Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Si:4]([N:11]1[CH:14]([CH2:15][CH2:16][O:17]C(=O)C(F)(F)F)[CH:13]([N:24]=[N+:25]=[N-:26])[C:12]1=[O:27])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C(O)(=O)C>CO>[Si:4]([N:11]1[CH:14]([CH2:15][CH2:16][OH:17])[CH:13]([N:24]=[N+:25]=[N-:26])[C:12]1=[O:27])([C:7]([CH3:9])([CH3:10])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium methoxide (0.02 mol) in methanol (20 ml) is added to an ice-cold solution of N-(t-butyldimethylsilyl)-3-azido- 4-(2-trifluoroacetoxyethyl)-azetidin-2-one (0.1 mol) in methanol (100 ml). After stirring in the cold for 10 min, the solution is treated with acetic acid (2 ml) and concentrated under vacuum. The residue is taken up in ethyl acetate, washed with water, 5% sodium bicarbonate solution, and brine, dried, and evaporated. The residue is chromatographed on silica gel to give N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[C:25]([CH:26]2[CH2:28][CH2:27]2)=[CH:24][C:9]2[C:10]([C:20]([O:22]C)=[O:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[OH-].[K+]>C(O)C.O>[CH:26]1([C:25]2[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20]([OH:22])=[O:21])[C:9]=3[CH:24]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1

Procedure:
A suspension of methyl 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate (2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was treated with potassium hydroxide (6.71 g, 120 mmol) and heated at reflux for 1 hour (the suspension went into solution upon heating). The reaction was concentrated under vacuum, water (100 mL) was added and the solution acidified with 2M HCl (50 mL). The resulting precipitate was filtered, washed with 0.5 M HCl, then dissolved in methanol. This solution was evaporated to dryness and azeotroped twice with toluene to give 5-Cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylic acid. LCMS (m/z, ES+)=390 (M+H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][S:40]([CH2:43][C:44](=[N:46]O)[NH2:45])(=[O:42])=[O:41]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:46]=[C:44]([CH2:43][S:40]([CH2:39][C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)(=[O:42])=[O:41])[N:45]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(CS(=O)(=O)Cc1ccco1)=NO
Product: CON=C1C[C@@H](c2nc(CS(=O)(=O)Cc3ccco3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and 2-[(2-furylmethyl)sulfonyl]-N′-hydroxy-ethanimidamide, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=521.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][O:17][C:16]([C:7]1[C:8]2[O:12][C:11]([CH3:13])([CH3:14])[O:10][C:9]=2[CH:15]=[C:4]2[O:3][C:2]([CH3:19])([CH3:1])[O:6][C:5]=12)=[O:18]
Reactant: CC1(C)Oc2cc3c(c(C(=O)O)c2O1)OC(C)(C)O3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c2c(cc3c1OC(C)(C)O3)OC(C)(C)O2
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-carboxylic acid (10.0 g, 38.0 mmol) was dissolved in dry DMF (100 mL). Potassium carbonate (15.2 g, 110.0 mmol) was added and the reaction was heated to 55° C. for 30 min. After cooling to ambient temperature, methyl iodide (15.6 g, 110.0 mmol) was added and the solution was stirred overnight. The precipitate was filtered off and the solution was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and ether. The aqueous layer was discarded and the organic phase was dried (Na2SO4), filtered and evaporated to give 9.4 g (88%) of the pure product.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[C:10]3[C:15]([N:16]=[CH:17][C:8]2=[N:7][N:6]=1)=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[CH:11]=3)[CH2:2][CH2:3][CH3:4].[OH:20]O>CC(O)=O>[CH2:1]([C:5]1[N:9]2[C:10]3[C:15]([NH:16][C:17](=[O:20])[C:8]2=[N:7][N:6]=1)=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[CH:11]=3)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1nnc2cnc3cc(Cl)c(Cl)cc3n12
Solvent: CC(=O)O
Product: CCCCc1nnc2c(=O)[nH]c3cc(Cl)c(Cl)cc3n12
Temperature: 60 °C

Procedure:
The carbonyl compound was prepared by combining 500 mg (1.7 mmol) of the quinoxaline compound (7) and 16 ml HOAc, and then adding 5 ml of 30% H2O2. The mixture was heated to 60° C. for 16 hours, and then cooled. The product was recovered by filtration and dried at 0.5 mm and 60° C. overnight, yielding 150 mg of 1-n-butyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (8).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[CH:21]=[O:23]
Reactant: CC(=O)O
Reactant: Cc1ccc(C)c(O)c1C
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)c(C)c(C)c1O
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 2,3,6-trimethylphenol (5 g, 0.036 mol) and hexamethylenetetramine (2.06 g, 0.0147 mol) in acetic acid (20 ml) was stirred at 115° C. for 2 hrs. The solvent (10 ml) was distilled and 20% (v/v) H2SO4 (20 ml) was added, and then the mixture was stirred at 115° C. for 20 min. The mixture was then poured on ice cold water (50 ml) and the separated solid was filtered, washed well with cold water (25 ml) and suck-dried. The wet cake was dried at 90° C. for 2 hrs under vacuum to yield 2,3,5-trimethyl-4-hydroxy-benzaldehyde (4.5 g, 75%; Table 1, no. 12).
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[CH2:43]([O:45][N:46]=[C:47]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)[C:48](Cl)=[O:49])[CH3:44].O>C(OCC)(=O)C.O1CCCC1>[CH2:43]([O:45][N:46]=[C:47]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)[C:48]([NH:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:49])[CH3:44]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
A mixture of benzhydryl 7-amino-3-[2-(2-pyridyl)-vinyl]-3-cephem-4-carboxylate (trans isomer) (25 g) and N-(trimethylsilyl)acetamide (4.2 g) in ethyl acetate (20 ml) and tetrahydrofuran (10 ml) was stirred at ambient temperature for 20 minutes to give a clear solution. To the solution was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetylchloride (syn isomer) (1.4 g) at -15°~-20° C. and stirred at the same temperature for 30 minutes. Water (20 ml) was added to the resulting solution, and the separated organic layer was washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.6 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:17][C:18]2[CH:42]=[CH:41][C:21]([C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:25]=3)=[O:23])=[CH:20][CH:19]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:25]=3)=[O:23])=[CH:41][CH:42]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]butyrate (270 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1 N aqueous solution of sodium hydroxide (1.5 ml). The mixture was stirred at room temperature for 3 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]butyric acid (230 mg) as powder.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
N-Benzylmaleimide (5.0 g, 26.7 mmol), and N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (7.0 g, 29.4 mmol) were dissolved in toluene (150 mL). Trifluoroacetic acid (500 μL, 6.5 mmol) was added at room temperature. The reaction was allowed to stir for two hours at room temperature, and the precipitate was filtered off (˜440 mg). The filtrate was concentrated and purified by silica gel column chromatography (20-50% ethyl acetate in hexanes) to afford a white solid (6.2 g, 72%). 1H NMR (400 MHz, CDCl3): δ 7.22-7.05 (m, 8H), 7.01-6.96 (m, 2H), 4.45 (s, 2H), 3.95 (s, 2H), 3.50 (d, J=11.0 Hz), 3.37 (d, J=8.8 Hz), 3.10 (app t, J=9.1 Hz); 13C NMR (400 MHz, CDCl3): δ 175.8 (C═O), 134.8 (Ph), 130.6 (Ph), 129.6 (Ph), 129.3 (Ph), 128.8 (Ph), 128.6 (Ph), 128.3 (Ph), 127.7 (Ph), 57.3 (CH2), 54.0 (CH2), 42.9 (CH), 42.6 (CH2).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[N:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=c1[nH]cncc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1cncc(Br)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
5-Bromopyrimidin-4(3H)-one (578 mg) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (685 mg) and methyl iodide (247 μL) were added, followed by stirring at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 5-bromo-3-methylpyrimidin-4(3H)-one (337 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[CH3:33])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH3:33])[C:6]2[CH:34]=[CH:35][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:44])[CH3:43]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (364 mg, 774 μmol) in CH2Cl2 (7.74 ml) was added pyridine (306 mg, 315 μl, 3.87 mmol), followed by acetyl chloride (71.8 μl, 1.01 mmol), dropwise. The reaction was stirred at 0° C. for 1 h, then allowed to warm to rt and stirred for an additional 15 h, then quenched by the addition of H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (235 mg, 59%) as a white solid. MS m/z 535 (MNa)+.
Reaction SMILES: [C:1]([C@:3]12[CH2:20][CH2:19][C@@:17]3([CH3:18])[C@@H:13]([CH2:14][C@@H:15](CC([O-])=O)[CH2:16]3)[C@@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([OH:25])[CH:6]=[CH:5][C:4]2=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+]>CO>[C:1]([C@:3]12[CH2:20][CH2:19][C@@:17]3([CH3:18])[C@@H:13]([CH2:14][C@@H:15]([OH:27])[CH2:16]3)[C@@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([OH:25])[CH:6]=[CH:5][C:4]2=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: C[C@]12CC[C@]3(C#N)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](CC(=O)[O-])C2
Agent: [K+]
Solvent: CO
Product: C[C@]12CC[C@]3(C#N)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Yield: 926.7 %

Procedure:
At room temperature, 0.43 g (1.27 mmol) of 9α-cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate is stirred for 2 hours with 1.0 g (7.24 mmol) of potassium carbonate in 40 ml of methanol (1% water). Then, the methanol is distilled off in a vacuum, and the organic residue is dissolved in methylene chloride. The organic phase is washed with water and concentrated by evaporation. 3.5 g (93%) of 9α-cyano-estra-1,3,5(10)-triene-3,16α-diol is obtained.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:14]N1C(=O)CCC1=O>CN(C=O)C>[Br:14][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Nc1cccc(OC(F)(F)F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(OC(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 2-fluoro-3-(trifluoromethoxy)aniline (1.0 g, 5.13 mmol) dissolved in DMF (2 mL) at 0° C. was slowly added a solution of cold N-bromosuccinimide (0.91 g, 5.13 mmol) dissolved in DMF (6 mL) over 5 min. The reaction mixture was stirred at 0° C. for 1 h, extracted with EtOAc (125 mL) and washed with water (3×25 mL). The combined aqueous layers were extracted with EtOAc (75 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to produce the title compound as a dark colored liquid (1.27 g, 90% yield). (m/z): [M+H]+ calcd for C7H4BrF4NO 273.94. found 273.8.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N+]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O-])=O.[C:32](=[O:35])([O-])[O-].[K+].[K+]>C1CCCCC1.C1(C)C=CC=CC=1.[Cu]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:29]3[CH:30]=[CH:31][C:26]([C:3]4[CH:8]=[CH:7][C:6]([O:35][CH3:32])=[CH:5][CH:4]=4)=[CH:27][CH:28]=3)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(Nc3ccc(C)cc3)cc2)cc1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CCc1ccc(-c2ccc(N(c3ccc(C)cc3)c3ccc(-c4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 210 °C
Reaction time: 11 h

Procedure:
To 4.31 g (15.0 mmol) of the thus obtained 4'-ethyl-N-(4-methylphenyl) -[1,1'-biphenyl]-4-amine were added 60 ml of nitrobenzene, 5.58 g (18.0 mmol) of 4'-iodine-4'-methoxy-[1,1'-biphenyl], 4.15 g of potassium carbonate, and 0.48 g of copper powder. The mixture was placed in an ester pipe and azeotropically heated for dehydration, with stirring, at 210° C. for 11 hours as a nitrogen gas was caused to flow over the mixture. The reaction mixture was then cooled to room temperature and filtered through a Celite filter to obtain a filtrate. The nitrobenzene was distilled away from the filtrate under reduced pressure. The residue was extracted with toluene, washed with water, dried by use of magnesium sulfate, and condensed under reduced pressure, whereby orange brown crystals were obtained. The thus obtained product was subjected to a silica gel column chromatography by use of a mixed solvent of cyclohexane and toluene as an eluent, and recrystallized from a mixed solvent of ethanol and toluene, whereby 4'-ethyl-N-(4'-methoxy-[1,1'-biphenyl]-4-yl)-N-(4-methylphenyl)-[1,1'-biphenyl]-4-amine (Aminobiphenyl Compound No. 2-62 in Table 3) was obtained in the form of colorless needles with a yield of 4.00 g (56.8%). The melting point of the product was 159.5° C. to 161.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[N:19]O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CS(Cl)(=O)=O.C(N(CC)CC)C.C(OCC)(=O)C>C(COC)OC.[Fe](Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2cccc(Cl)n2)=NO)cc1Br
Agent: Cl[Fe]Cl
Agent: CS(=O)(=O)Cl
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
To a solution of 1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (1.00 g, 2.8 mmol) in dimethoxyethane (30 mL) at 0° C. was added slowly methylsulfonyl chloride (0.24 mL, 3.08 mmol). The reaction was stirred for 15 minutes and then triethylamine (1.7 mL, 12.3 mmol) in dimethoxyethane (3 mL) was added to the reaction. Upon addition of the triethylamine a precipitate formed. Once the addition of the triethylamine solution had been completed the reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The precipitate was removed by filteration and the precipitate was washed with dimethoxyethane. To the combined filtrate was added iron (II) chloride (14 mg, 0.12 mmol) and the resulting mixture was heated at 80° C. for 15 hours. The reaction mixture was allowed to cool to room temperature. Ethyl acetate was added to dilute the mixture and the organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration of the filtrate, followed by flash chromatography (4:6 ethyl acetate:hexanes) gave 2-(3-bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridine (86 mg, 9%). 1H NMR (CDCl3): δ 8.21 (d, 1H), 7.95 (d, 1H), 7.48 (d, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.88 (d, 1H), 6.84 (s, 1H), 3.96 (s, 3H); MS m/z 337 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)=[O:20])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-iodo-4-methylaniline (1.17 g, 5 mmol) and 3-(trifluoromethyl)-phenylisocyanate (1.03 g, 5.5 mmol) was stirred at rt for 4 h. Filtration (ethyl acetate wash) yielded the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)[CH:2]=[CH2:3].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:16])=[CH:7][C:8]=2[N+:13]([O-:15])=[O:14])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid allyl ester (84.3 g, 0.37 mol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (75.0 g, 0.37 mol, 1.0 equiv; commercially available) in DMF (500 mL) was added N-ethyldiisopropylamine (111.3 g, 0.86 mol, 2.3 equiv) and the reaction mixture heated at 70° C. for 6 h. The reaction mixture was cooled, poured into water (2 L) and the resulting mixture stirred at rt for 1 h. The precipitate was filtered, washed with water and hexane and finally dried over MgSO4 to obtain 129.1 g (85%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.46 (s, 9H), 1.46-1.56 (m, 2H), 1.92-1.98 (m, 2H), 2.90-2.98 (m, 2H), 3.88-3.95 (m, 3H), 4.78 (d, J=5.2 Hz, 2H), 5.27 (d, J=10.4 Hz, 1H), 5.38 (d, J=17.3 Hz, 1H), 6.00-6.06 (m, 1H), 7.29 (d, J=9.2 Hz, 1H), 7.99 (dd, J=9.2 Hz, J=1.6 Hz, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][NH:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][N:30]([C:18]2[C:19]([F:21])=[CH:20][C:10]3[C:11]([CH:17]=2)=[N:12][C:13]2[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=2[CH:9]=3)[CH2:29]1
Reactant: CN(C)C1CNC1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Temperature: 95 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, 1.2 g of 3-(dimethylamino)azetidine dihydrochloride and 1.5 g of sodium carbonate in 30 cm3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95° C. for 5 hours. After cooling to approximately 20° C., the reaction mixture is treated with 60 cm3 of water. The insoluble matter is drained and washed with 3 times 20 cm3 of water. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine are obtained in the form of a yellow solid, melting point 224° C., which is used without further purification for the subsequent steps.