Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:37]1=[O:50]>>[OH:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[C:36]1([CH2:5][OH:16])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:37]1=[O:50]
Reactant: CCCCCN1C(=O)C(c2ccc(OC)cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2ccc(OC)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(2-hydroxy-4-methoxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (41%): 1H NMR (300 MHz, CDCl3) δ 10.79 (s, 1H), 7.51-7.37 (m, 2H), 7.26 (td, 1H), 6.99 (d, 1H), 6.95 (d, 1H), 6.59 (d, 1H), 6.34 (dd, 1H), 4.67 (d, 1H), 4.14 (d, 1H), 3.76 (s, 3H), 3.78-3.69 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 338 (M−17), 378 (M+23).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([Cl:28])[CH:27]=1)=[O:9])([CH3:6])[CH3:5].Cl.[CH3:32][OH:33]>[OH-].[Na+]>[Cl:28][C:26]1[CH:27]=[C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:2])=[O:30])=[O:9])[CH:23]=[N:24][C:25]=1[O:33][CH3:32]
Reactant: CO
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ncc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1Cl

Procedure:
82 mg 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 0.5 ml MeOH and 0.5 ml 2 M aqueous sodium hydroxide solution were heated to 120° C. for 3 min using a microwave reactor. The reaction mixture was acidified with 2 M HCl and the precipitated solid was collected by filtration and purified by RP-HPLC to yield 36 mg 2-{[1-(5-chloro-6-methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=1)([O-])=O>O1CCCC1.CO.[Pt]=O>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2[N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
tert-Butyl 4-(1-nitro-2-naphthylamino)phenylcarbamate (18.67 g, 49.21 mmol) was dissolved in tetrahydrofuran (180 mL) and methanol (180 mL), the mixture was added with platinum oxide (360 mg), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was separated by filtration, then the solvent was evaporated under reduced pressure, and the residue was washed with methanol to give the title compound (15.67 g, yield 91%) as off-white crystals.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[N:10]2)=[C:4]([F:29])[CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[F:29][C:4]1[CH:3]=[C:2]([N:30]2[CH2:34][CH2:33][CH2:32][C:31]2=[O:35])[C:7]([F:8])=[CH:6][C:5]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2cc(F)c(Br)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cn(-c2cc(F)c(N3CCCC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 14 h
Yield: 5.9 %

Procedure:
A suspension of 1-(4-bromo-2,5-difluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (200 mg, 0.44 mmol), pyrrolidin-2-one (0.040 mL, 0.53 mmol), CuI (17 mg, 0.088 mmol), N,N′-dimethylethane-1,2-diamine (0.019 mL, 0.18 mmol), and K3PO4 (187 mg, 0.88 mmol) in 1,4-dioxane (4.0 mL) was stirred at 80° C. for 14 h under N2 atmosphere. After cooling to rt, the reaction mixture was purified by silica gel column chromatography eluting with hexane/AcOEt (1/0 to 0/1) then AcOEt/MeOH (10/1) and recrystallized from AcOEt to give the title compound (12 mg, 6% yield) as a pale brown solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.06-2.23 (2H, m), 3.29 (3H, s), 3.69-3.91 (4H, m), 7.27-7.42 (2H, m), 7.43-7.56 (2H, m), 7.78 (1H, dd, J=11.3, 6.4 Hz), 7.85-7.91 (2H, m), 7.95 (1H, dd, J=10.5, 7.2 Hz), 8.57 (1H, d, J=2.3 Hz), 8.60 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 464 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12](N(C(C)C)CC)(C)[CH3:13].C([Sn](CCCC)(CCCC)C=C)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1)=[CH2:13]
Reactant: COc1cc(Br)ccc1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)c(OC)c1
Temperature: 90 °C
Yield: 91.3 %

Procedure:
To a solution of 4-bromo-2-methoxybenzonitrile (−0.5 g, 2.36 mmol, 1.0 eq) in toluene (12 mL) was added diisopropylethylamine (0.61 g, 0.82 mL, 4.72 mmol, 2.0 eq), and tributyl(vinyl)tin (1.12 g, 1.03 mL, 3.54 mmol, 1.5 eq). The reaction mixture was degrassed by bubbling agron through the mixture. Tetrakis(triphenylphosphine)palladium (0.10 g, 0.12 mmol, 0.05 eq) was added and the reaction further degassed before heating to 90° C. for 16 hours. The reaction was cooled and partitioned between EtOAc (100 mL) and NaHCO3 (100 mL). The organics were washed with brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (5→30% EtOAc-hexane) yielded the title compound (0.343 g, 91%) as a white solid; 1H nmr (CDCl3) δ 7.56-7.53 (2H, m, ArH-5, H-6), 6.92 (1H, d, J 9.0 Hz, ArH-2), 6.59 (1H, dd, J 17.5, 11.0 Hz, CH═CH2), 5.63 (1H, d, J 17.5 Hz, CH═CH2 trans), 5.23 (1H, d, J 11.0 Hz, CH═CH2 cis), 3.91 (3H, s, OCH3); m/z 160 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH:2]([CH3:4])[CH3:3].[ClH:24].C(OCC)(=O)C>>[ClH:24].[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of the compound obtained in step 1 (0.33 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized from ethanol-diisopropyl ether to give the title compound (0.22 g, 83%) as a white powder.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])([OH:3])=O.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:1]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: CN(C)CCN
Reactant: COC(=O)c1cc(O)cc(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCC(=O)NCCN(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 3-carboxymethoxy-5-hydroxybenzoate (2 g), N,N-dimethylethylenediamine (1.07 ml) and 1-hydroxybenzotriazole (1.31 g) in N,N-dimethylformamide (40 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.86 g) under ice cooling. After stirring at room temperature for 5 hours, the solvent of the reaction mixture was removed under reduced pressure. The residue was purified by column chromatography on aluminum eluting with a mixture of chloroform and methanol (20:1 to 5:1). The fractions containing the desired product were collected and evaporated in vacuo. Then the residue was triturated with diethyl ether, collected by filtration and washed with diethyl ether to give methyl 3-[(2-dimethylaminoethyl)carbamoylmethoxy]-5-hydroxybenzoate (1.94 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([C:13](=[O:29])[CH2:14][C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)(O)[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:11]=1[F:12].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([C:13](=[O:29])[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:16]([F:17])([F:18])[F:19])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of thionyl chloride (0.618 g, 5.52 mmol) in toluene (1 mL) was added to a mixture of the product from Step A (1.2 g, 2.60 mmol) and pyridine (0.41 g, 5.18 mmol) in toluene (15 mL) at 60-65° C. When the addition was complete, pyridine (0.2 g, 2.53 mmol) was added incrementally to the reaction mixture. When the addition was complete, the mixture was allowed to cool to ambient temperature and then poured into 1N hydrochloric acid (100 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined extracts dried and evaporated to give the title product as an oil (1.12 g, 97% yield).
Reaction SMILES: [Li].[Li].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].C([Li:26])CCC.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>CCCCCC>[Li:26][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([Li:26])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]
Reactant: [Li]CCCC
Reactant: c1cc[cH-]c1
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]
Solvent: CCCCCC
Product: [Li][c-]1cccc1
Reaction time: 0.17 h

Procedure:
During a first step, ferrocene dilithium complexed with tetramethylethylenediamine (TMEDA) was prepared: In a glove box under argon, there is added 37 ml of freshly distilled TMEDA (247 mmoles) and 40 ml of anhydrous hexane in a 1 1 flask. There is then added drop wise 154 ml of a 1.6 M solution of butyllithium in hexane (247 mmoles, commercially available from Aldrich). After 10 min, there is added drop wise 18.6 g of ferrocene (100 mmoles) in solution in 500 ml of anhydrous hexane while keeping a strong stirring of the solution. After one night, orange crystals appeared in the solution, which were recovered by filtering the solution on a fritted glass of porosity No 4. After drying under vacuum, there is obtained 28.4 g of 1,1′-dilithio-ferrocene&Circlesolid;2 TMEDA (66% yield) which was preserved under argon.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([F:18])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[C:12]([F:18])=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([F:1])[CH:14]=1
Reactant: CC(C)(C)OC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(F)c(N)cc1F

Procedure:
A solution of 1000 mg (2.82 mmol) of tert-butyl 2,5-difluoro-4-nitrobenzoate in 8 ml of tetrahydrofuran and 8 ml of ethyl acetate was hydrogenated in the presence of 65.6 mg of palladium (10% on activated carbon) at RT and standard pressure. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 15%-20% mixtures). Yield: 155 mg (purity 85%, 20% of theory)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[C:11]1[C:20]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](OC)=[O:14].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[N:4]1([C:1]2[O:3][C:11]3[C:20]([O:21][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:23])=[O:24])=[CH:19][CH:18]=[CH:17][C:12]=3[C:13](=[O:14])[CH:2]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(=O)N1CCOCC1
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12

Procedure:
Condensation of the lithium enolate of N-acetyl morpholine (2.2 ml) with methyl 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoate (3.56 g, 11.9 mmol) yielded the salicylacatamide (3.6 g). Cyclodehydration of the product with trifluormethanesulfonic anhydride (5.5 ml) as described above yielded the product as a colourless solid (1.21 g).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O.CO.[Pd]>[OH:1][NH:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NO)c1ccccc1C#Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NO)c1ccccc1CCc1ccccc1
Temperature: 21 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
A solution of N-hydroxy-2-(phenylethynyl)benzamide 37 (40 mg, 0.169 mmol) in EtOAc (1533 μL) and MeOH (153 pit) was degassed under vacuum and put under N2 atmosphere (3 cycles). Then a suspension of Pd/C (17.94 g, 0.017 mmol) in EtOAc (1 mL) was added and the resulting suspension was degassed and put under H2 atmosphere (3 cycles) and the resulting black suspension was stirred at 21° C. for 2 h. The reaction mixture was filtered through Celite®. The filtrate was concentrated in vacuo then crystallized from a mixture of Et2O and hexane to afford title compound 38 (25 mgs, 62% yield) as a white solid. 1H NMR: (DMSO-d6) δ (ppm): 10.90 (s, 1H), 9.10 (s, 1H), 7.37-7.22 (m, 8H), 7.18 (t, J=7.2 Hz, 1H), 2.93 (dt, J=9.8, 6.3 Hz, 2H), 2.84 (dt, J=9.7, 5.7 Hz, 2H). LRMS (ESI): (calc.) 241.29 (found) 242.22 (MH)+
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC1c2ccccc2-c2ccccc21)c1ccncc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ON=C(CC1c2ccccc2-c2ccccc21)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 2-(9H-fluoren-9-yl)-1-pyridin-4-yl-ethanone and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1:1) as a white foam, MS (ESI+): m/z=301.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>C(O)(C)C.Cl>[Cl:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Nc1cccc(OCCCl)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Temperature: 85 °C
Yield: 78.9 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.0 g, 2.75 mmol) was stirred in 20 ml of isopropanol, 3-[(2-chloroethyl)oxy]aniline (0.494 g, 2.89 mmol) was added along with 3 drops of conc. HCl and heated to 85° C. for 18 h. The mixture was filtered hot and washed with isopropanol. The product obtained was the HCl salt as a yellow solid (1.2 g, 74% yield). ES-LCMS m/z 553 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH:2]=1
Reactant: CCCCSCC(=O)O
Reactant: Clc1ccc(CNc2cccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(Cc1ccc(Cl)cc1)c1cccnc1

Procedure:
N-(3-pyridyl)-N-[(4-chlorophenyl)methyl]-α-(n-butylthio)acetamide was prepared by reacting 5.0 g. of N-(3-pyridyl)-[(4-chlorophenyl)methyl]amine with 3.5 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide in 100 ml. of dichloromethane according to the method of Example 2. Weight collected was 3.9 g as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41]CCCCC(OCC)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[N:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:33])[C:12]2[CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:9]([OH:41])=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH:11]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A mixture of 5-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-pentanoic acid, ethyl ester (0.409 g, 0.573 mmol) and 1N KOH (1.15 ml) in THF (6 ml) and methanol (3 ml) was stirred under nitrogen. After 18 h, the reaction mixture was concentrated in vac. The residue was suspended in water (25 ml) and acidified with 2 N HCl (1.15 ml) then extracted with EtOAc (3×25 ml). The combined organics were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by preparatory plate chromatography (50% EtOAc/Hex) to give the title compound as a light yellow foam (0.249 g, 63%); dec. >50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.32 (m, 12H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 1.87 (t, J=7.0 Hz, 2H), 3.16-3.27 (m, 4H), 4.12 (t, J=7.0 Hz, 2H), 6.37-6.38 (m, 1H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.66-7.69 (m, 2H), 7.87 (s, 2H), 8.52 (t, J=5.7 Hz, 1H), 11.85 (s, 1H); IR (KBr) 3400, 2940, 1710, 1630, 1550, 1220 cm−1; mass spectrum [(+)APCI], m/z 685 (M+H)+; Anal. Calcd. for C40H42Cl2N2O4: C, 70.07; H, 6.17; N, 4.09, Found: C, 69.66; H, 6.17; N, 3.85.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)C.[Pd]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of 5-methyl-2-nitrobenzoic acid (20 g, 110 mmol) in ethanol was added 10% Pd/C (1 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The solution was filtered through celite and evaporated under reduced pressure to yield 16 g (96%) of white solids. M.P. 162° C. 1H NMR (DMSO-d6): δ 2.13 (s, 3H), 6.65 (d, J=8.6 Hz, 1H), 7.06 (dd, J=8.6, 1.8 Hz, 1H), 7.48 (d, J=1.1, 1H). EIMS m/z 174 (M+1), 152 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.N1C=CN=C1.Cl[Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>O>[CH3:26][Si:21]([CH3:27])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncccc1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 6.2 parts of 2-amino-3-pyridinemethanol in 23.5 parts of N,N-dimethylformamide there were added 6.8 parts of 1H-imidazole and 7.5 parts of chlorodimethyl(1,1-dimethylethyl)silane. The whole was cooled for 10 min in an ice-bath and was stirred overnight at room temperature. The reaction mixture was diluted with 100 parts of water and the product was extracted with 1,1'-oxybisethane (2x). The combined extracts were washed with water and NaCl (sat.), dried, filtered and evaporated, yielding 11.1 parts (93.1% ) of 3-[[dimethyl(1,1-dimethylethyl)silyloxy]methyl]-2-pyridinamine (interm. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([CH3:23])[CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]([CH3:23])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(C)CNc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CNc1ccc(Cl)cc1)COc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
Methyl 4-[3 [N-[4-chlorophenyl)amino]-2-methylpropoxy]benzoate (2.80 g) was dissolved in methanol (30 ml) and thereto was added a solution of sodium hydroxide (1.00 g) in water (8 ml), and the mixture was heated with stirring at 60° C. for 15 hours. The reaction mixture was cooled and thereto was added conc. hydrochloric acid (2.20 ml), and the mixture was concentrated under reduced pressure. To the residue was added water and it was crushed, and was collected by filtration. The resultant was dissolved in methanol, and filtered. Water (about half volume of the filtrate) was added to the filtrate gradually, and the resulting crystal was collected by filtration to give the desired product (2.16 g). mp. 148°-150° C.