Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:18]=3)[N:13](S(C3C=CC=CC=3)(=O)=O)[CH:12]=2)[N:10]=1)=[O:5])C.[OH-].[Na+]>CCO>[CH2:20]([C:17]1[CH:18]=[C:19]2[C:11]([C:9]3[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=3)=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CC(C)C)cc23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1cnc2[nH]cc(-c3csc(C(=O)O)n3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a stirred solution of 81 (412 mg, 0.99 mmol) in EtOH (10 mL) was added 10% aqueous NaOH (5 mL) and the reaction mixture heated to reflux. After 2 h, the solution was cooled to r.t., and the mixture concentrated to 5 mL under reduced pressure. Acetic acid was then added dropwise with stirring until a precipitate appeared, which was filtered off and dried to afford 82 (267 mg, 0.89 mmol, 90%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, J=6.6 Hz, 2H), 1.92 (nonet, J=6.6 Hz, 1H), 2.60 (d, J=7.2 Hz, 2H), 7.69 (s, 1H), 7.95 (s, 1H), 8.08 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 11.73 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:15][CH:9]([CH2:10][N:11]([CH:13]=O)[CH2:12]1)[CH2:8][C:7]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=1.[ClH:16].[OH-].[Na+].Cl.CCOC(C)=O.N>CO>[ClH:16].[ClH:16].[CH3:13][N:11]1[CH2:12][CH:1]2[CH2:15][CH:9]([CH2:8][C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=32)[CH2:10]1
Reactant: O=CN1CC2Cc3cccnc3C(C2)C1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CC2Cc3cccnc3C(C2)C1
Reaction time: 72 h

Procedure:
3,11-Diaza-tricyclo[7.3.1.02,7]trideca-2,4,6-triene-11-carbaldehyde (75 mg, 0.4 mmol) was stirred in 1M BH3.THF complex (3 mL) at reflux for 18 h at which time additional 1M BH3.THF complex was introduced (3 mL). Heating was continued for 3 days at which time the mixture was cooled and treated with 1N HCl (5 mL) and conc. HCl (1 mL) and the resulting mixture refluxed for 24 h. The mixture was cooled, treated with solid NaOH to achieve pH 10 and extracted with EtOAc (4×10 mL). The organic layer was washed with saturated aqueous NaCl solution (30 mL), dried over Na2SO4, filtered and concentrated to give 48 mg. This material was dissolved in MeOH and treated with 1 mL 3N HCl/EtOAc solution, stirred and concentrated. After recrystallization from MeOH/Et2O, product was filtered and dried to give white solids (49 mg 59%). Mp 260–266° C.; (TLC ˜0.2% NH3/5% CH3OH/dichloromethane Rf 0.33); 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=5.0 Hz, 1H), 8.42 (d, J=8.1 Hz, 1H), 7.95 (m, 1H), 3.78–3.15 (m, 7H), 2.82 (s, 3H), 2.74 (br s, 1H), 2.28 (d, J=13.6 Hz, 1H), 2.09 (d, J=13.6 Hz, 1H); GCMS m/z 188 (M+).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][C:14]3[CH:20]=[C:19]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=3[O:16][C:8]=12>CC(C)=O>[C:21]([C:19]1[CH:18]=[CH:17][C:15]2[O:16][C:8]3=[N:7][CH:12]=[CH:11][CH:10]=[C:9]3[C:13](=[O:2])[C:14]=2[CH:20]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)C(O)c1ccc2c(c1)Cc1cccnc1O2
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)C(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
11 g of potassium permanganate is added in small portions to a solution of 6 g of 1-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-2-methyl-1 -propanol in 160 ml of acetone, and the mixture is stirred at 20°C for 3 hours. The reaction mixture is filtered, and the residue is washed thoroughly with chloroform. The filtrate and washings are concentrated, and the residue is purified by column chromatography on silica gel with chloroform as eluent, and further by recrystallization from acetone to give 7-isobutyryl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 155°-156°C.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cc2)CC1
Reaction time: 2 h

Procedure:
1-Boc-4-(4-nitrophenyl)homopiperazine (prepared with 1-fluoro-4-nitrobenzene, 1-Boc-homopiperazine, Cs2CO3 in heated DMF) was dissolved in methanol. To it was added 10% Pd/C. The slurry was stirred under a hydrogen balloon for 2 hrs. It was filtered through celite and evaporated in vacuuo to give 1-(4-aminophenyl)-4-Boc-homopiperazine. ES-MS: (M+H)+292.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:10]1([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][CH:16]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(OCCN2CCOCC2)c1
Yield: 86 %

Procedure:
A mixture of 4-[2-(3-nitro-phenoxy)-ethyl]-morpholine (4.0 g, 13 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (100 mL) was hydrogenated under 50 psi hydrogen for 23 hours. The mixture was filtered through Celite, and the filtrate was evaporated in vacuo, providing 3.0 g, in 86% yield; 1H NMR (CDCl3) δ 2.58 (t, J=4.7 Hz, 4H), 2.78 (t, J=5.8 Hz, 2H), 3.65 (br, 2H), 3.73 (t, J=4.7 Hz, 4H), 4.07 (t, J=5.8 Hz, 2H), 6.24-6.34 (m, 3H), 7.05 (t, J=8.1 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:11]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[N+](C1C([N+]([O-])=O)=C(C)C=CC=1)([O-])=O.O>[Ni].[Pd]>[C:6]1([CH3:10])[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH2:11]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Ni]
Agent: [Pd]
Solvent: O
Product: Cc1cccc(N)c1N

Procedure:
U.S. Pat. No. 6,005,143 discloses a process for the adiabatic hydrogenation of dinitrotoluene in a monolith catalyst employing nickel and palladium as the catalytic metals. A single phase dinitrotoluene/water mixture in the absence of solvent is cycled through the monolith catalyst under plug flow conditions for producing toluenediamine.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1(OB(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:15]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([O-:17])=[O:16]
Reactant: OB(O)Oc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
3-(4-Bromo-3-nitrobenzoyl)propionic acid (45.3 g, 150.0 mmol) was dissolved in 1,4-dioxane (400 mL), thereto were added phenyl boric acid (27.4 g, 225.0 mmol), cesium carbonate (146.6 g, 450.0 mmol), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.7 g, 4.5 mmol), and purified water (150 mL), and the reaction mixture was stirred under a nitrogen flow at 80° C. for 18 hours. The reaction solution was filtered through celite, alumina, and Florisil, and, thereafter, the aqueous layer was separated. The organic layer was extracted with a dilute aqueous solution of sodium hydroxide. After the aqueous layers were combined and washed with ethyl acetate, the layer was acidified, under ice-water cooling, with 6 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-(3-nitro-4-phenylbenzoyl)propionic acid (39.4 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[CH3:9][CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[N:4]=1)[CH3:10]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CC(C)c1nc(CCl)cs1
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 60-63° C.; 1H NMR (300 MHz, CDCl3) δ7.28-7.21 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06-6.98 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 6.26 (s, 1H), 5.15 (d, J=16.2 Hz, 1H), 4.95 (d, J=16.2 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H), 3.37-3.22 (m, 1H), 1.39 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 178.5, 177.2, 155.2, 150.2, 144.6, 142.1, 138.3, 132.2, 128.8, 123.7, 123.4, 121.1, 114.1, 111.6, 109.7, 99.4, 80.1, 64.5, 63.9, 58.1, 40.6, 33.3, 23.1; MS (ES+) m/z 434.9 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[O:8][CH2:7][CH2:6]2.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:14])[F:15])[O:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Agent: Br
Solvent: CC(=O)O
Product: CC1(C(F)(F)F)OCCc2cc(O)ccc21
Temperature: 130 °C
Reaction time: 13 h
Yield: 99.5 %

Procedure:
To a stirred solution of 6-Methoxy-1-methyl-1-trifluoromethylisochroman (71 g, 0.29 mol) in acetic acid (600 mL) was added aqueous 48% HBr (300 mL) and the mixture was stirred at 130° C. for 13 hr. After removing acetic acid in vacuo, the reaction mixture was treated with aqueous NaOH (8 M) until the pH became 5-6. The resultant solution was extracted with ethyl acetate (400 mL×2) and the combined ethyl acetate extracts were washed with brine(100 mL), dried over MgSO4, and concentrated in vacuo. Flash chromatography (Silica-gel, 15×20 cm, 17% ethyl acetate/hexane) afforded 6-hydroxy-1-methyl-1-trifluoromethylisochroman (67 g, 100%) as a colorless oil. 1H-NMR(CDCl3): 7.22 (d, J=9.1 Hz, 1H), 6.73 (dd, J=9.1, 2.6 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 5.00 (s, 1H, 4.17-4.07 (m, 1H), 3.90 (dt, J=11, 5.8 Hz, 1H), 2.84-2.78 (m, 2H), 1.64 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1.C(S(C1[CH:26]=[CH:27][C:28](OC)=[C:29]([C:31]2[NH:32][CH:33]=CC=2)C=1)(=O)=O)C>>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:13]2[NH:14][C:15]([CH2:33][N:32]3[CH2:31][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:17]=2)[CH:5]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1
Reactant: CCS(=O)(=O)c1cc(Br)c(OC)c(-c2ccc[nH]2)c1
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2ccc[nH]2)c1
Product: CCS(=O)(=O)c1cc(Br)c(OC)c(-c2ccc(CN3CCCCC3)[nH]2)c1

Procedure:
This compound was prepared by a method analogous to that used to prepare example 2, but using 2-(3-bromo-5ethylsulphonyl-2-methoxy-phenyl)-1H-pyrrole (prepared according to the method of Kruse et al., [Heterocycles, 26,3141, 1987] from the corresponding acid chloride) in place of 2-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole. NMR δ(CDCl3) 1.30-1.70 (9H, m), 2.40 (4H, m), 3.15 (2H, q, J=7 Hz), 3.50 (2H, s), 3.80 (3H, s), 6.10 (1H, t, J=2 Hz), 6.60 (1H, t, J=2 Hz), 7.80 (1H, d, J=1 Hz), 8.00 (1H, d, J=1 Hz), 9.9 (1H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][NH:7]1)=[O:5])C.C(C1CCNC1C(O)=O)C.C(C1(C(OCC)=O)C(CC)CCN1)(OCC)=O>>[CH:11]([CH:10]1[CH2:9][CH2:8][NH:7][CH:6]1[C:4]([OH:5])=[O:3])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C1(C(=O)OCC)NCCC1C(C)C
Agent: CCC1CCNC1C(=O)O
Agent: CCOC(=O)C1(C(=O)OCC)NCCC1CC
Product: CC(C)C1CCNC1C(=O)O

Procedure:
The title compound was prepared from diethyl-3-isopropylpyrrolidine-2,2-dicarboxylate (3.06 g, 12.0 mmol) essentially according to the basic hydrolysis procedure described in Morgan, B. A.; Schafer, D. J. U.S. Pat. No. 4,060,603, Nov. 29, 1977 for the preparation of 3-ethyl-dl-proline from 2,2-dicarboethoxy-3-ethylpyrrolidine. The product was isolated as a yellow solid. LCMS (M+H): 158.0. 1H NMR (CD3OD, 400 MHz): δ 3.70 (d, J=6.4 Hz, 1 H), 3.31–3.27 (m, 1 H), 2.29–2.22 (m, 1 H), 2.08–1.99 (m, 1 H), 1.94–1.74 (m, 3 H), 1.05 (d, J=6.8 Hz), 0.97(d, J=6.8Hz, 3 H).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[CH:17][CH:18]=1.[C:20]1([C:26]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:30][CH:29]=[CH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCCC1>[F:19][C:15]1[CH:14]=[C:13]([C:29]2[N:30]=[C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][CH:28]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc(Br)c1
Reactant: c1ccc(-c2nccnc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Fc1cccc(-c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1
Reaction time: 0.5 h
Yield: 8 %

Procedure:
First, 7.5 mL (1.58 mol/L) of hexane solution of n-butyllithium was added dropwise to a mixed solution of 1.49 g of 3-bromofluorobenzene and 11 mL of tetrahydrofuran at −78° C. under an atmosphere of nitrogen, and stirred for 30 minutes, keeping the temperature at −78° C. The obtained solution was added dropwise to a mixed solution, which was cooled with ice, of 2.45 g of 2,3-diphenylpyrazine and 20 mL of tetrahydrofuran, and stirred for 1 hour at room temperature. Water was added to this mixture and an organic layer was extracted using ethyl acetate as an extraction solvent. The obtained organic layer was washed with water and dried with anhydrous magnesium sulfate. After drying, the solution was filtrated. The solvent of the solution was distilled off and the residue obtained by distillation was purified by silica gel column chromatography using dichloromethane as a developing solvent. In this way, Hdppr-3FP (an orange powder, yield: 8%), which was a target substance was obtained. A synthetic scheme of Step 1 is shown by a following (c-2).
Reaction SMILES: [O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH:28]1([S:33][CH2:34][CH2:35]Cl)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:35][CH2:34][S:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: ClCCSC1CCCC1
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 65 °C
Reaction time: 17 h
Yield: 39.4 %

Procedure:
A mixture of 4.9 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate, 2.9 g of 2-chloroethyl cyclopentyl sulfide, 9 g of potassium carbonate, and 2.7 g of potassium iodide in 130 cm3 of acetonitrile was stirred for 17 hours at a temperature in the region of 65° C. After cooling to a temperature in the region of 20° C., the reaction mixture has 150 cm3 of water added and was extracted with 3 times 60 cm3 of ethyl acetate. The organic extracts were combined, washed with 2 times 50 cm3, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil was obtained, which product was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 4 cm; silica volume 300 cm3), elution was carried out with pure ethyl acetate, and approximately 70-cm3 fractions were collected. The fractions comprising the expected product were combined and then concentrated under the above conditions. 2.6 g of methyl (3R,4R)-4-(3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CC(C)=O>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL of acetone. The solution was cooled to −30° C. under the protection of nitrogen flow and then 50 mmol of lithium tert-butoxide was added. The mixture was stirred at −30° C.˜20° C. for 2 hours, (S)-1-chloro-3-(dibenzylamino)propan-2-ol (2.9 g, 10 mmol) was added and then the solution was heated slowly to 60° C. and stirred for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 285 mg of white solid in 60% yield. HPLC: 99.2%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5](OCC)=[O:6])[CH3:2].[NH4+:13].[OH-]>>[CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([NH2:13])=[O:6])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(OCC)OCC
Agent: [OH-]
Product: CCOC(OCC)C(N)=O
Yield: 99 %

Procedure:
Ethyl diethoxyacetate (Aldrich) (10 mL, 56.41 mmol) was added to concentrated NH4OH (50 mL) and the mixture allowed to stir until a homogeneous solution was obtained (40 hours). The solvent was then removed under reduced pressure to yield the sub-title compound as fine white needles (8.209 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@@H:9]1[CH:14]=CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].[O:23]=[O+][O-]>CO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@H:9]1[CH:14]=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@@H]1C=Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@H]1C=O
Temperature: 23 °C
Yield: 98 %

Procedure:
Through a stirring solution of [(2R,3R)-2-styryl-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (27 mg, 0.089 mmol) in methanol (2 mL) at −78° C. was bubbled ozone until the reaction solution was blue in color. Excess triphenylphosine (500 mg) was added, and the reaction was allowed to warm to 23° C. The resulting mixture was concentrated and purified by flash chromatography (SiO2, 7-40% ethyl acetate in hexanes) to give the desired aldehyde (20 mg, 98%) as a pale yellow oil. MS (APCI), m+/z: (M+H)+=230.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17][CH2:18]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:18][CH2:17][O:16][CH3:15])[CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cncc(Br)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 611 mg, 3.51 mmol), potassium carbonate (971 mg, 7.02 mmol) and 2-bromoethyl methyl ether (537 mg, 3.86 mmol) in 30 ml DMF was stirred for 14 h at rt and for 2 h at 80° C. The reaction mixture was quenched with water and extracted with EtOAc (2×). The organic layers were washed with brine (3×), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (dichloromethane/MeOH 0% to 3%) to give the title compound as an oil. (HPLC: tR 2.38 min (Method A); M+H=232, 234 MS-ES).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])=[C:14]([NH:19][C:20](=O)[CH2:21][O:22][CH2:23][CH3:24])[CH:15]=[N:16]2)=[N:11][CH:10]=1>C(O)C>[Br:8][C:9]1[CH:10]=[N:11][C:12]2[C:13]3[N:26]([CH2:27][C:28]([CH3:30])([OH:31])[CH3:29])[C:20]([CH2:21][O:22][CH2:23][CH3:24])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1
Reactant: CCOCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Temperature: 77 °C
Yield: 90.9 %

Procedure:
Potassium carbonate (113 g) water (565 mL) were sequentially added to a solution of N-{7-bromo-4-[(2-hydroxy-2-methylpropyl)amino][1,5]naphthyridin-3-yl}-2-ethoxyacetamide hydrochloride (113 g, 261 mmol) in denatured ethanol (1.695 L), and the resulting mixture was heated at reflux (77° C.) overnight and allowed to cool to room temperature. The ethanol was removed under reduced pressure, and the resulting mixture was filtered to isolate a solid. The solid washed with water (100 mL) and dried over two nights in a vacuum oven at 40° C. to provide 90 g of 1-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a brown solid.
Reaction SMILES: [CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29][CH:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:31])=[O:27])=[CH:20][CH:19]=2)[C:8]([O:10]C2CCCC2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29][CH:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:31])=[O:27])=[CH:20][CH:19]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)/C=C/c1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cc1
Solvent: CO
Product: CC(C)COC(C)ONC(=O)/C=C/c1ccc(CN[C@H](C(=O)O)C2CCCCC2)cc1
Temperature: 45 °C
Reaction time: 96 h
Yield: 53.9 %

Procedure:
1N NaOHaq (3 mL) was charged to a solution of cyclopentyl (2S)-cyclohexyl[(4-{(1E)-3-[(1-isobutoxyethoxy)amino]-3-oxoprop-1-en-1-yl}benzyl)amino]acetate (prepared as described in Example 14—0.3 g, 0.6 mmol) in MeOH (5 mL) and stirred at 45° C. for 4 days. The MeOH was removed in vacuo and the residue washed with EtOAc (10 mL). The aqueous phase was acidified to pH ˜2 with saturated citric acid solution, extracted with EtOAc (2×10 mL) and the organic phase dried (MgSO4) and concentrated in vacuo to afford the product as a yellow oil (0.14 g, 53%). m/z=433 [M+H]+.