Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([N:20]=[CH:21][C:22]1[CH:23]=[N:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=1[CH3:28])([CH3:19])([CH3:18])[CH3:17].CN(C=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO.C(O)(=O)C>[C:16]([N:20]1[CH2:1][CH2:28][C:27]2[C:22](=[CH:23][N:24]=[C:25]([O:29][CH3:30])[CH:26]=2)[CH2:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cc(C)c(C=NC(C)(C)C)cn1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [BH3-]C#N
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(cn1)CN(C(C)(C)C)CC2
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (9.0 mL, 60 mmol) in dry THF (300 mL) under argon at −20° C. was slowly added 1.6M n-BuLi in hexanes (40 mL, 60 mmol) while the temperature was kept at −20° C. After the addition was complete, stirring was continued at −20° C. for 40 min. Then a solution of tert-butyl-[(6-methoxy-4-methylpyridin-3-yl)methylene]amine (6.3 g, 30 mmol) in dry THF (100 mL) was added dropwise at −20° C. The mixture was stirred at −15 to −10° C. for 1.5 h and then cooled to −20° C. Anhydrous DMF (6.5 ml, 70 mmol) was added dropwise over five minutes and stirring continued at −10° C. for 1.5 h. Then glacial acetic acid (60 mL) in MeOH (250 ml) was added, followed by the portion-wise addition of sodium cyanoborohydride (2.3 g, 40 mmol) over five minutes. After stirring overnight, the solvent was evaporated and 20% potassium carbonate solution was added slowly to raise the pH to 9. The mixture was extracted four times with TBME. The combined organic phases were washed with brine, dried and concentrated to give a crude oil. Vacuum distillation gave 5.2 g (77%) of the title compound as a colourless oil, b.p. 105-106° C./0.5 mmHg.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14].C(NC(C)C)(C)C.ClC(Cl)(Cl)[C@H]1OC(=O)[C@H]2N1CCC2.C(Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Agent: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Solvent: CC(C)NC(C)C
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12Cc1ccccc1
Yield: 21.6 %

Procedure:
(Wang et al. Synlett 1999, 1, 33). The reaction was carried out following a similar procedure to that described for the preparation of oxazolidinone 8 using n-butyllithium (1.31 M, 5.53 cm3, 7.2 mmol), diisopropylamine (1.01 cm3, 7.24 mmol), oxazolidinone 7 (1.18 g, 4.8 mmol) and benzyl bromide (1.72 cm3, 14.5 mmol) to afford oxazolidinone 11 (0.52 g, 32%) as a colourless crystalline solid: mp 75-77° C. (lit. Wang 72-77): δH (400 MHz; CDCl3) 1.32-1.55 (2H, m, Proγ-H2), 1.93-2.13 (2H, m, Proβ-H2), 2.58-2.65 (1H, m, Proδ-H2), 2.92 (1H, d, J 13.6, PhCHAHB), 2.98-3.03 (1H, m, Proδ-H2), 3.32 (1H, d, J 13.6, PhCHAHB), 4.99 (1H, s, NCH) and 7.21-7.35 (5H, m, PhH); δC (100 MHz; CDCl3) 24.8 (CH2, Proγ-C), 34.6 (CH2, Proβ-C), 41.6 (CH2, Proδ-C), 58.4 (CH2, PhCH2), 72.3 (quat., Proα-C), 100.6 (quat., CCl3), 102.8 (CH, NCH), 127.0 (CH, Ph), 128.2 (CH, Ph), 130.9 (CH, Ph), 135.5 (quat., Ph) and 176.6 (quat., C═O); m/z (EI+) 333.0081 [(M+H)+.C14H1435Cl3NO2 requires 333.0090], 335.0069 [(M+H)+.C14H1435Cl237ClNO2 requires 335.0061], 337.0014 [(M+H)+.C14H1435Cl37Cl2NO2 requires 337.0031] and 339.0009 [(M+H)+.C14H1437Cl3NO2 requires 339.0002].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>C(O)(C)C>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:13][C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]3)=[N:3][CH:4]=[N:5]2
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Fc1cccc2ncnc(Cl)c12
Solvent: CC(C)O
Product: Fc1cccc2ncnc(Nc3ccc4[nH]ncc4c3)c12
Yield: 89 %

Procedure:
A stirred partial solution of 4-chloro-5-fluoroquinazoline (10.95 g, 60 mmol) and 5-aminoindazole (7.98 g, 60 mmol) in isopropanol (300 ml) was heated under reflux for 3 hours. On cooling to ambient temperature the product hydrochloride salt was filtered off and washed with isopropanol and ether. The salt was heated with water (400 ml)/ethanol (100 ml) and the partial solution was basified with aqueous ammonia. The precipitated solid was filtered off and washed with water to provide 5-fluoro-N-1H-indazol-5-ylquinazolin-4-amine (14.91 g, 89%); NMR spectrum (300 MHz) 7.42 (dd, 1H), 7.53 (s, 2H), 7.60 (d, 1H), 7.83 (m, 1H), 8.08 (d, 2H), 8.50 (s, 1H), 9.20 (d, 1H), 13.05 (s, 1H); Mass spectrum MH+ 280.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([C@@H:17]3[CH:22]4[CH2:23][CH2:24][CH:19]([CH2:20][CH2:21]4)[N:18]3C(OC(C)(C)C)=O)=[N:10][C:9]=2[CH:8]=1.[ClH:32].C(OCC)(=O)C>CO>[ClH:32].[ClH:32].[CH:19]12[CH2:20][CH2:21][CH:22]([CH2:23][CH2:24]1)[C@@H:17]([C:11]1[NH:12][C:13](=[O:16])[C:14]3[S:15][C:7]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:8][C:9]=3[N:10]=1)[NH:18]2
Reactant: Cc1[nH]ncc1-c1cc2nc([C@@H]3C4CCC(CC4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]ncc1-c1cc2nc([C@H]3NC4CCC3CC4)[nH]c(=O)c2s1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (3S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate (143 mg) produced in Example 106, step B, in methanol (3.0 mL) was added 4M hydrochloric acid/ethyl acetate solution (1.0 mL) with stirring at room temperature. The reaction system was stirred with heating at 50° C. for 1 hr, and the precipitate was collected by filtration, and washed with ethyl acetate to give the title compound (128 mg) as a colorless solid.
Reaction SMILES: NCC(O)=O.C([O-])([O-])=O.[Na+].[Na+].[I:12]([C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:18]([NH:20][CH2:21][C:22]([O:24]CC(Cl)(Cl)Cl)=[O:23])=[O:19])(=O)=O>IC1C=C(C=CC=1[N+]([O-])=O)C(Cl)=O>[I:12][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1)OCC(Cl)(Cl)Cl
Agent: NCC(=O)O
Agent: O=C(Cl)c1ccc([N+](=O)[O-])c(I)c1
Agent: O=C([O-])[O-]
Product: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])c(I)c1

Procedure:
The reaction of 3-iodo-4-nitrobenzoyl chloride (prepared from 3-iodo-4-nitrobenzoic acid, 1.2 g and SOCl2, 10 mL) with glycine (0.38 g, 5.12 mmol) in the presence of Na2CO3 (0.54 g, 5.12 mmol) as described in intermediate 2 gave the title compound as a pale yellow color solid (1.3 g, 91%), mp 140-142° C. 1H NMR (400 MHz, DMSO-d6): δ 12.69 (1H, br s), 9.19 (1H, t, J=5.6 Hz), 8.52 (1H, br s), 8.05 (2H, br s), 3.96 (2H, d, J=6.0 Hz); LC-MS (negative ion mode): m/z 349 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([CH2:21][O:22][CH3:23])=[C:9]([CH:18]=[N:19][OH:20])[N:10]=[CH:11][C:12]=1[NH:13]2.Cl[O-].[Na+].[CH3:31][O:32][CH2:33][C:34]#[CH:35]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([CH2:21][O:22][CH3:23])=[C:9]([C:18]3[CH:35]=[C:34]([CH2:33][O:32][CH3:31])[O:20][N:19]=3)[N:10]=[CH:11][C:12]=1[NH:13]2
Reactant: C#CCOC
Reactant: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(-c2ncc3[nH]c4cccc(Cc5ccccc5Cl)c4c3c2COC)no1
Reaction time: 0.33 h
Yield: 8 %

Procedure:
1.06 g (0.0028 mol) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde-oxime in 25 ml tetrahydrofuran is mixed with 10 ml of sodium hypochlorite solution at 35° C. under argon. After 20 minutes no more initial material can be detected by thin-layer chromatography. 0.32 ml (0.004 mol) of methylpropargylether is instilled at room temperature and it is stirred for 3 more hours. After being left standing overnight it is diluted with ethyl acetate, washed neutral with water, dried and concentrated by evaporation. The residue is chromatographically separated on silica gel with a mixture of 2 parts tetrahydrofuran and one part of toluene. First a fraction is isolated, which after recrystallization from a dichloromethane/cyclohexane mixture yields 0.1 g (8% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-3-(5-methoxymethylisoxazol-3-yl)-β-carboline, melting point 178°-180° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH:9]=[O:10])([O-:3])=[O:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1)([O-:3])=[O:2]
Reactant: O=Cc1ccsc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1sccc1C1OCCO1
Reaction time: 2.5 h
Yield: 65 %

Procedure:
2-Nitro-thiophene-3-carbaldehyde described in Preparation Example T-2 (367 mg, 2.33 mmol), ethane-1,2-diol (651 μl, 11.7 mmol) and toluene-4-sulfonic acid monohydrate (40 mg, 0.233 mmol) were dissolved in toluene (8 mL), and the solution was stirred for 2.5 hours under reflux. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (304 mg, 1.51 mmol, 65%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[NH:15][C:14](=[S:16])[NH:13][C:9]3=[N:10][C:11]=2[CH:12]=1.[OH-].[Na+].[CH3:21]I>CO>[CH3:21][S:16][C:14]1[NH:15][C:8]2[C:9]([N:13]=1)=[N:10][C:11]1[CH:12]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:4]=[CH:5][C:6]=1[CH:7]=2
Reactant: CI
Reactant: FC(F)(F)c1ccc2cc3[nH]c(=S)[nH]c3nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2nc3cc(C(F)(F)F)ccc3cc2[nH]1
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A suspension of 1,3-dihydro-6-(trifluoromethyl)-2H-imdazo[4,5-b]quinolin-2-thione (0.53 g, 2 mmol) in methanol (5 mL) was treated with 50% aqueous sodium hydroxide (0.18 g) to afford a solution which was cooled in an ice bath. Methyl iodide (0.3 g, 0.13 mL, 2.1 mmol) was added and the mixture stirred for 90 minutes before being filtered. The solid was washed with methanol and dried in air to give 2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (0.34 g, 61%), m.p. >270° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O.CCCCCC>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A solution of 2-bromophenol (17.3 g) in dimethylformamide (200 mL) was treated with potassium carbonate (15.2 g) followed by benzyl bromide (17.1 g, 11.9 mL). After stirring for 3 hours at the room temperature, the reaction mixture was diluted water and hexane. The aqueous layer was extracted with hexane; and the organic layers were washed (water, 1N sodium hydroxide, brine), dried and evaporated to give the product as a colorless oil (22.94 g). This material was fractionally distilled under reduced pressure to afford the bromobenzene (16.52 g); bp 110°-145° C. (1333 Pa); NMR (CDCl3): 5.17 (s, 2), 6.65 (d of t,1, J=8, J=1), 6.92-6.96 (d of d, 1, J=8, J=1), 7.19-7.26 (m, 1), 7.33-7.42 (m, 3), 7.46-7.50 (m, 2), 7.55 (d of d, 1, J=9, J=2). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH:13]=O)[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=2[CH:23]=1.[NH2:28][CH2:29][C@@H:30]1[C@H:34]2[O:35][C:36]([CH3:39])([CH3:38])[O:37][C@H:33]2[C@H:32]([N:40]2[C:44]3[N:45]=[CH:46][N:47]=[C:48]([NH:49][CH:50]4[CH2:52][CH2:51]4)[C:43]=3[CH:42]=[CH:41]2)[CH2:31]1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>ClCCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:24]([F:27])([F:25])[F:26])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:28][CH2:29][C@@H:30]3[C@H:34]4[O:35][C:36]([CH3:38])([CH3:39])[O:37][C@H:33]4[C@H:32]([N:40]4[C:44]5[N:45]=[CH:46][N:47]=[C:48]([NH:49][CH:50]6[CH2:52][CH2:51]6)[C:43]=5[CH:42]=[CH:41]4)[CH2:31]3)[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reactant: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(C(F)(F)F)c(Cl)cc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(F)(F)F)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reaction time: 1 h

Procedure:
A solution of the 4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butanal (367 mg, 0.87 mmol), 7-[(3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.87 mmol) and MgSO4 (1.05 g, 8.74 mmol) in DCE (10 ml) was stirred at RT for 15 min. Na(AcO)3BH (259 mg, 1.22 mmol) was then added to the reaction mixture and stirred for 1 hour. Sat. NaHCO3 (20 ml) was added to the reaction mixture and stirred for 5 mins. Brine (10 ml) was added to the reaction mixture, and the product was extracted with DCM (2×30 ml), the combined extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:199-3:97) gave the desired product as a pink foamy solid. The mixed fractions were combined and purified on a preparative TLC plate eluting with 7N NH3 in MeOH:DCM (2×4:96) to give an off white solid (270 mg, 41%): MS (ESI+) for C36H49ClF3N7O3Si m/z 748.25 [M+H]+; HPLC purity>95% (ret. time, 1.75 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.14-8.47 (1H, m), 7.78-8.11 (1H, m), 7.40-7.78 (1H, m), 6.99 (1H, d, J=3.63 Hz), 6.63 (1H, br. s.), 5.34-5.69 (3H, m), 4.81-5.11 (2H, m), 4.53 (1H, t, J=6.15 Hz), 3.33-3.71 (2H, m), 2.89-3.14 (3H, m), 2.77-2.90 (1H, m), 2.68-2.79 (3H, m), 2.25-2.49 (2H, m), 2.15 (1H, q, J=11.87 Hz), 1.89-2.06 (2H, m), 1.63-1.71 (2H, m), 1.51-1.61 (3H, m), 1.21-1.37 (3H, m), 0.84-1.00 (4H, m), 0.62-0.78 (2H, m), −0.15-0.06 (9H, m).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:5](=[O:20])[NH:4]1)[CH3:2].CC1CC2(CCNCC2)C(=O)N1[C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1>>[CH2:1]([CH:3]1[CH2:7][C:6]2([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[C:5](=[O:20])[N:4]1[C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1)[CH3:2]
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Reactant: CCC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Product: CCC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1

Procedure:
The title compound was prepared in two steps from tert-butyl 3-ethyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate in an analogous fashion as described for 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:19])[C:11](=[CH2:18])[CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13].CO[CH2:22][N:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][Si](C)(C)C>C(Cl)Cl>[CH3:8][O:9][C:10]([C:11]1([CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH2:18][CH2:22][N:23]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24]1)=[O:19]
Reactant: C=C(C(=O)OC)C(C)OC(C)=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C(C)OC(C)=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Trifluoroacetic acid (0.5 g, 4.38 mmol) was added to a solution of methyl-3-acetoxy-2-methylenebutyrate (5 g, 29.03 mmol) (1) and N-Methoxymethyl-N-trimethylsilylmethylbenzylamine (6.89 g, 29.03 mmol) (2) in MeCl2 (100 ml) at 0° C., then stirred overnight at room temperature. The solvent was evaporated, and residue extracted with EtOAc (200 ml), NaHCO3 (30 ml and H2O (100 ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated yielding an oil which chromatographed on silica gel eluting with 30% v/v (EtOAc/hexanes) yielding product (3) as colorless oil (7.53 g, 85% yield). ESMS MH, 306 (C17H23NO4)
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=[O:25])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:26](O)([C:28]([F:31])(F)F)=O.C(Cl)Cl>FC1C=CC(N=C=O)=CC=1>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:11][C:14]4[CH:23]=[CH:26][C:28]([F:31])=[CH:16][CH:15]=4)=[O:5])[CH2:13][CH2:12]3)=[CH:15][C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-quinolone (100 mg) is deprotected with TFA-CH2Cl2 1:1 (0.5 mL) and transformed to the title product with 4-fluorophenyl isocyanate (50 μL) according to method C.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1>CCO.[Pd]>[C:20]1([CH2:19][CH2:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCCCOCCCCc1ccccc1
Yield: 97.7 %

Procedure:
A solution of 4.02 g (11.86 mmol) N-benzyl-6-(4-phenylbutoxy)hexylamine in 40 ml EtOH is hydrogenated at room temperature and atmospheric pressure with 0.4 g 5% Pd/C. When 300 ml H2 have been absorbed, the mixture is filtered on decalite and the filtrate is concentrated to yield 2.89 g (97.9%) 6-(4-phenylbutoxy)hexylamine as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:25][CH:26]=1
Reactant: Cc1nc2ccccc2nc1Oc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccccc2nc1Oc1ccc(O)cc1
Yield: 50.7 %

Procedure:
A solution of 12.5 g (0.05 mole) borontribromide in 100 cc methylene chloride was added, over a period of 40 minutes, to a well stirred, cold (-62° C.) solution of 17.1 g 2-(4-benzyloxyphenoxy)-3-methylquinoxaline (0.05 mole) in 400 cc methylene chloride. When the addition was complete, the temperature of the reaction was allowed to rise slowly (2 hours) to room temperature. The reaction mixture was then poured into 1 liter of water and an additional 500 cc of methylene chloride was added. The mixture was stirred vigorously for 40 minutes and the insoluble solid was filtered. Crystallization from an ethanol-water mixture (1:1) gave 6.4 g of product, m.p. 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[CH:6]=[CH:5]2.ClC1C(Cl)=CC(C(O)=O)=C(C=O)C=1.C([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH2:55])[CH:41]([OH:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([NH:55][C@H:40]([C:41](=[O:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])[CH2:39][C:38]([OH:56])=[O:37])=[O:17])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1ccc2cc(Cl)c(Cl)cc2c1=O
Agent: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2cc(Cl)c(Cl)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(6,7-dichloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (synthesized from 4,5-dichloro-2-formyl-benzoic acid [prepared as described in methods Q-S] using procedures similar to those described in methods A-E) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The title compound was isolated as a white solid (94% last step). IR (solid) 1784.5, 1734.7, 1650.1, 1610.2, 1585.4, 1515.7, 1490.8, 1426.0, 1216.9, 1172.1, 1092.5, 933.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.80 (3H, t), 1.90-1.98 (1H, m), 2.04-2.12 (1H, m), 2.55-2.79 (2H, m), 4.56-4.71 (1H, m), 5.08-5.41 (3H, m), 6.67 (1H, d), 7.56-7.59 (2H, m), 8.07 (1H, brd s), 8.25 (1H, d), 8.85-8.95 (1H, 2×d), 12.73 (1H, brd s) ppm; 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −140.93, −140.95, −140.99, −141.01, −141.04, −141.07, −141.10, −156.76, −156.79, −156.82, −156.85, −156.89, −156.91; MS ES (+): 577.14 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O)=[S:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:14](=[S:15])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCCNC(=S)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNC(=S)Nc1ccccc1N

Procedure:
1.78 g (4.8 mmol) of 1-(4-tert-butyloxycarbonylaminobutyl)-3-(2-nitrophenyl)thiourea (Example 23a) were dissolved in 120 ml of methanol and hydrogenated (1 bar) over 1 g of Pd/C at RT for 3 h. The catalyst was filtered off, the filtrate was concentrated and the residue was chromatographed through silica gel (EA:n-heptane 1:1). Yield: 1.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[K+].[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH:15][C:25](=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc2ccccc2c1CCN
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)NCCc1c(OC)ccc2ccccc12
Reaction time: 0.5 h
Yield: 48 %

Procedure:
0.45 g (2.23 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine, which is solubilized in 20 cm3 of anhydrous dichloromethane, is introduced into a 100-cm3 two-necked flask under an inert atmosphere. The mixture is cooled with an ice bath and stirred, and 0.47 cm3 (3.37 mmol) of triethylamine dried over potassium hydroxide is introduced, followed by 0.28 cm3 (2.69 mmol) of butyryl chloride. After the introduction of the reactants, the ice bath is removed and reaction is allowed to proceed at room temperature for 30 min. Hydrolysis of the excess chloride is carried out by pouring the reaction mixture into water. After extraction three times with dichloromethane, the organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization of the solid obtained, in the heated state, in a pentane/ethyl acetate mixture, 0.29 g (1.07 mmol) of N-[2-(2-methoxynaphthyl)ethyl]butyramide (white solid) is obtained, equivalent to a yield after purification of 48%.