Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=C>CC(O)(C)C.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=[O:2]
Reactant: C=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate are added at room temperature to a solution of 10 mmol of the product obtained in Step D in a mixture of 50 ml of dioxane and 25 ml of water. After stirring overnight at room temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography over silica gel to yield the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7].[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 72.2 %

Procedure:
A mixture of methyl 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.25 mmol) in methanol (4.5 mL) and 1N sodium hydroxide aqueous solution (3.7 mL, 3.7 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and washed with water, dried in vacuo to afford 69 mg of 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 71.9%. LC-MS (M+1)=383.2.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:13][NH:14]2.Br[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46]>C(OCC)(=O)C.O>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:13][N:14]2[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2[C:38](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]1=[O:46]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN3C(=O)c4ccccc4C3=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Sodium hydride (60% oil base, 800 mg, 18.3 mmol) was added to a DMF solution (25 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (5.0 g, 15.2 mmol). The mixture was stirred for 30 minutes at room temperature. N-Bromopropyl phthalimide (4.48 g, 16.7 mmol) was added to the mixture and stirred at room temperature for 30 minutes and at 50° C. for 5 hours. The reaction mixture was ice-cooled and water (20 ml) and ethyl acetate were added thereto, followed by stirring for 2 hours. The generated insoluble matter was separated, washed with water, and then dried, giving a pale yellow powder of 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1yl]propyl}isoindole-1,3-dione (4.63 g, yield: 59%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:25][C:24]3[C:23]([F:22])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])=[CH:17][CH:18]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3c(F)cccc3F)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2c), the alkylation of the (S)-[1-(4-hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester [Example 16 a)] with 2,6-difluorobenzylbromide in presence of potassium carbonate yields the title compound as a white solid; MS: m/e=419 (M+H)+.
Reaction SMILES: C[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.CCN(CC)CC.[Si]([I:29])(C)(C)C.II>C(Cl)Cl>[I:29][N:7]1[C:8](=[O:9])[CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]1=2
Reactant: C[Si](C)(C)I
Reactant: CC1C(=O)Nc2ccccc2-c2ccccc21
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 3-A) and Et3N (2.66 mL, 19.12 mmol) was stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2. and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:20])=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[N:8][CH:9]=1)([O-])=O.O.O.[Cl:23][Sn]Cl.[OH-].[Na+]>Cl>[Cl:23][C:9]1[C:4]([NH2:1])=[C:5]([NH2:20])[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:8]=1
Reactant: Nc1cc(-c2ccccc2C(F)(F)F)ncc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(-c2ccccc2C(F)(F)F)nc(Cl)c1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (749 mg, 2.65 mmol, prepared as in the previous step) was dissolved in concentrated HCl (12 mL) and heated to 90° C. SnCl2.2H2O (2.98 g, 13.2 mmol) was added to the stirred mixture in small portions and resulting mixture was stirred at 90° C. for 1 h. After completion of addition, the resulting mixture was cooled to 0° C. in an ice bath, treated with 6 M aqueous NaOH (30 mL) and then extracted with DCM (3×40 mL). The combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on a 40-g SiO2 pre-packed column eluting with 0:1-3:2 EtOAc/hexanes to yield 2-chloro-6-(2-trifluoromethyl-phenyl)-pyridine-3,4-diamine. 1H-NMR (400 MHz, CDCl3) δ: 7.67 (d, J=7.8 Hz, 1H), 7.47-7.55 (m, 1H), 7.37-7.46 (m, 2H), 6.57 (s, 1H), 4.09 (br s., 2H), 3.74 (br. s., 2H).
Reaction SMILES: CS(O[CH:6]([C:10]1[C:11]([CH:16]([CH3:18])[CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1)[CH:7]([CH3:9])[CH3:8])(=O)=O.[CH3:19][NH2:20]>C(O)(C)C>[CH3:19][NH:20][CH:6]([C:10]1[C:11]([CH:16]([CH3:18])[CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)c1ncncc1C(OS(C)(=O)=O)C(C)C
Reactant: CN
Solvent: CC(C)O
Product: CNC(c1cncnc1C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
10.6 g (39 mmol) of 5-(1-methylsulfonyloxy-2-methylpropyl)-4-isopropylpyrimidine was dissolved in 50 ml of isopropyl alcohol, and 10 ml (129 mmol) of a 40% methylamine aqueous solution was added, followed by stirring at room temperature for 8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and 100 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent=ethyl acetate) to obtain 2.9 g (yield: 36%) of 5-[1-(N-methylamino)-2-methylpropyl]-4-isopropylpyrimidine as slightly yellow crystals (melting point: 37-39° C.).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:44]([NH:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:45])[C@@H:41]([CH3:43])[OH:42].C(N(CC)CC)C>O.O1CCCC1>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:44]([NH:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:45])[C@@H:41]([CH3:43])[OH:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@H](C(=O)O)[C@@H](C)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of N-hydroxysuccinimide ester of 3-hexadecanoyloxyoctadecanoic acid (1.5 g) prepared by the method of Example 8 (1), L-threonyl-L-threonine (0.7 g) and triethylamine (0.44 ml) in tetrahydrofuran water (100 ml-200 ml) was stirred at room temperature for 5 hours. After removal of tetrahydrofuran under reduced pressure, the residue was acidified with 1% hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to give a residue which was purified by column chromatography on silica gel. Elution with a mixture of chloroform and methanol (20:1) afforded N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-threonine (1.2 ) as powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][C:34]([F:37])([F:36])[F:35])=[N:21][O:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[CH:13][C:12]=2[CH3:38])=[C:8]([CH3:10])[CH:9]=1)=O.O.[NH2:40][NH2:41]>CCO>[CH:24]([C:23]1[O:22][N:21]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:36])[F:35])[C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[S:6][C:5]([C:3]([NH:40][NH2:41])=[O:2])=[CH:9][C:8]=2[CH3:10])=[C:12]([CH3:38])[CH:13]=1)([CH3:26])[CH3:25]
Reactant: NN
Reactant: COC(=O)c1cc(C)c(-c2ccc(OCc3c(-c4ccccc4OC(F)(F)F)noc3C(C)C)cc2C)s1
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2c(-c3ccccc3OC(F)(F)F)noc2C(C)C)ccc1-c1sc(C(=O)NN)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-{4-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid methyl ester (980 mg, 1.8 mmol) in EtOH (7 mL) is added hydrazine hydrate (5 mL) and the mixture is stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue is partitioned between EtOAc and water. The layers are separated and the organic phase is concentrated under reduced pressure to give 5-{4-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid hydrazide (890 mg, 90%) as a light yellow foam. LC-ES/MS m/e 546 (M+1), 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.ClCCOC1C=CC(C=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Reactant: O=Cc1ccc(OCCCCl)cc1
Agent: O=Cc1ccc(OCCCl)cc1
Product: O=Cc1ccc(OCCCN2CCN(c3ccc(Cl)cc3)C2=O)cc1
Yield: 34 %

Procedure:
A reaction was conducted in a manner similar to Referential Example 13 by using 1-(4-chlorophenyl)-2-imidazolidinone (Compound No. 2) in place of 1-(4-ethylphenyl)-2-imidazolidinone (Compound No. 1) and 4-(3-chloropropoxy)benzaldehyde in lieu of 4-(2-chloroethoxy)benzaldehyde, whereby the title compound was obtained in a yield of 34%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][CH:31]([NH2:33])[CH3:32])[CH:26]=[CH:27][C:28]=1[F:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:33][CH:31]([CH3:32])[CH2:30][C:25]2[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=2)=[O:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)O
Reactant: CC(N)Cc1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cc1ccc(F)c(F)c1)NC(=O)c1c(N)ccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
4-amino-2-(trifluoromethyl)nicotinic acid (4.4 g, 18.14 mmol) was suspended in a mixture of anhydrous DMF (100 mL) and anhydrous dichloromethane (200 mL). To this was added triethylamine (6 g, 60 mmol), followed by 1-(3,4-difluorophenyl)propan-2-amine (3.75 g, 21.90 mmol). HBTU (9.63 g, 25.4 mmol) was added and the mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo to remove dichloromethane. The resultant DMF solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed successively with 1N NaOH and water, then dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography using 20-40% acetone/hexanes as eluant to provide the product as a colorless solid (6.57 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.1 (m, 2H), 6.95 (m, 1H), 6.7 (d, 1H), 4.07 (m, 1H), 4.9 (bd, 2H), 4.4 (m, 1H), 2.7-2.9 (dd, 2H), 1.2 (d, 2H). MS m/z 360.2 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([O:9][NH2:10])[CH2:5][CH2:4]1.[CH3:11][C@:12]12[CH2:29][CH2:28][C@H:27]3[C@@H:17]([CH2:18][C:19](=[O:31])[CH:20]4[C@:25]3([CH3:26])[CH2:24][CH2:23][C:22](=O)[CH2:21]4)[C@@H:16]1[CH2:15][CH2:14][C:13]2=[O:32].[Na+].[Cl-]>O.C1COCC1>[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([O:9][N:10]=[C:22]2[CH2:23][CH2:24][C@@:25]3([CH3:26])[CH:20]([C:19](=[O:31])[CH2:18][C@@H:17]4[C@@H:27]3[CH2:28][CH2:29][C@@:12]3([CH3:11])[C@H:16]4[CH2:15][CH2:14][C:13]3=[O:32])[CH2:21]2)[CH2:5][CH2:4]1
Reactant: NOC1CCNCC1
Reactant: C[C@]12CCC(=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=NOC3CCNCC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 4-piperidyloxyamine dihydrochloride (III-a, Prepn. 1, 100 mg) and Na2HPO4.12H2O (380 mg) in water (1.6 mL), a solution of androstane-3,6,17-trione (160 mg) in THF (3.2 mL) was added. After 2 hours at room temperature, NaCl (150 mg) was added and stirred for 15 min. The mixture was extracted with THF (2×2 mL) and the combined organic phases were washed with brine (3×3 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3 9:1:0.1). To the concentrated fractions 5M HCl in EtOAc was added. After dilution with Et2O, the solid was collected by filtration to give the title compound I-aa (140 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.68 (2H, bb), 4.17 (1H, m), 3.15-2.90 (5H, m), 2.60-1.10 (23H, m), 0.79 (3H, s), 0.78 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([C:47]([F:50])([F:49])[F:48])[C:43]([NH2:46])=[N:44][CH:45]=2)O1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>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.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:40]5[CH:45]=[N:44][C:43]([NH2:46])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 7 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (73 mg, 0.253 mmol, 1.5 eq), 1,4-dioxane (5 ml), K2CO3 (70 mg, 0.507 mmol, 3 eq), H2O (2 ml) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). Solvents were removed and the residue was partitioned between H2O and EtOAc. The organic layer was dried, filtered and evaporated. The residue was purified in an Isolute Flash Si II column (10-25% EtOAc in c-hexane and 20% MeOH in DCM) and by HPLC-prep to give the desired product (7 mg) as a yellow solid. The aqueous phase was further extracted with MeOH/DCM 1:9, the organic layers were dried, filtered and evaporated. The residue was triturated with MeOH/DMSO, filtered and washed with CH3CN to give the desired product (18 mg, overall yield: 25%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=2.95 min, [M+H]+ m/z 591.2; 1H NMR (300 MHz, DMSO) δ 8.86 (d, J=1.8 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 7.77 (s, 1H), 7.49 (m, 2H), 7.27 (d, J=9.2 Hz, 1H), 6.73 (s, 2H), 4.67 (m, 1H), 3.89 (s, 3H), 3.68 (m, 2H), 3.21 (m, 2H), 1.92 (m, 2H), 1.57 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.[N:37]1C=CN=CC=1C(O)=O>>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:37][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: O=C(O)c1cnccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2c(F)cccc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2c(F)cccc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2,6-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 235 and pyrazine-2-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]CC6C=CC=CC=6)=[O:33])([CH2:27][CH2:28]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.C1COCC1.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)OCc6ccccc6)(CC4)OC5)cc3)nc2)o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)nc2)o1
Yield: 33.5 %

Procedure:
Benzyl 2-(4-(4-(5-((5-(tert-butyl)oxazol-2-yl)amino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (100 mg, 0.181 mmol) was dissolved in EtOAc/THF and hydrogenated with 10% Pd(OH)2/C under H2 balloon for 3 hr. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to give the title compound (28 mg, 31.5% yield). HR/MS [M+H]+: found 462.2390. calc. 462.2393. RT: 2.83 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 9H), 1.86-2.03 (m, 8H), 2.32 (s, 2H), 3.90 (s, 2H), 6.60 (s, 1H), 7.39 (d, J=8.59 Hz, 2H), 7.87 (d, J=8.59 Hz, 1H), 7.95 (d, J=8.59 Hz, 2H), 8.15 (dd, J=8.84, 2.78 Hz, 1H), 8.77 (d, J=2.78 Hz, 1H), 10.36 (br. s., 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g of N,N'-carbonyldiimidazole are introduced into a solution of 5 g of indole-2-carboxylic acid in 50 ml of dry tetrahydrofuran; after stirring for 12 hours at ambient temperature, 3.7 g of benzyl alcohol are added and the reaction mixture is brought to its reflux temperature; this is maintained for 8 hours, before removing the solvent by distillation under reduced pressure. The residue is dissolved in ethyl acetate and the organic phase is washed with a N aqueous NaOH solution and then dried before evaporation of the solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:56]3[CH2:57][CH2:58][S:54][CH2:55]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
200 mg (0.55 mmol) of the compound of Example 34A is reacted analogously to the synthesis of the compound of Example 1 with 0.05 ml (0.60 mmol) of thiazolidine. 193 mg (80% of theory) of the title compound is obtained.