Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>FC(C1C=CC=CC=1)(F)F>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:17]=2)[CH:14]=1
Reactant: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of N-{6-[(4-methoxybenzyl)oxy]imidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (10.1 g, 29.9 mmol) and anisole (25.97 mL, 239.2 mmol) in trifluoromethylbenzene (200 mL) was added trifluoroacetic acid (40.4 mL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 5 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (5.7 g, 88%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.[CH2:22]1COC[CH2:23]1.CO.O[Li].O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[CH:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To 450 mg (1.36 mmole) of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 9 mL of a solvent mixture of THF/MeOH (7:2) followed by 172 mgs of LiOH—H2O in 1 mL of H2O. The mixture was stirred for 30 min at rt. The mixture was concd, treated with 10 mL of water and acidified with conc. HCl (approx. 0.4 mL). The producted oiled out of solution and was extracted three times with diethyl ether. Combined extracts were dried and concd to afford 0.32 g of a crude yellow solid. Chromatography (C18, Gilson 10×4 cm, 7 injections of 50 mgs each) afforded 0.18 g (43.7%) of a white solid: 1H NMR (d6-acetone/400 MHz) 3.74 (s, 1H), 6.03 (q, 1H, 6.8 Hz), 7.61 (m, 2H), 7.92 (s, 1H); 13C NMR (d6-acetone/400 MHz) 72.0 (q, J=33.2 Hz), 80.0, 81.6, 118.3, 119.6, 121.7, 121.8 (q, J=0.7 Hz), 124.2 (q, J=286.6 Hz), 132.5, 136.1, 136.7, 149.9, 164.6; 19F NMR (d6-acetone/400 MHz) −79.6 (d, 3F, J=6.5 Hz); MS (ES+) 303 (M+1, 27), 291 (65), 289 (51), 235 (100), 233 (79); MS(ES−) 301 (M−1, 100), 303 (35); HRMS (EI−) m/z calcd for (C13H5O3ClF3) 300.9874, found 300.9837.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>>[ClH:21].[CH:18]([O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CC(C)Oc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-isopropoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 178.3 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([NH:6][C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[C:4]([F:19])[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:33]([O-])([O-:35])=[O:34].[NH4+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:17]([CH3:18])=[C:16]([N+:33]([O-:35])=[O:34])[C:5]([NH:6][C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[C:4]([F:19])[CH:3]=1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)c(F)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Cl)cc(F)c(NC(=O)Oc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.1 %

Procedure:
4-Chloro-2-fluoro-5-methyl-N-phenoxycarbonylaniline (7.1 g, 25.4 mmol) was dissolved in chloroform (68 ml) and trifluoroaceticanhydride (13.5 ml) and ammonium nitrate (2.4 g, 30.5 mmol) were slowly added with stirring at ambient temperature. The stirring was continued for 18 hr when a second batch of ammonium nitrate (0.4 g, 5 mmol) was added and stirring continued for 8 hr. Water was added and solution was neutralized by slow addition of sodium bicarbonate solution followed by extraction with chloroform. Organic layer was dried and evaporated under reduced pressure to afford an oily product (8.5 g) which was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=2[N:7]=[C:6]1CO.[O-][Mn](=O)(=O)=O.[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=2[N:7]=[CH:6]1
Reactant: Cc1cccc2c1nc(CO)n2Cc1c(F)cccc1F
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cccc2c1ncn2Cc1c(F)cccc1F
Reaction time: 1 h
Yield: 80 %

Procedure:
In this Example, 1-(2,6-difluorobenzyl)-4-methylbenzimidazole (49) was prepared according to Method D. To 1-(2,6-difluorobenzyl)-2-hydroxymethyl-4-methylbenzimidazole (Example 40) (1.82 g, 4.52 mmol) dissolved in 1.5 M H2SO4 (40 mL) was added KMnO4 (1.50 g, 9.49 mmol, 160 M%). After 1 h at room temperature, the reaction mixture was filtered and washed with water. The brown solid was collected, suspended in acetone/methanol and filtered. The filtrate was collected and purified by flash chromatography eluting with 10% MeOH/CH2Cl2 increasing to 50% MeOH/CH2Cl2 to produce 1.42 g (4.70 mmol, 80% yield) of white powder. 1H-NMR (200 MHz, CD2Cl2): δ7.99 (br s, 1H, H2), 7.37 (br d, J=7.9 Hz, 1H, H7), 7.32 (m, 1H, H4″), 7.17 (dd, J=7.3, 7.9 Hz, 1H, H6), 7.03 (d, J=3.2 Hz, 1H, H5), 6.96 (m, 2H, H3″,5″,), 5.40 (s, 2H, CH2PhF2), 2.59 (s, 3H, CH3).
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)Cl.[C:6]1([N-:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:27]1([N-:26][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Ti+4:1]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Li+]
Agent: c1ccc([N-]c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Ti+4]
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The same apparatus described in Step (1) of Example 1-E is used in this procedure. The 250 ml dropping funnel is charged with toluene, 50 ml, and titanium tetrachloride, 2.4 ml (0.022 mole). This is added dropwise to the flask containing lithium diphenylamide which is maintained at -20° C. during the addition while stirring magnetically. Total addition time is 30 minutes. The mixture is warmed to room temperature and then refluxed for 2 hours. All volatiles are removed under vacuum to give a deep red oily residue. Unreacted diphenylamine is sublimed from the oil under reduced pressure at 120° C. to give a red solid: Extraction of the solid with hexane, 50 ml, followed by solvent volume reduction under vacuum then cooling to -30° C. yields red crystals of titanium tetrakis(diphenylamide).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@@H:13]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15].CNN>ClCCl>[NH2:3][O:12][C@@H:13]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)ON2C(=O)c3ccccc3C2=O)cc1
Agent: CNN
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)ON)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-((1,3-dioxoisoindolin-2-yl)oxy)succinate (68 g, 149 mmol) in Dichloromethane (DCM) (500 mL) was added methylhydrazine (7.86 mL, 149 mmol) dropwise at 0° C. over 30 min. The mixture was allowed to warm to rt and stirred at rt for 1 h. LCMS indicated completion of the reaction. The insoluble material was removed by filtration and the filtrate was concentrated and diluted with toluene. The resulting precipitate was removed by filtration again and the filtrate was concentrated to afford crude (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(aminooxy)succinate (47 g, 144 mmol, 97% yield) as a pale yellow oil. The product was used in next step without further purification. LCMS: (M+H)+: 326.1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][C:18](=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:19]3=[O:22])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:30][CH3:31]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH:18]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:19]3=[O:22])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:30][CH3:31]
Reactant: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)C(=Cc2ccccc2)CC3)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)C(Cc2ccccc2)CC3)ccc1O
Yield: 69.7 %

Procedure:
The compound of Example 248 (500 mg) is dissolved in ethyl acetate (20 ml), and thereto is added 10% palladium on carbon (50 mg), and the mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (350 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[N:6][C:7]=1[C:8](=[O:16])[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.[OH-].[Na+]>CCOC(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])=[N:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][NH:26][CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: COCCCN(CCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCNCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Reaction time: 3 h

Procedure:
A mixture of the product of step (v) (300 g, 0.58 mol) in 4N—HCl in EtOAc (3 L) was stirred for 3 hours. The suspension was filtered and the yellow solid obtained. The solid was dissolved in H2O (1.2 L). 2N—NaOH was added dropwise into the solution to basified to pH=11. The mixture was extracted with a mixture of THF and EtOAc (5 L×2, 1:1) and the organic phase washed with aqueous 10%—NaCl and concentrated in vacuo. The subtitle compound (vi) was obtained (pale yellow solid, 210 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([NH:39][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 17 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as described in Example 164B (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.035 g, 17%). 1H NMR (300 MHz, CDCl3) δ 9.45 (br, 1H), 8.77 (s, 1H), 7.80 (s, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.35 (m, 2H), 7.28 (s, 1H), 7.21 (s, 1H), 6.31 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.91 (s, 3H); LC-MS (ESI) m/z 505 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:35][CH3:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[C:19]([O:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15].[Br:37]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Br:37][C:22]1[CH:21]=[C:20]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])[C:19]([O:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[CH:18][C:17]=1[C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:35][CH3:36])[CH:6]=1
Reactant: CCC(C)COc1ccc(-c2ccc(OCC(C)CC)c(OCC(C)CC)c2)cc1OCC(C)CC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)COc1ccc(-c2cc(OCC(C)CC)c(OCC(C)CC)cc2Br)cc1OCC(C)CC
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
339 g (679.7) mmol of 3,3′,4,4′-tetra(2-methylbutyloxy)biphenyl were dissolved in 800 ml of ethyl acetate. 120.98 g (679.7 mmol) of N-bromosuccinimide were then added in solid form over a period of 15 minutes under protective gas, in the absence of light and with cooling to 0-5° C. The suspension was slowly warmed to room temperature under a blanket of protective gas and was then stirred vigorously at room temperature for 4 hours. 500 ml of ethyl acetate and 300 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml each time of ethyl acetate. The combined organic phases were washed twice with 50 ml each time of water and dried over MgSO4. The oil obtained was filtered through silica gel with the aid of hexane. Taking off the solvent gave 361.2 g (625.3 mmol, 92%) of 2-bromo-4,5,3′,4′-tetra(2-methylbutyloxy)biphenyl as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=2)[CH2:3][CH2:2]1.[NH3:13]>O1CCOCC1>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH2:11])[N:8]=[C:7]([NH2:13])[N:6]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: Nc1nc(Cl)nc(NC2CC2)n1
Solvent: C1COCCO1
Product: Nc1nc(N)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 100 g of 2-cyclopropylamino-4-amino-6-chloro-s-triazine, 51 g of ammonia and 500 ml of dioxan is heated at 140° C. in an autoclave for 24 hours. After cooling, the dioxan is removed by filtering with suction in vacuo and the crystalline residue is washed with water and dried. The crude product is recrystallised from methanol; melting point 219°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 40 h
Yield: 32 %

Procedure:
A stirred mixture of 3.14 g of 4-fluoro-2-nitrophenol, 13 g of cesium carbonate and 20 mL of anhydrous dimethylformamide was heated at 100° C. for 4 hours. After this period, 6.65 g of 2,2,2-trifluoroethyl p-toluenesulphonate was added and the mixture was stirred at the same temperature for 40 hours. Afterwards, the solvent was removed under reduced pressure at 35° C. and 50 mL of water was added to the residue. The mixture was acidified with 37% hydrochloric acid and extracted with 3×40 mL of ethyl acetate. The organic layer was washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (petroleum ether:ethyl acetate 100:7) to afford 1.53 g (32%) of Compound 5A as an oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]N(C)C(=O)CCC)=[C:20]([F:33])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][CH:3]([CH2:2][CH3:12])[C:4]([NH:6][CH3:7])=[O:5])=[C:20]([F:33])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: Cc1ccccc1
Product: CCC(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g of 2,6-difluorobenzoylisocyanate in 5 ml of a 1:1 v:v mixture of toluene and petroleum ether was added at room temperature over 30 minutes to a stirred solution of 4.4 g of 33 in 20 ml of the same solvent. After stirring at room temperature for 2 hours, the mixture was filtered, and the collected solid product was recrystallized from a mixture of diethyl ether and petroleum ether to give 36, as a white solid, m.p.: 136°-138° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.S(OCC)(O[CH2:16][CH3:17])(=O)=O.C(N(C(C)C)CC)(C)C>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:16][CH3:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCOS(=O)(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNc1ccc(C(=O)OC)cc1
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A mixture of 25.0 g (0.165 mol) 4-aminobenzoic acid methyl ester, 21.75 mL (0.165 mol) of diethyl sulfate and 30 mL (0.174 mol) of diisopropyl ethyl amine was heated to 120° C. for 1 hour. The reaction was exothermic and the temperature rose to 140° C. The mixture was allowed to cool down to room temperature and 100 mL of water was added. 4-(ethylamino)benzoic acid methyl ester crystallized over night, was isolated by filtration, washed 3 times with water and dried. The crude 4-(ethylamino)benzoic acid methyl ester was recrystallized from methanol. 14.44 g of 4-(ethylamino)benzoic acid methyl ester was isolated (m.p. 132-135° C.).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH3:26]>C(O)C>[NH2:26][C:12]1[CH2:13][CH2:14][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][C:11]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1

Procedure:
855 g of methyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride, 176 g of sodium carbonate and 450 ml of 25% aqueous ammonia solution in 6.5 1 of ethanol were heated for 5 h at an internal temperature of 70° C., with stirring. After concentration under reduced pressure, the mixture was worked up by extraction with dichloromethane and water. The combined dichloromethane phases were dried over sodium sulfate and concentrated under reduced pressure to give 788 g of oily methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate as a crude product, which was used in Example 1b) without further purification.
Reaction SMILES: C(O[C:4](=[O:10])[C@H:5]([N:7]=[N+:8]=[N-:9])[CH3:6])C>C(N)(C)C>[CH:5]([NH:7][C:4](=[O:10])[CH:5]([N:7]=[N+:8]=[N-:9])[CH3:6])([CH3:6])[CH3:4]
Reactant: CCOC(=O)[C@@H](C)N=[N+]=[N-]
Solvent: CC(C)N
Product: CC(C)NC(=O)C(C)N=[N+]=[N-]
Reaction time: 24 h

Procedure:
A 14.3 g sample of (R)-ethyl-2-azidopropionate was taken up in 50 mL of isopropylamine and allowed to stand for 24 hours. After stripping excess amine, 14.8 g of pure N-isopropyl-2-azidopropionamide was obtained. The amide thus obtained, 3.12 g, was stirred with 5.0 g of Raney nickel catalyst in 40 mL of isopropanol until nitrogen evolution ceased. The solution was filtered and concentrated in vacuo at 40° C. to give 2.5 g of crude N-isopropyl-D-alanine amide.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.CO.[NH3:31]>>[C:24]([O:23][C:21](=[O:22])[NH:20][C@@H:5]([C:4](=[O:3])[NH2:31])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)[C@@H](CCCc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(OC(C)(C)C)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(R)-2-tert-Butoxycarbonylamino-5-(4-tert-butoxy-phenyl)-pentanoic acid ethyl ester (179 g, 460 mmol) is dissolved in 7M NH3 in MeOH (400 ml, 2800 mmol) and stirred at room temperature for 4 days. The reaction is concentrated in vacuo keeping the temperature below 30° C. to afford [(R)-4-(4-tert-Butoxy-phenyl)-1-carbamoyl-butyl]-carbamic acid tert-butyl ester [M+H]+ 364
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]2([CH3:8])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[O:10]2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccsc1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccsc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.3 g, 1.2 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM)in ethanol (75 mL), was added 1N aqueous sodium hydroxide (2 mL, 2 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown oil. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow solid (1.8 g, 62% yield), m.p. 97°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19].O>CN(C=O)C>[CH2:18]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
To 5-fluoro-2-nitrophenol (8.3 g, 52.83 mmol) in 50 mL of DMF was added K2CO3 (14.6 g, 105.7 mmol), and ethyl iodide (8.53 mL, 105.7 mmol). The mixture was stirred at 60° C. for 24 h in a sealed tube. The mixture was poured into 500 mL of H2O and extracted with diethyl ether, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (9.69 g, 52.33 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.94 (m, 1H), 6.71-6.77 (m, 1H), 6.66-6.71 (m, 1H), 4.11-4.19 (m, 2H), 1.45-1.51 (m, 3H).