Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([F:28])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:29][CH2:30][C:31]1[S:35][C:34]([Cl:36])=[CH:33][CH:32]=1)=[O:12])=O)(C)(C)C>Cl.O1CCOCC1>[ClH:36].[NH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([F:28])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:29][CH2:30][C:31]1[S:35][C:34]([Cl:36])=[CH:33][CH:32]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)s1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.82 g of 5'-O-[N-(t-butoxycarbonyl)-β-alanyl]3'-O-(5-chloro-2-thenyl)-2'-deoxy-5-fluorouridine obtained in Example 7 was added 10 ml of 4N hydrochloric acid-dioxane, and the mixture was stirred at room temperature for 30 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1C=CC=CC=1>[C:18]([O:17][C:3]1[C:2]([Br:1])=[C:7]([CH3:8])[C:6]([Br:9])=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(Br)cc(-c2ccc(=O)[nH]n2)c(O)c1Br
Solvent: c1ccccc1
Product: CC(=O)Oc1c(-c2ccc(=O)[nH]n2)cc(Br)c(C)c1Br
Yield: 71.5 %

Procedure:
A mixture of 1.0 g. of 6-(3,5-dibromo-2-hydroxy-4-methylphenyl)-3-(2H)pyridazinone and 2 ml. of acetic anhydride in 10 ml. of benzene was heated under reflux for 3 hours. After cooling, the so separated crystalline substance was recovered by filtration and dried to give 0.8 g. of the desired product as yellow needles of m.p. 220° C. (Yield 71.5%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][CH2:13][C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2>[OH-].[Na+].O>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][CH:12]=2
Reactant: O=C1Cc2c(ccc(F)c2CCC(=O)c2ccc[nH]2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2ccc(F)c3ccc(-c4ccc[nH]4)c1c23

Procedure:
A suspension of 5-fluoro-4-[3-oxo-3-(1H-pyrrol-2-yl)-propyl]-1,3-dihydro-indol-2-one (from Example 5 above) (20 mg, 0.073 mmol) in 1.0 N NaOH (10 mL) was heated under reflux for 2.5 days. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 16.5 mg, 89.0%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.P(Cl)(Cl)(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:23])[C:16](=[C:20]([Cl:22])[CH:21]=1)[C:17](O)=[O:18].N1C2C(=CC=CC=2)C(=O)C1=O.OO.ClC1C=CC=C(C(O)=O)C=1N.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[C:16]2[C:17](=[O:18])[N:1]3[CH2:5][CH2:4][CH2:3][C:2]3=[N:23][C:15]=2[CH:14]=1
Reactant: O=C1CCCN1
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Agent: Nc1c(Cl)cccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1Nc2ccccc2C1=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1c2c(Cl)cc(Cl)cc2nc2n1CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24.2 %

Procedure:
To a stirred solution of 2.5 g of 2-pyrrolidinone (Aldrich) in 100 mL of chloroform was added 4.5 g of phosphorus oxychloride at room temperature. The mixture was stirred for 2.5 hours at room temperature. To the above mixture was then added dropwise a solution of 5 g of 4,6-dichloroanthranilic acid (prepared from the corresponding isatine: T. Sandmeyer, Helv. Chim. Acta, 2:234 (1919), by oxidation with alkaline hydrogen peroxide, following the procedure described by Baker, et al, J. Org. Chem., 18:141 (1952) for the synthesis of 3-chloroanthranilic acid) in 50 mL of chloroform, containing 10 mL of triethylamine. Then the mixture was heated to reflux for 6 hours. Then the reaction mixture was carefully treated with 10 mL of water (exothermic!), followed by 10 g of solid anhydrous potassium carbonate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using 10:1 chloroform:ethyl acetate as eluent. After concentration in vacuo of the appropriate fractions, there was obtained 1.5 g of crystalline 6,8-dichloro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one), which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:24]#[N:25]>>[C:24]([C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:25]
Reactant: Clc1c2ccccc2nc2cc3ccccc3cc12
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Product: N#Cc1c2ccccc2nc2cc3ccccc3cc12

Procedure:
treating 12-chloro-benz[b]acridine with potassium cyanide and copper (I) cyanide to produce 12-cyano-benz[b]acridine;
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cc(COC3CCCCO3)cn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (429 mg, 1.5 mmol) and (RS)-3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K17) (601 mg, 1.5 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (710 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].CN(C)P(=O)(N(C)C)N(C)C.C([N-]C(C)C)(C)C.[Li+].[C:25]([O:29][C:30]([N:32]1[CH2:38][C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:36][C@H:33]1[CH:34]=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.C(OCC)(=O)C.O.O>[C:25]([O:29][C:30]([N:32]1[CH2:38][C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:36][C@H:33]1[CH:34]([OH:35])[CH2:4][C:3](=[O:5])[NH:2][CH3:1])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CNC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)CC(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
Under a nitrogen atmosphere, a solution of N-methylacetamide (116 μl, 1.52 mmol) in tetrahydrofuran (2 ml) and then hexamethylphosphoric triamide (555 μl, 3.19 mmol) were dropwise added at -78° C. to a solution comprising 2.0M lithium diisopropylamide--tetrahydrofuran (1.6 ml, 3.19 mmol) and tetrahydrofuran (10 ml). The mixture was stirred at -78° C. for 30 minutes. Then, a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (500 mg, 1.52 mmol) in tetrahydrofuran (2 ml) was dropwise added. The reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture. Then, the reaction mixture was poured into a mixture of ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained oily residue was subjected to silica gel column chromatography (chloroform--methanol=20:1) to give the title compound (158 mg, yield: 25.9%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[C@H:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1.C(O)C.[H][H]>[Pd].CCOCC>[ClH:1].[NH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C@H:6]1[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][C@H:5]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CC[C@H](Oc2cccc([N+](=O)[O-])c2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN1CC[C@H](Oc2cccc(N)c2)[C@H](c2ccccc2)C1

Procedure:
A solution of 4.6 g of cis-1-methyl-4-(3-nitrophenoxy)-3-phenylpiperidine hydrochloride of Example 18, in 110 ml of 190 proof ethanol is hydrogenated at 45 psi of hydrogen and room temperature over 0.46 g of 10% palladium on carbon catalyst. Hydrogen uptake stops after 2.5 hours. The catalyst is filtered off, and the filtrate is concentrated in vacuo to afford a foam which solidifies upon trituration with ether to afford a crude solid, mp s 232°, 249.5° C. dec, This material is recrystallized from absolute ethanol by boiling the filtered solution down, cooling, filtering and washing with absolute ethanol and then ether to yield cis-4-(3-aminophenoxy)-1-methyl-3-phenylpiperidine hydrochloride, mp 259°-260.5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:29][NH:30][O:31][CH3:32]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[N:30]([O:31][CH3:32])[CH3:29])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: CC(C)c1ccc(CCOc2ccc(NC(=O)Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C(C)C)cc2)cc1
Temperature: 0 °C
Yield: 42 %

Procedure:
Into a solution of 10.6 g of 4-(4-isopropylphenethyloxy)phenylcarbamyl chloride in 200 ml of toluene are added 4 ml of pyridine and a solution of 2.5 g of N,O-dimethylhydroxylamine in 50 ml of toluene at a temperature below 20° C. The mixture is heated under reflux for 4 hours. The reaction mixture is then poured into ice water, and the separated organic layer is washed with dilute hydrochloric acid, thoroughly washed with water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the crude crystals are recrystallized from ethanol to obtain 4.8 g of N'-[4-(4-isopropylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 81°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1>>[Br:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=2)=[CH:10]1
Reactant: BrCc1cccc(Br)c1
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ncccc3c2=O)cc1C
Yield: 21.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one, and 1-Bromo-3-bromomethyl-benzene 55 mg (0.22 mmol), to give 17 mg of desired compound. LCMS (M+H)+: 463.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:24]([O:23][C:22]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([N+:19]([O-:21])=[O:20])[C:2]=1[OH:1])=[O:26])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1c(-c2noc(C)n2)cc(O)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1cc(-c2noc(C)n2)c(C(=O)OC)c([N+](=O)[O-])c1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), ethyl chlorocarbonate (0.02 mL), potassium carbonate (28 mg) and N,N-dimethylformamide (2 mL) was stirred at 50° C. for 3 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20%-100% ethyl acetate/hexane, gradient elution) to give the title compound (51 mg). The structural formula was illustrated in table 13.
Reaction SMILES: Cl[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][OH:15])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(CO)cc2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 170 °C
Yield: 45.1 %

Procedure:
A mixture of 5-chloro-2,4-dinitrotoluene (1.0 g), 4-(hydroxymethyl)phenylboronic acid (0.84 g), bis(triphenylphosphine)palladium(II) chloride (150 mg) and potassium carbonate (2.0 g) in a mixture of 1,4-dioxane and water (10/1, 11 mL) was heated at 170° C. in a microwave reactor for 10 minutes. The reaction mixture was then cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (acetone/DCM, 3/97) to give 0.6 g of (5′-methyl-2′,4′-dinitro-biphenyl-4-yl)-methanol.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]2[C:41]([F:42])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[F:43])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:44].O1CCOCC1>O1CCOCC1>[ClH:44].[F:42][C:41]1[CH:40]=[C:36]([CH:35]=[C:34]([F:43])[C:33]=1[N:24]1[CH2:25][C@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:23]1)[C:37]([OH:39])=[O:38]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(c2c(F)cc(C(=O)O)cc2F)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(c2c(F)cc(C(=O)O)cc2F)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 ml 1,4-dioxane solution of 2.01 g of 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoic acid was mixed with 2.0 ml of 4 M hydrogen chloride/1,4-dioxane and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol). The purified product was dissolved in 1,4-dioxane-diethyl ether, 4 M hydrogen chloride/1,4-dioxane was added thereto, and the thus precipitated crystals were collected by filtration and then recrystallized from 1,4-dioxane-water, thereby obtaining 484 mg of 3,5-difluoro-4-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]benzoic acid hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31](OC)=O)=[CH:24][C:23]=2[O:22]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31]3[NH:20][C:18](=[O:19])[C:3]4[C:4]([CH2:16][CH3:17])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=4[N:1]=3)=[CH:24][C:23]=2[O:22]1
Reactant: CCCCCCC(CC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 12.7 %

Procedure:
10 mg (0.037 mmol) of 5-amino-3-ethyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 30 mg (0.129 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 2 mg (11%) of a solid, Rf=0.76 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[C:15]([F:25])=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.[PH2](=O)O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[C:15]([F:25])=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CC(c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Yield: 63.2 %

Procedure:
A solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethanol (530 mg, 1.457 mmol), Iodine (925 mg, 3.64 mmol) and phosphinic acid (50%, 0.556 mL) in 20 mL of acetic acid was heated at 110° C. for 2 h. Solvent was evaporated and the residue was dissolved in water, neutralized with saturated NaHCO3 solution and extracted with DCM three times. Organic layers were combined and washed with brine, dried over Na2SO4. Solvent was then evaporated and the crude was purified by flash chromatography (hexane:EtOAc=1:2) to give the title compound as light yellow solid (320 mg, 63.2%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.03 (s, 1H), 8.0 (d, 1H), 7.8 (s, 1H), 7.23 (d, 1H), 7.19 (d, 1H), 5.1 (q, 1H), 4.0 (s, 3H), 1.92 (d, 3H). LCMS (method B): [MH]+=347.9, tR=2.69 min.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].[OH:21][N:22]=[C:23](N)[CH:24]([CH3:26])[CH3:25]>C(OC(=O)C)C.[Cl-].[Zn+2].[Cl-]>[CH:24]([C:23]1[N:2]=[C:1]([N:3]2[CH2:8][CH2:7][CH:6]([C:9]3[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[O:21][N:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)C(N)=NO
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C#N)CC2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.9 mL (0.45 mmol) Zinc(II)chloride (0.5 M solution in THF) is added dropwise to a mixture of 40.7 mg (0.15 mmol) (S)—N-{1-[4-(1-cyano-piperidin-4-yl)-phenyl]-ethyl}-acetamide (XXVII.1) and 30.6 mg (0.30 mmol N′-hydroxy-2-methylpropanimidamide in 12 mL ethylacetate. The mixture is stirred for 12 h at rt. After that the solvent is removed in vacuo and 15 mL ethanol and 2 mL conc. HCl solution are added. The mixture is refluxed for 3 h. Subsequently the mixture is concentrated, water is added and the precipitate is collected and washed with water to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>>[C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:29]([CH3:30])[CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CCOC(=O)c1ccnc(CN(CCCCC=O)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(CN(CCCCCN(C)C)C(=O)OC(C)(C)C)c1

Procedure:
Prepared by General Procedure A from ethyl 2-({[(tert-butoxy)carbonyl](5-oxopentyl)amino}methyl)pyridine-4-carboxylate (1.0 equiv.), dimethylamine hydrochloride (1.2 equiv.), and triethylamine (1.3 equiv.). Purification by column chromatography (MeOH/DCM (5:95)) gave the title compound as colorless oil. 1H-NMR (300 MHz, CDCl3): δ 8.50 (d, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 4.50 (d, 2H), 4.20 (q, 2H), 3.05 (m, 2H), 2.01 (s, 6H), 1.50-1.05 (m, 20H) ppm.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[C:9]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=O)=[N:11][CH:12]=1.CC(C)([O-])C.[K+]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][C:15](=[O:17])[N:20]2[CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[N:11][CH:12]=1
Reactant: CCOC(=O)CCc1ncc(Cl)cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3ncc(Cl)cc32)CC1
Yield: 64.2 %

Procedure:
Under ice cooling, to a tetrahydrofuran solution (500 ml) of tert-butyl 4-{[5-chloro-2-(3-ethoxy-3-oxopropyl)pyridin-3-yl]amino}piperidine-1-carboxylate (54.7 g) was added dropwise a tetrahydrofuran solution (1 M, 159 ml) of potassium tert-butoxide over 15 minutes. After stirring for 15 minutes at the same temperature, water was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (31.2 g).
Reaction SMILES: O.[CH3:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:8][NH2:9])=[O:7].C(N(CC)CC)C.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>ClCCl>[CH3:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([CH3:2])[CH:4]=1)=[O:26]
Reactant: Cc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NNC(=O)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Water is added to a mixture consisting of 3-methyl-4-nitrobenzhydrazide (3.9 g), triethylamine (3 ml) and 2,2-dimethylpropanoyl chloride (2.6 ml) in dichloromethane (120 ml) stirred for 2 h. After drying, evaporation and trituration of the organic phase in petroleum ether, N′-(2,2-dimethylpropanoyl)-3-methyl-4-nitrobenzhydrazide is obtained in the form of a precipitate.