.I[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CCOC(C)=O>[OH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[O:8])=[CH:11][CH:12]=1
Reactant: OCc1ccc(I)cc1
Reactant: Cc1nccnc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nccn(-c2ccc(CO)cc2)c1=O

Procedure:
3-Methyl-2-hydroxypyrazine (1.10 g, 10.0 mmol), 4-Iodobenzyl alcohol from Example 1, Step 1 (4.0 g, 17.0 mmol), K2CO3 (1.52 g, 110 mmol), and copper (15 mg , 0.2 mmol) were heated under argon for 40 hours. The dark residue was partitioned between CHCl3 and saturated NaHCO3. The aqueous layer was back extracted twice with CHCl13. The organic layers were combined, washed with brine, dried (MgSO4,), filtered and concentrated to give a light brown solid. Flash chromatography (EtOAc) yielded the title compound as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[N:15]=1.C(OCC)C>C(#N)C.O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][N:22]1[CH:21]=[C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[N:15]=2)[CH:24]=[N:23]1
Reactant: COC(=O)CBr
Reactant: Brc1cccc(-c2cn[nH]c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COC(=O)Cn1cc(-c2cccc(Br)n2)cn1
Temperature: 70 °C

Procedure:
Potassium Carbonate (740 mg, 5.36 mmol), methyl bromoacetate (0.37 mL, 4.02 mmol) and 2-bromo-6-(1H-pyrazol-4-yl)pyridine (Example 398, Step 1) were taken up in acetonitrile. The mixture was heated at 70° C. for 72 hours. It was then poured into 300 mL diethyl ether and 50 mL water. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([CH3:27])([CH3:26])[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+]>[Pd].CO>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([C:9]([CH3:27])([CH3:26])[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
20.0 g of 3-phenoxybenzyl 2-(3-chloro-4-hydroxyphenyl)-2-methylpropyl ether prepared in the above step (1), 2.67 g of 95% sodium hydroxide and 1.0 g of 5% Pd-C (50% hydrous) were added to 100 ml of 80% methanol and the mixture was stirred at 100° C. under a hydrogen pressure of 20 to 30 kg/cm2G for 6 h. After cooling, the catalyst was removed by filtration and the catalyst was washed thoroughly with benzene. The solvent wa distilled off under reduced pressure. A dilute aqueous hydrochloric acid solution was added to the distillation residue. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure to obtain 18.2 g of intended 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether (m.p. 69.2° to 70.0° C.).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[S:17])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]1[C:2](=[O:8])[C:3](=[O:5])[N:15]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:16]1=[S:17]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)CNC(=S)Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)C(=O)N(c2cccnc2)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Ethyl chlorooxoacetate (0.33 mL, 2.90 mmol) was added to a stirring solution of the above thiourea (0.50 g, 2.24 mmol) and K2CO3 (0.31 g) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.50 g (81%) 1-(2,2-dimethyl-propyl)-3-pyridin-3-yl-2-thioxo-imidazolidine-4,5-dione as a yellow solid: mp 111.4–112.8° C.; IR (KBr): 3500, 2980, 1770 cm1; MS (m/z) 378 (M+H+).
Reaction SMILES: [C:1]([Si:5]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[OH-].[Na+]>[C:48]([Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:35][CH:36]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)CO[Si](c4ccccc4)(C(C)(C)C)C(C)(C)C)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Ethyl (2-{7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl)acetate (480 mg) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (7 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The precipitated solid was collected by filtration to give the title compound (320 mg, yield 70%) as a yellow solid. MS 743 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:18][CH2:19][C@H:20]([S:22][CH2:23][C@@:24]([CH3:29])([C:26]([OH:28])=[O:27])[NH2:25])[CH3:21])=O)C1C=CC=CC=1.[ClH:30]>>[ClH:30].[NH2:18][CH2:19][C@H:20]([S:22][CH2:23][C@@:24]([CH3:29])([C:26]([OH:28])=[O:27])[NH2:25])[CH3:21]
Reactant: C[C@H](CNC(=O)OCc1ccccc1)SC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CN)SC[C@](C)(N)C(=O)O
Temperature: 25 °C

Procedure:
The product of Example-3C, S-[(1R)-2-(Benzyloxycarbonylamino)-1-methylethyl]-2-methyl-L-cysteine trifluoroacetate, (0.5 g, 1.14 mmol) was dissolved in 6N HCl and refluxed for 1.5 hour. The mixture was then cooled to room temperature and extracted with EtOAc. The aqueous layer was concentrated in vacuo to give the title product, (2R,5R)-S-(1-amino-2-propyl)-2-methyl-cysteine hydrochloride (0.29 g), which was used without further purification. 1H NMR (H2O, 400 MHz) δ 1.2 (m, 3H), 1.4 (m, 3H), 2.7 (m, 1H), 2.8–3.2 (m, 2H), 3.4 (m, 1H). (some doubling of peaks due to rotameric forms). MS m/z (electrospray): 193 [M+H+] (61%), 176 (53), 142 (34), 134 (100), and 102 (10).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]([OH:30])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:32]=[C:33]([NH2:38])[CH2:34][CH2:35][O:36][CH3:37]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]3[O:30][N:38]=[C:33]([CH2:34][CH2:35][O:36][CH3:37])[N:32]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)c(C)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.221 mmol) of the compound from Example 170A and 52 mg (0.331 mmol) of the compound from Example 64A were reacted according to the General Method 2. Yield: 39 mg (35% of theory)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:12]([Si:15]([Cl:18])([Cl:17])[Cl:16])(Cl)Cl>>[C:1]1([C:12]([Si:15]([Cl:18])([Cl:17])[Cl:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: ClC(Cl)(Cl)[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 18.9 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 22.88 ml (256 mmol) of benzene and 0.80 g (6.0 mmol) of aluminum chloride were alkylated with 9.04 g (17.2 mmol) of (trichloromethyl)trichlorosilane under dry nitrogen atmospheric pressure for 1 hr at 50° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane(50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, recrystallization from chloroform yielded 1.23 g of (triphenylmethyl)trichlorosilane (mp; 195-7: E, yield; 19%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:26]/[C:25](=[N:27]/[NH2:28])/[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>COC(OC)(OC)CCC>[C:30]1([C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH:7][C:6](=[O:36])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:29][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:11]([CH2:8][CH2:9][CH3:10])=[N:28][N:27]=4)[C:21]=3[CH:20]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/N)CO4)cc2)CCC1
Agent: CCCC(OC)(OC)OC
Product: CCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Yield: 90 %

Procedure:
A solution of (E)-tert-butyl(1-(4-(2-hydrazono-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.124 mmol) in 1,1,1-trimethoxybutane (1 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 100% ethyl acetate in n-hexanes) to give the title compound (30 mg, 45%). LCMS (Method A): RT=7.34 min, M+1=538. 1H NMR (500 MHz, CDCl3): 7.80 (1H, s), 7.36-7.32 (5H, m), 7.31-7.27 (2H, m), 7.23-7.19 (2H, m), 5.57 (2H, s), 3.08 (2H, t), 2.55-2.40 (4H, m), 2.15-2.03 (1H, m), 2.00 (2H, q), 1.89-1.77 (1H, m), 1.41-1.29 (9H, br), 1.12 (3H, t).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[CH:43]([CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54][C:55](N2C=CN=C2)=[O:56])[CH2:48][CH2:47]1)([CH3:45])[CH3:44]>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:55]([NH:54][CH2:53][CH2:52][N:49]3[CH2:50][CH2:51][CH:46]([CH:43]([CH3:45])[CH3:44])[CH2:47][CH2:48]3)=[O:56])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)C1CCN(CCNC(=O)n2ccnc2)CC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN4CCC(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-[2-(4-isopropyl-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 22) by a similar method to Example 1.
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].[C:18]1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C:19]([OH:28])=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2.C(N(CC)CC)C.[OH-:46].[Na+]>ClCCl.O>[S:5]([C:4]([C:3]([C:2]([C:13]([F:16])([F:15])[F:14])([F:17])[F:1])([F:12])[F:11])([F:10])[F:9])([OH:28])(=[O:7])=[O:6].[S:5]([C:4]([C:3]([C:2]([C:13]([F:14])([F:15])[F:16])([F:1])[F:17])([F:12])[F:11])([F:10])[F:9])([OH:7])(=[O:6])=[O:46].[C:18]1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C:19]([OH:28])=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [OH-]
Agent: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 4 h

Procedure:
111.6 g of nonafluoro-n-butanesulfonyl fluoride (370 mmol) were added at room temperature to a solution of 45.6 g of racemic binaphthol (160 mmol) and 47.6 g of triethylamine (470 mmol; 65.5 ml) in 350 ml of dichloromethane. After a few minutes, the denser sulfonyl phase had disappeared, without the mixture warming appreciably. After stirring for 4 hours, the mixture was shaken once with 80 ml of aqueous sodium hydroxide solution (5% by weight) and once with 80 ml of water, and the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The product crystallized out on cooling and was purified further by washing with a small amount of cold methanol and subsequent filtration with suction. This gave 123 g of binaphthol dinonaflate (90.0%) as colourless crystals having a melting point of 104.1° C.; HPLC purity>99% (RP-18; methanol/water 80:20; 254 nm)
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH:3]([OH:6])[C:4]#[CH:5].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:22]=[CH:23][C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([CH3:27])[CH:26]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=1>>[CH2:29]([O:28][C:24]1[CH:23]=[CH:22][C:21]([C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:5]#[C:4][CH:3]([OH:6])[C:2]([CH3:8])([CH3:7])[CH3:1])=[CH:15][CH:14]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:26][C:25]=1[CH3:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C#CC(O)C(C)(C)C
Reactant: CCC(CC)(c1ccc(Br)cc1)c1ccc(OCc2ccccc2)c(C)c1
Product: CCC(CC)(c1ccc(C#CC(O)C(C)(C)C)cc1)c1ccc(OCc2ccccc2)c(C)c1

Procedure:
In a manner similar to that described for Example 1D, but replacing 2-methyl-3-butyn-2-ol with 4,4-dimethylpent-1-yn-3-ol, the title compound was prepared from 5-[1-(4-bromophenyl)-1-ethylpropyl]-2-benzyloxytoluene: 1H-NMR (CDCl3) δ 7.44-7.48 (2H, m), 7.37-7.42 (2H, m), 7.31-7.36 (3H, m), 7.14 (2H, d, J=8.6), 6.94 (1H, dd, J=2.3, 8.3), 6.90 (1H, d, J=2.3), 6.79 (1H, d, J=8.3), 5.05 (2H, s), 2.22 (3H, s), 2.07 (4H, q, J=7.3), 1.07 (9H, s), 0.62 (6H, t, J=7.3).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][C@H:27]([C:29]([NH:31][C@@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:33]([OH:40])[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:30])[CH3:28].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([NH:26][C@H:27]([C:29]([NH:31][C@@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:33]([OH:40])[C:34]([O:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[O:30])[CH3:28])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)N)C(O)C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 79 mg of 2-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid and 90 mg of isopropyl (2RS, 3S)-3-(L-alanyl)amino-2-hydroxy-5-methylhexanoate hydrochloride in 5ml of N,N-dimethylformamide were added 0.062 ml of diphenylphosphoryl azide and 0.110 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol = 5/1 by volume: Rf2 =0.70) to obtain 19 mg of isopropyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-alanyl}amino-2-hydroxy-5-methylhexanoate as a white powder.