Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@@H:6](O)[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.C(OCC)C.CCOC(C)=O>[N:31]([C@H:6]1[CH2:7][C@@H:2]([F:1])[CH2:3][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H](F)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=N[C@H]1C[C@@H](F)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of (3R,5R)-benzyl 3-fluoro-5-hydroxypiperidine-1-carboxylate (1 eq) in 14 mL of dichloromethane was added triethyl amine (3 eq) and methanesulfonyl chloride (1.5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 1.5 hours. The crude mixture was diluted with 120 mL of diethyl ether, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in 16 mL of NMP. Sodium azide (3.0 eq) was added and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was diluted with 200 mL of EtOAc and 100 mL of hexanes, washed with water, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:3) to yield (3S,5R)-benzyl 3-azido-5-fluoropiperidine-1-carboxylate (90%). LC/MS (m/z): 251.1 (MH+-28).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13](=[O:54])[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:53])[NH:22][C:23]2[CH:28]=[C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37](=[NH:40])[NH:38]O)=[CH:33][CH:32]=3)[CH:26]=[C:25]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49](=[NH:52])[NH:50]O)=[CH:45][CH:44]=3)[CH:24]=2)[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9]>C(O)(=O)C.[Zn]>[C:8]([O:12][C:13](=[O:54])[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:53])[NH:22][C:23]2[CH:24]=[C:25]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49](=[NH:50])[NH2:52])=[CH:45][CH:44]=3)[CH:26]=[C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37](=[NH:38])[NH2:40])=[CH:35][CH:36]=3)[CH:28]=2)[CH2:17][CH2:16]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3ccc(C(=N)NO)cc3)cc(OCc3ccc(C(=N)NO)cc3)c2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3ccc(C(=N)N)cc3)cc(OCc3ccc(C(=N)N)cc3)c2)CC1
Reaction time: 3 h
Yield: 136.4 %

Procedure:
Acetic anhydride (0.36 ml, 3.72 mmol) was added to the solution of (4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, 0.62 mmol) in 10 ml of acetic acid and reaction mixture was stirred for 3 h. After completion of reaction, at RT zinc dust (0.4 g, 6.2 mmol) was added and resulting mixture was stirred over night. Recation mixture was filtered through celite and filterate was concentrated to dryness. Product was washed with cold diethyl ether and dried to afford 0.52 g of the required product. Percentage purity (LCMS): 100.0%, (M−1)=615.2-1.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([Br:30])=[CH:25][C:24]=2[CH3:31])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([F:29])[C:26]([Br:30])=[CH:25][C:24]=1[CH3:31])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(F)c(Br)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Yield: 84.7 %

Procedure:
A pressure tube was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methylphenyl)amino)phenyl)acrylate (3.19 g, 6.37 mmol) and MeOH (31.9 ml) to give a yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.697 ml, 2.55 mmol) was added. The tube was sealed and heated to 70° C. for 18 h. The whole was cooled to rt, quenched with saturated aq NH4Cl, and concentrated. The whole was extracted with EtOAc (3×50-mL). The organic layer was separated, combined, dried over MgSO4, filtered, and concentrated to afford orange residue. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in heptane, to provide 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methylphenyl)quinolin-2(1H)-one (2.45 g, 85% yield) as yellow solid. m/z (ESI) [M+H]+=454.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (s, 3 H) 3.36 (s, 2 H) 5.74 (d, J=8.80 Hz, 1H) 5.93 (d, J=9.59 Hz, 1 H) 6.34-6.50 (m, 6 H) 6.62 (dd, J=8.85, 2.10 Hz, 1 H) 6.89 (d, J=2.05 Hz, 1 H) 6.99 (m, 1 H) 7.16 (d, J=9.39 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:32]4[CH2:33][CH2:34][CH:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH2:36][CH2:37]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CS(=O)(=O)NC1CCNCC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: CS(=O)(=O)NC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and N-(piperidin-4-yl)methanesulfonamide (86.5 mg; 0.48 mmol) to give Example 146 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.72 (2H, dd, J=4.5, 1.6 Hz), 8.04 (2H, d, J=8.1 Hz), 7.63-7.52 (2H, m), 7.44-7.33 (5H, m), 7.22-7.15 (1H, m), 4.20 (1H, d, J=7.7 Hz), 3.55 (2H, s), 3.40-3.31 (1H, m), 2.98 (3H, s), 2.82 (2H, d, J=11.4 Hz), 2.16 (2H, t, J=11.3 Hz), 1.99 (2H, d, J=12.5 Hz), 1.66-1.50 (2H, m). LC/MS (Method C): 573 (M+H)+. HPLC (Method F) Rt 3.33 min (Purity: 99.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cnc1F
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)c1ncc(Br)cc1C(=O)O
Temperature: 80 °C

Procedure:
880 mg (4.00 mmol) of 5-bromo-2-fluoronicotinic acid was dissolved in 3 ml of acetonitrile. 1.0 ml (9.7 mmol) of diethylamine was added and the resulting mixture heated to 80° C. for 18 h. The mixture was evaporated and the resulting brown oil used without further purification. MS: m/z 273 [MH+].
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][OH:5].[Cl:6][C:7]1[C:12](O)=[CH:11][CH:10]=[CH:9][N:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:6][C:7]1[C:12]([O:5][CH2:4][C@@H:2]2[CH2:3][O:1]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Oc1cccnc1Cl
Reactant: OC[C@@H]1CO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncccc1OC[C@@H]1CO1
Temperature: 0 °C
Yield: 43.6 %

Procedure:
Combine (R)-oxiranemethanol (32.85 g, 443.5 mmol) with 2-chloro-3-hydroxypyridine (52.23 g, 403.18 mmol) in THF (1.34 L). Stir the mixture until the solids dissolve. Cool it to 0° C. and slowly add triphenylphosphine (116.33 g, 443.5 mmol). After all the solids dissolve, add diisopropyl azodicarboxylate (87.92 mL, 443.5 mmol) drop-wise over 25 minutes at a sufficiently slow rate to maintain the internal temperature of the reaction below 10° C. Stir the mixture while cooling for 30 minutes then allow the mixture to warm to ambient temperature and continue stirring overnight. Add EtOAc, and wash with NaOH (2×1.0 N). Dry the organic layer over Na2SO4; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with a mixture of 2:1 Et2O: hexanes and stir for 5 minutes. Filter and concentrate the filtrate under reduced pressure to provide a residue. Purify the residue via flash column chromatography (2×330 g SiO2), eluting with a gradient of 0-66% THF/Hexane. Combine the desired fractions, and concentrate under reduced pressure to provide the title compound (32.6 g, 43.6%) as a white solid. MS (m/z): 186 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[Br:14][C:15]1[CH:19]=[C:18]([Cl:20])[S:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[Br:14][C:15]1[CH:19]=[C:18]([Cl:20])[S:17][C:16]=1[S:21]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Product: CC1(C)CC(=O)c2sc(NS(=O)(=O)c3sc(Cl)cc3Br)nc2C1

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and 3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic method to give a white solid (62.2 mg) with purity >90%: MS (pos) m/z 455.2, 457.2.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:27]([C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccs1

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-thiophenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give thiophene-2-sulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow solid. MS: 487.0 ([M+NH4]+)
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:12][C:10]([CH3:11])=[CH:9][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: C[Si](C)(C)Cl
Agent: Cn1ccnc1
Product: CC(=O)C=C(C)O[Si](C)(C)C
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 81.4 %

Procedure:
5.97 g (55.0 mmol) of chlorotrimethylsilane were added dropwise while stirring at 0° C. to a solution of 5.00 g (49.9 mmol) of acetylacetone and 4.50 g (55.0 mmol) of 1-methylimidazole. The reaction mixture was stirred at 0° C. for a further 1 h and at 80° C. for 5 min to form a liquid biphasic mixture. Removal of the upper phase gave 7.00 g (theory: 8.60 g) of 4-trimethylsilyloxypent-3-en-2-one as a bright yellow, cloudy oil having a purity of 84% (GC).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)Cl
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2ccc3ncc(C(C)c4c(F)cc5ncccc5c4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 50 mg, 0.127 mmol) was dissolved in pyridine (1.27 mL) and acetyl chloride (0.014 mL, 0.190 mmol) was added. The RM was stirred at RT for 0.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a beige foam (tR 3.36 min (conditions 1), MH+ 437).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:11](O)(C)C>>[CH:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:2]
Reactant: CCOc1cccc(N)n1
Reactant: CC(C)O
Product: CC(C)Oc1cccc(N)n1

Procedure:
This intermediate is prepared according to the procedure described for 6-ethoxypyridin-2-ylamine, replacing the ethanol with isopropanol. The expected product is obtained in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)[C:14]([N+:27]([O-])=O)=[CH:13][N:12]=2)[CH3:9])=[N:6][CH:7]=1.[CH2:30](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]3[C:14]([N:27]=[CH:30][N:17]3[C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)=[CH:13][N:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(-n2cnc3cnc(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidine-2,4-diamine (Intermediate 32, 0.2 g) was dissolved into ethanol (20 mL) with Pd—C (40 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.08 g desired product. MS (electrospray): 384 (M+1) for C17H18FN9O. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.60 (s, 1H) 8.40 (s, 1H) 6.20 (s, 1H) 5.30 (m, 1H) 4.60 (m, 1H) 1.60 (d, 3H) 1.50 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14]>C(Cl)Cl.C(O)C.[Pd]>[NH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CN1Cc2cccc(N)c2C1=O
Yield: 88.5 %

Procedure:
A solution of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 17F, 6.09 g, 31 mmol) in DCM:ethanol (8:2) was hydrogenated under 40 psi of H2 in the presence of 5% Pd/C (500 mg) until cessation of H2 uptake. The reaction mixture was filtered, and the filtrate dried (Na2SO4) and concentrated in vacuo to afford 4.45 g of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (yield: 73%). 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 4.27 (s, 2H), 5.19 (bs, 2H), 5.5 (d, 1H, J=7.8 Hz), 6.71 (d, 1H, J=7.2 Hz).
Reaction SMILES: C(OC([N:8]1[C@H:17](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][C:29](=[O:31])[N:28]([CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[S:27]3(=[O:39])=[O:38])=[C:22]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:21]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([O:40][C:22]1[CH:21]=[C:20](/[CH:19]=[CH:18]/[C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)[CH:25]=[CH:24][C:23]=1[N:26]1[S:27](=[O:38])(=[O:39])[N:28]([CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:29](=[O:31])[CH2:30]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-3-((E)-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-vinyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.22 g, 0.32 mmol) in CH2Cl2 (8 mL) is added TFA (3 mL). After stirring at RT for 1.5 h, the mixture is concentrated under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A solution of ethyl 4-[(3-aminoquinolin-4-yl)amino]butanoate (49.7 g, 182 mmol, prepared as described in Parts A and B of Example 3) in toluene (500 mL) was heated at reflux for 10 minutes and then cooled slightly. Trimethyl orthobutyrate (29.0 g, 197 mmol) and pyridinium p-toluenesulfonate (0.70 g, 2.8 mmol) were added, and the reaction was heated at reflux under a Dean-Stark trap for 1.5 hours while the distillate was periodically removed. The reaction was allowed to stand overnight at ambient temperature. The toluene was removed under reduced pressure; chloroform (500 mL) and charcoal (4 g) were sequentially added. The resulting mixture was heated at reflux for one hour and then filtered through a layer of CELITE filter agent. The filtrate was washed with saturated aqueous sodium bicarbonate (100 mL), dried over potassium sulfate, filtered, and concentrated under reduced pressure to provide 49.4 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate as a dark oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[O:21]=[C:2]1[O:1][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1C2CCOC(=O)C21
Reaction time: 15 h
Yield: 60 %

Procedure:
To a stirred solution of ethyl (1SR,5RS,6SR)-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate (34.8 g, 207.2 mmol) in dichloromethane (300 mL), 70% m-chloroperbenzoic acid (51.1 g, 207.2 mmol) was added and refluxed overnight. The following day, additional 70% m-chloroperbenzoic acid (51.1 g, 207.2 mmol) was added and reflux continued for 15 hours. After that time, the mixture was diluted with dichloromethane (200 mL), filtered and washed with 10% Na2SO3 (2×200 mL) and with a saturated aqueous solution of sodium bicarbonate (2×200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to give 22.89 g (60% yield) of ethyl (1SR,6SR,7SR)-2-oxo-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate as a colorless oil
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(N(CC)CC)C>[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([NH:49][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:13])[CH2:45][CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a stirred mixture of 5-hydroxy-1H-indole-2-carboxylic acid (1.85 g, 10.43 mmol) in anhydrous dimethylformamide (15 mL) was added triethylamine (1.73 mL), 1-hydroxybenzotriazole (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g) and 1-benzylpiperidin-4-ylamine (2.39 g, 12.54 mmol). The reaction mixture was stirred at room temperature over-night and then solvents were removed under reduced pressure, poured into water, filter the solid and washed with water. The solid was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH (93:7) to afford 0.87 g (24%) of N-(1-benzylpiperidin-4-yl)-5-hydroxy-1H-indole-2-carboxamide as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.17 (s, 1H), 8.72 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.7.29 (m, 6H), 6.91 (s, 1H), 6.82 (s, 1H), 6.68 (m, 1H), 3.75 (br s, 1H), 3.46 (s, 2H), 2.81 (d, J=11.4 Hz, 2H), 2.02 (t, J =10.8 Hz, 2H), 1.77 (m, 2H), 1.56 (m, 2H); LCMS (m/z): 350 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]2[CH2:25][C:26]([O:28]C)=[O:27])=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([CH:19]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]2[CH2:25][C:26]([OH:28])=[O:27])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1C(=O)CCC1C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a stirring solution of methyl (2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-5-oxopyrrolidin-1-yl)acetate obtained in Example 64 (0.39 g, 0.97 mmol) in methanol (12 mL) was added 1 M lithium hydroxide (2.9 mmol, 2.9 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified with 1 M hydrochloric acid (pH 3) and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallized from hexane-diethyl ether to give the title compound (0.24 g, 64%) as a white solid, mp 273° C.