Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(CC)=O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH2:6][C:5]2=[O:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.2 g (131.2 mmol) of 6-hydroxy-2,2-dimethylchroman-4-one were introduced into 350 ml of diethyl ketone with stirring at RT and, after addition of 18.0 g (131 mmol) of powdered potassium carbonate, stirred at 75° C. for 30 min. After cooling to 60° C., 15.7 ml (131 mmol) of benzyl bromide were added dropwise, the mixture was concentrated in vac. after 2 h, the residue was treated with water and the solid was filtered off with suction, 37 g, m.p. 105-107° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].CS(O[CH:21]([CH2:25][O:26][CH3:27])[CH2:22][O:23][CH3:24])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].S([O-])(=O)(=O)C>CN(C=O)C.C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH:21]([CH2:25][O:26][CH3:27])[CH2:22][O:23][CH3:24])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(COC)OS(C)(=O)=O
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COCC(COC)Oc1cc(C(=O)OC)cc(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 60.3 %

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 2.28 g) and 2-methoxy-l-methoxymethyl-ethyl methanesulfonate (2.93 g) were dissolved in DMF (50 ml), and cesium carbonate (4.82 g) was added. After stirring at 50° C. for 6 h, the mixture was left to stand overnight. After stirring at 50° C. for 4 further hours, one further eq. of cesium carbonate and one further eq. of the mesylate were added, and the mixture was stirred at 50° C. for a further 4 h and left to stand overnight. Then the mixture was stirred at 50° C. for a further 8 h and left to stand for 6 days, and then a further 0.5 eq. of cesium carbonate and mesylate was added. After stirring at 50° C. for a further 8 h, the mixture was left to stand for 5 days, then the DMF was drawn off and the residue was taken up with DCM/water. The DCM phase was removed and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MTB ether gradient 0-50% within 60 min). 2.05 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][C@H:31]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[N:43]4[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]4)[C:32]([F:35])([F:34])[F:33])[N:27]=[C:26](S(C)(=O)=O)[N:25]=3)[CH2:20][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1([OH:59])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][C@H:31]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[N:43]4[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]4)[C:32]([F:35])([F:34])[F:33])[N:27]=[C:26]([O:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:25]=3)[CH2:20][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(S(C)(=O)=O)n2)C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(Oc3ccccc3)n2)C(F)(F)F)n1
Temperature: 70 °C

Procedure:
To a solution of 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (300 mg, 0.393 mmol) in 1,4-dioxane (10 mL) was added phenol (74 mg, 0.79 mmol), Cs2CO3 (512 mg, 1.5 mmol), and the reaction was heated to 70° C. for 21 h. The reaction was then cooled to RT, diluted with water, acidified to pH<1 with 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 50 g Isco Gold RediSep reverse phase silica cartridge (H2O:HOAc: 99:1 MeOH:HOAc 99:1) provided 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1([CH2:37][CH2:38]O)[CH:36]=[CH:35][N:34]=[CH:33]1.N(C(OCC)=O)=NC(OCC)=O>CCOC(C)=O.C1COCC1>[N:32]1([CH2:37][CH2:38][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]3)=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: OCCn1ccnc1
Reactant: O=c1ccoc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1ccoc2cc(OCCn3ccnc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Under N2, a solution of 0.75 g (4.6 mmol) of 7-hydroxy-4H-4-chromenone (J. Med. Chem., 1991;34:248) in 20 ml, of THF was treated with 1.21 g (4.6 mmol) of triphenylphosphine and 0.5 g (5.1 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and the solution cooled in ice. This was then treated over 10 minutes with 0.72 mL (4.6 mmol) of diethyl azodicarboxylate, and the solution stirred at room temperature overnight. The solution was diluted with EtOAc, washed twice with H2O, twice with saturated NaHCO3, and then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 to CH2Cl2/MeOH (96/4) gave 0.12 g (10% yield) of the product as a pink solid, mp 131-133° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 257 (M+H+).
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H]2CC[C@H](CC(OC)=O)CC2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].COC(=O)C(NC1C=CC([S:37]([C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])(=[O:39])=[O:38])=CC=1)=O>>[NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:37]([C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])(=[O:39])=[O:38])=[CH:11][CH:12]=1)=[O:5])[NH2:2]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: COC(=O)C(=O)Nc1ccc(S(=O)(=O)C(C)(C)C(=O)OC)cc1
Product: COC(=O)C(C)(C)S(=O)(=O)c1ccc(NC(=O)C(=O)NN)cc1

Procedure:
The procedure described for Intermediate 43 (part iv) was followed starting with methyl 2-[(4-{[methoxy(oxo)acetyl]amino}phenyl)sulphonyl]-2-methylpropanoate to give the title compound; 1H NMR δ 1.56 (s, 6H), 3.67 (s, 3H), 4.77 (s, 2H), 7.77 (d, 2H), 8.11 (d, 2H); MS m/e (M+Na)+ 366.
Reaction SMILES: [N:1]([C@@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+]=[N-]>CO>[NH2:1][C@@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@H]1N=[N+]=[N-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@H]1N
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To a clean dry 1 L RBF charged with tert-butyl [(1R,2S)-2-azido-3,3-difluorocyclohexyl]carbamate 35 (18.84 g, 68.2 mmol) was added 400 mL methanol. The system was degassed and purged (3× with N2) before the addition of Pd/C (1.45 g). The reaction was stirred for 2 d under 1 atm of hydrogen. Upon reaction completion, the reaction was filtered through a plug of celite and concentrated to dryness to yield tert-butyl [(1R,2S)-2-amino-3,3-difluorocyclohexyl]carbamate 38 (16.47 g, 97% yield) as a pure white solid. 1H NMR (CDCl3, 500 MHz) δ 4.76-4.74 (1H, d, J=10 Hz), 3.61-3.56 (1H, m), 2.63-2.59 (1H, dd J=9.5 Hz), 2.2-2.0 (2H, m), 1.8-1.68, (2H, m), 1.53-1.42 (11H, m), 1.29-1.21 (m, 2H); 19F NMR (CDCl3, 564 MHz) δ −101.7-−102.1 (1F, J=241 Hz), −114.3-−114.9 (1F, m)
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1.C(O)(=O)C>O1CCCC1.O>[CH3:3][CH:4]1[CH2:8][CH2:7][N:6]([C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)[C:5]1=[O:9]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)N2CCC(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
While 2 g of sodium hydride (60% oily) was being stirred in 50 ml of tetrahydrofuran, 5 g of 3-methyl-2-pyrrolidinone was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to not higher than 0° C., and 7.5 g of 4-methoxyphenyl isocyanate was added dropwise to the mixture, followed by stirring at the same temperature for 5 hours. Acetic acid was then added to the reaction mixture for neutralization, water was thereafter added to the mixture, and the solvent was distilled off in a vacuum. Water was added to the residue, and the precipitate was filtered off, giving 8.2 g of 3-methyl-1-(4-methoxyphenylcarbamoyl)-2-pyrrolidinone (yield 66%) having a melting point of 71° to 72° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20].[O:33]([CH2:51][CH2:52][CH2:53][OH:54])[Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:34]([O:33][CH2:51][CH2:52][C@@H:53]([OH:54])[C@H:22]([C:16]1[CH:15]=[C:14]([F:13])[C:19]([F:20])=[C:18]([F:21])[CH:17]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([C:47]([CH3:49])([CH3:50])[CH3:48])([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1.[Si:34]([O:33][CH2:51][CH2:52][C@H:53]([OH:54])[C@H:22]([C:16]1[CH:15]=[C:14]([F:13])[C:19]([F:20])=[C:18]([F:21])[CH:17]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([C:47]([CH3:49])([CH3:50])[CH3:48])([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1cc(F)c(F)c(F)c1)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC[C@@H](O)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OCC[C@H](O)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (1.82 mL; 2.66 M solution in hexane) was added dropwise to a solution of diisopropylamine (0.735 mL) in THF (6 mL) at 0° C. The reaction solution was stirred at 0° C. for 20 minutes and then cooled to −78° C. Benzyl (3,4,5-trifluorophenyl)acetate (1.13 g) in THF (18 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at −78° C. for 15 minutes. Thereafter, 3-(tert-butyldiphenylsiloxy)propanol (CAS No. 112897-03-7, 1.26 g) in THF (6 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at −78° C. for 30 minutes. A saturated ammonium chloride solution was added to the reaction solution, and the reaction solution was returned to room temperature. Ethyl acetate was added and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 840 mg of benzyl (2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate and 765 mg of benzyl (2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:13]([C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](O)=[O:25])[CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[N:9]2)=[CH:4][CH:3]=1.C(O)C>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
A solution of 2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid (74.9 kg, 175.9 mol), (1S, 2R)-ephedrine hemihydrate (32.5 kg, 186.5 mol), 200 proof ethanol (290 Kg) and water (17 L) were stirred and heated to about 35° C. for 35 minutes. The solution was filtered and then cooled to about 20° C. until the onset of crystallization. The reaction was further cooled to 0–5° C. for about 2 hours. The intermediate ephedrine salt was filtered and washed with a cold (0–5° C) solution of 200 proof ethanol (206 Kg) and water (10 L). The ephedrine salt was dissolved in 377 L of dichloromethane and stirred with 125 L water and 9.7 kg 37% hydrochloric acid. The aqueous layer was removed. The organic layer was washed with water (125 L). The organic layer was distilled to 60% of the original volume. Carbonyldiimidazole was dissolved in CH2Cl2 (128 L) and slowly transferred to the reaction solution. The reaction was complete after 20 minutes. The reaction was washed two times with water (250 L each). The CH2Cl2 solution was distilled atmospherically, the volume being replaced-with of 200 proof ethanol (500 Kg). The ethanol solution was cooled at a rate of 20±5° C. per hour to 0–5° C. The solution was then held at 0–5° C. for 16 hours. The product was filtered and washed with 200 proof ethanol (100 kg). The product was dried for 16 hours under vacuum at 60° C. This afforded 26.0 Kg of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone as a white solid (36% yield). 1H-NMR: δ 8.87 (d, J=8.8, 1H), 8.61 (m, 2H), 7.93 (d, J=7.0, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m, 1H), 3.28 (dd, J=7.0, 17.2, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J=6.2, 6H); Cl (MS) M+1 at 408, 100%; [α]D20=+135° (c=1, dichloromethane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[H-].[Na+]>CN(C=O)C.O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH2:18])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Nc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Temperature: 50 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.52 g, 2.0 mmol) and 2-aminophenol (0.26 g, 2.4 mmol, Aldrich) in DMF (10 mL) was added sodium hydride (0.09 g, 2.2 mmol, 60% dispersion in mineral oil, Aldrich). The mixture was heated at 50° C. for 2 h, allowed to cool to room temperature and diluted with H2O. The resulting solid was filtered, washed with H2O and dried in vacuum at room temperature for 20 h to afford the title compound as a white powder. Mp: 188° C., MS (ESI, pos. ion) m/z: 332 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>[C].[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: COCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(N)c(F)c1
Yield: 73.1 %

Procedure:
10% Palladium-carbon (390 mg) as a catalyst was added to an ethanol (100 mL) solution of 2-fluoro-4-(methoxymethoxy)-1-nitrobenzene (3.86 g), and stirred overnight in a hydrogen atmosphere at room temperature. The catalyst was removed through filtration, the solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (methanol/chloroform=from 0% to 20%, gradient) to give the entitled compound (2.40 g, 73%) as a brown oily substance.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[N:20]=[C:19]3[C:14]([CH2:15][CH2:16][C:17](=[O:21])[NH:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:31]1([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]3[N:20]=[C:19]4[C:14]([CH2:15][CH2:16][C:17](=[O:21])[NH:18]4)=[CH:13][CH:12]=3)[CH2:2][CH2:3]2)[C:32]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Brc1cccc2ccccc12
Reactant: O=C1CCc2ccc(OCCCN3CCNCC3)nc2N1
Product: O=C1CCc2ccc(OCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1

Procedure:
In a similar manner to the example shown above, 7-(3-piperazin-1-yl-propoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one was coupled to 1-bromo-naphthalene to give the title compound (0.189 g). MS: APCI: M+1: 417.2 (Exact Mass: 416.22).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]([O:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])[O:17][CH2:18][CH3:19])=[CH:9][CH:8]=1.[C:27]1([CH3:38])[CH:32]=[CH:31][C:30]([S:33]([O:36]C)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[CH:39](OC(C)C)(C)C>C(Cl)Cl>[C:27]1([CH3:38])[CH:28]=[CH:29][C:30]([S:33]([O-:36])(=[O:34])=[O:35])=[CH:31][CH:32]=1.[CH2:18]([O:17][CH:16]([O:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:5]([CH2:4][CH2:3][S+:2]([CH3:39])[CH3:1])=[O:26])=[CH:12][CH:11]=1)[CH3:19]
Reactant: CCOC(CCOc1ccc(NC(=O)CCSC)cc1)OC(=O)COC
Reactant: CC(C)OC(C)C
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: CCOC(CCOc1ccc(NC(=O)CC[S+](C)C)cc1)OC(=O)COC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
Dissolved in 30 ml of methylene chloride was 3.85 g of 2-{4-(3-ethoxy-2-methoxyacetoxypropoxy)phenylcarbamoyl}ethyl methyl sulfide. Thereto was added 5.58 g of methyl p-toluenesulfonate and the mixture was stirred at room temperature for 48 hours. Isopropyl ether was adde to the reaction mixture and the insoluble solid was separated. The solid was purified with acetonitrile-ether, giving 5.30 g of 2-{4-(3-ethoxy-2-methoxyacetoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate (Compound 62) in 92.7% yield.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N:16]([O-])=O.[Na+]>O.Cl.CC#N>[ClH:1].[NH:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)[NH2:16]
Reactant: Nc1ccc(C(=O)O)c2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NNc1ccc(C(=O)O)c2ccccc12
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2.4 g of 4-amino-1-naphthalenecarboxylic acid hydrochloride are mixed at 0° C. with 80 ml of concentrated HCl. A solution of 0.89 g of sodium nitrite in 19 ml of water is added and the mixture is left stirring for 2 hours at 2-3° C. It is cooled to -10° C., and a solution of 9.7 g of stannous chloride dihydrate in 90 ml of concentrated HCl is added slowly. The temperature is allowed to rise to RT and the mixture is kept stirring for 30 minutes. 200 ml of water are added, the mixture is left stirring for 30 minutes and the solid formed is drained. The solid is taken up in MeCN, drained, washed with ether and dried. 2.2 g of the expected product are obtained, m.p.=190° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 4-(3-(piperidin-1-yl)propoxy)benzaldehyde (WO 02/12214 A2) (1.90 g, 7.68 mmol) in dichloromethane (25 ml) was added 1-N tert butoxy carbonyl piperazine (1.57 g, 8.45 mmol) followed by acetic acid (1 ml), and the reaction stirred for 1 hour at room temperature, then treated with sodium triacetoxy borohydride (2 g, 9.61 mmol) and stirred for 16 hours at room temperature. The reaction was then diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane was then washed sequentially with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo to yield a residue which was purified using silica gel chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (1.586 g, 50%); MS (ES+), m/e 418 [M+H]+.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[O:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.N1C=CC=CC=1.O>C1COCC1>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(-c2cc(C(N)=O)on2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(-c2ccc(CO)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A mixture of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 18; 800 mg, 2.4 mmol) in THF (8 mL) and HF/pyridine (70%; 0.25 mL) was stirred at room temperature. After 30 min, an addition portion of THF (8 mL) was added and the mixture was stirred for 5 h. H2O was added and the mixture was extracted four times with CHCl3/CH3OH (7:3). The organic layers were dried (Na2SO4), filtered and evaporated to give 3-(4-hydroxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (300 mg, 57%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].Cl.[CH3:18][O:19]N.C1(C)C=CC=CC=1.[N:28]1C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:19][CH3:18])[C:13]([N:15]=[NH:28])=[O:14])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OCc1ccccc1C(=O)C(N)=O
Reactant: c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(C(=O)N=N)c1ccccc1COC(C)=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-oxoacetamide (776 mg), O-methylhydroxylamine hydrochloride (439 mg), toluene (7.0 ml) and pyridine (3.5 ml) was stirred at 80° C. for 2 hours. After the reaction mixture was cooled by allowing it to stand, the reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water, saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (830 mg). This crude product was purified by column chromatography on silica gel to obtain the title compound (793 mg, yield: 90.3%, pale yellow crystals) as a mixture of the E- and Z-isomers (E/Z=56/44 determined by 1H-NMR analysis).