Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.C([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)C>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1)[O-:3]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCc1ccccc1[N+](=O)[O-]
Product: [O-][N+](=Nc1ccccc1)c1ccccc1

Procedure:
The reduction reaction was carried out in the same manner as set forth in Example 6 except for using a mixture of 1.0 mmol of nitrobenzene and 1.0 mmol of o-ethyl nitrobenzene instead of using nitrobenzene alone, and using 16.5 mg (the amount required for swelling of the reactant, i.e., the mixture, in 100%) of Polymer supported reagent-2, and thereby an azoxybenzene derivative of a symmetrical structure and an azoxybenzene derivative of an asymmetrical structure were obtained as a main product, respectively. Besides, a small amount of an azobenzene derivative of a symmetrical structure was also synthesized.
Reaction SMILES: [Cu][C:2]#[N:3].[C:4]([O:12][C@@H:13]1[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[O:15][C@H:14]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35](I)=[N:36][C:37]=2[NH:41][CH2:42][CH:43]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:4]([O:12][C@@H:13]1[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:16]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[O:15][C@H:14]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35]([C:2]#[N:3])=[N:36][C:37]=2[NH:41][CH2:42][CH:43]([C:44]1[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=1)[C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: N#C[Cu]
Solvent: O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Copper(I) cyanide was added to a solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (440 mg, 0.494 mmol) (Preparation 67) in N′N′-dimethylformamide (10 ml). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was poured into water (15 ml). The precipitate was filtered off and stirred in dichloromethane (50 ml) for 10 minutes. The dichloromethane was filtered, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98: 2 by volume). The solvent was removed under reduced pressure to give the title compound (227 mg) as a foam.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[S:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]2OCC[O:48]2)[C:44]([CH3:52])=[CH:43][C:42]=1[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]=[O:48])[C:44]([CH3:52])=[CH:43][C:42]=1[O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-(1,3-dioxolan-2-yl)-4-methylphenyl]-5-thio-D-glucopyranose (11.1 g, 13.5 mmol) in tetrahydrofuran (100 mL), 6N hydrochloric acid (100 mL) was added under ice cooling and stirred at room temperature for 12 hours. After addition of water under ice cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (10.1 g, quant.) as a light-yellow oily compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:31]C(=O)OC(C)(C)C)[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][F:26])[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[NH2:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1.C(O)(C(F)(F)F)=O.N[C@H](CC1C=CC(C2C=CC=CC=2)=CC=1)CC(N1CCC[C@@H](C2N(CCCOC)C3C=CC=CC=3N=2)C1)=O>>[NH2:31][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:43]2[CH:42]=[N:41][C:40]([NH2:39])=[N:45][CH:44]=2)=[CH:7][CH:6]=1)[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[N:23]([CH2:24][CH2:25][F:26])[C:22]3[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=3[N:20]=2)[CH2:14]1)=[O:12]
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3n2CCF)C1)Cc1ccc(Br)cc1
Agent: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-c4ccccc4)cc3)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2ccc(C[C@@H](N)CC(=O)N3CCC[C@@H](c4nc5ccccc5n4CCF)C3)cc2)cn1
Yield: 14.4 %

Procedure:
Suzuki coupling of 145A with 2-aminopyrimidin-5-ylboronic acid (145E) was carried out analogously to the synthesis of Compound 613 (Example 6, Step B). The crude Boc-protected intermediate was de-protected with TFA using procedure similar to that for the synthesis of Compound 72 from Compound 6B (Example 6, Step C). The crude product was purified by preparative HPLC using 15% CH3CN/water as mobile phase. Compound 509 was obtained in 14.4% yield over two steps (17.8 mg), MS: MH+=502.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][C:20]([NH2:22])=[O:21]>>[C:20]([CH2:19][NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12])(=[O:21])[NH2:22]
Reactant: NC(=O)CCl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: COc1ccc([N+](=O)[O-])cc1NCC(N)=O

Procedure:
In 2.7 liters of hydroalcoholic solution (2/3 alcohol, 1/3 water), one adds 2.1 mols (353 g) of 2-amino-4-nitro anisole, 2.1 mols (210 g) of calcium carbonate and 4.2 mols (393 g) of chloroacetamide. The mixture is brought to reflux for 64 hours and then drained while boiling. The precipitate which contains the expected product mixed with mineral salts is agitated in 1 liter of water at a temperature of 80° C. Hydrochloric acid is added in a quantity sufficient to destroy calcium carbonate. The expected product is drained, washed two times in boiling water, and recrystallized in acetic acid. After vacuum drying the product melts at 224° C.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:3]2[C:2]([S:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])=[CH:7][N:6]=[CH:5][N:4]=2)=[CH:9][CH:10]=1)#[N:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(-c2ncncc2Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1cncnc1-c1ccc(C#N)c2ccccc12
Temperature: 160 °C
Yield: 46.9 %

Procedure:
A mixture of 4-(5-bromopyrimidin-4-yl)-1-naphthonitrile (45 mg, 0.14 mmol), methyl thioglycolate (74 mg, 0.7 mmol) and potassium carbonate (27 mg, 0.2 mmol) in DMF (0.6 mL) was heated under microwave irradiation to 160° C. for 0.5 hour. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to yield methyl 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetate (22 mg, 47%).
Reaction SMILES: [CH:1]1([C:6]([CH:8]([NH:13]C(=O)OC(C)(C)C)[CH:9]([CH3:12])[CH2:10][CH3:11])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21]>>[Cl-:21].[CH:1]1([C:6](=[O:7])[CH:8]([NH3+:13])[CH:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)C1CCCC1
Product: CCC(C)C([NH3+])C(=O)C1CCCC1
Product: [Cl-]

Procedure:
4 (0.18 g, 0.63 mmol) was dissolved in 2 ml HCl (7 N in dioxane). After completion of the reaction the solvent was removed and the resulting oil was purified by column chromatography on silical gel using a chloroform/methanol/water gradient. The resulting oil was triturated with ether.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12](=[O:18])[C:13]([C:15](O)=[O:16])=[CH:14][N:8]3[N:7]([CH3:19])[CH2:6][CH2:5]2)[CH:11]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>O1CCCC1.CCOCC>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:15]([C:13]2[C:12](=[O:18])[C:10]3[CH:11]=[C:2]([I:1])[CH:3]=[C:4]4[C:9]=3[N:8]([CH:14]=2)[N:7]([CH3:19])[CH2:6][CH2:5]4)=[O:16])=[CH:35][CH:34]=1
Reactant: CN1CCc2cc(I)cc3c(=O)c(C(=O)O)cn1c23
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCc2cc(I)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C

Procedure:
A solution of 5-Iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid (Preparation 39, 0.900 g) in tetrahydrofuran (25 mL) is refluxed with 1,1′-carbonyldiimidazole (0.631 g) for 5 h. The reaction mixture is cooled to room temperature and treated with 4-chlorobenzylamine (0.828 g). The reaction mixture is diluted with ether (75 mL), filtered, and the filtrate is concentrated at reduced pressure. The crude product is purified by chromatography, using 75 g of silica gel packed and eluted with EtOAc-CH2Cl2-heptane (1:4:5), to afford the title compound. Physical characteristics: 1H NMR (CDCl3) δ8.91, 8.70, 7.87, 7.32, 4.65, 3.51, 3.13, 2.90; MS (ESI+) m/z 494.0; HRMS (FAB) m/z 494.0142 (C20H17ClIN3O2+H); TLC (silica gel GF): Rf=0.27 EtOAc/CH2Cl2 (1/6).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3c(c2)CCCC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methoxyphenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 253.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: CCOC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(N(C)C)cc2)N1

Procedure:
The same method as employed in the preparation of Intermediates 1 and 2 but starting from racemic tryptophan ethyl ester and 4-dimethylaminobenzaldehyde gave the title compound as white crystals m.p.:170° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8](CCC#N)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH2:25]([NH:24][C@H:20]1[C@@H:21]([OH:23])[CH2:22][N:18]([C:11]2[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]3)=[CH:13][C:12]=2[F:17])[CH2:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2nc(N3C[C@H](O)[C@H](NCc4ccccc4)C3)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 199B (0.1 g) in ethanol (1 mL) at 25° C. was treated with 1N NaOH (1 mL), stirred for 18 hours at 50° C., cooled, neutralized with 10% HCl, and filtered.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([O-:38])=O)=[N:5]1.[K+].[N:40]1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CC(N(C)C)=O.O>[OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:33])([F:35])[F:34])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([NH2:40])=[O:38])=[N:5]1
Reactant: O=C([O-])n1nnc2ccccc21
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(=O)[O-])nn3CCO)CC4)c2)CC1
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3CCO)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A suspension of potassium 1-(2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.54 g, 2.69 mmol) in anhydrous DMA (40 mL) was treated with N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (1.03 g, 5.38 mmol) and with ammonium 1H-1,2,3-benzotriazol-1-ate (0.819 g, 5.38 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (1.32 g, 88% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11](Br)[N:10]=1)=[O:8].[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH3:1][S:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11]([S:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1)=[O:8]
Reactant: CSc1ccccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccccc1CNC(=O)c1nc(Sc2ccccc2)c2cccnc2c1O
Temperature: 135 °C

Procedure:
To a 5 mL pyrex pressure vessel with a stirring bar was added 8-hydroxy-5-bromo-[1,6]naphthyridine-7-carboxylic acid 2-methylsulfanylbenzylamide (0.22 g, 0.54 mmol), thiophenol (0.181 g, 1.63 mmol) and triethylamine (0.557 mL, 4.00 mmol). The vessel was sealed under nitrogen and the stirred mixture heated in a 135° C. oil bath for 24 h. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed by reverse phase HPLC using water/acetonitrile as eluant to give 8-hydroxy-5-phenylsulfanyl-[1,6]naphthyridine-7-carboxylic acid 2-methylsulfanylbenzylamide as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[NH:36][C:37](=O)[C@@H:38]([N:40]1[CH:45]=[CH:44][CH:43]=[N:42][C:41]1=[O:46])[CH3:39])[CH2:5][C@@H:6]1[CH2:10][CH2:9][C@H:8]([C@H:11]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C(O)(=O)C>[Si:19]([O:18][C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:8]1[CH2:9][CH2:10][C@@H:6]([CH2:5][C:4]2[CH:33]=[CH:34][C:35]3[N:36]=[C:37]([C@@H:38]([N:40]4[CH:45]=[CH:44][CH:43]=[N:42][C:41]4=[O:46])[CH3:39])[NH:1][C:2]=3[CH:3]=2)[N:7]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C[C@@H](C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1N)n1cccnc1=O
Solvent: CC(=O)O
Product: C[C@@H](c1nc2ccc(C[C@@H]3CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c4ccccc4)N3C(=O)OC(C)(C)C)cc2[nH]1)n1cccnc1=O
Temperature: 25 °C

Procedure:
A solution of 0.020 g (0.030 mmol) of tert-butyl(2S,5R)-2-(3-amino-4-{[(2.5)-2-(2-oxopyrimidin-1(2H)-yl)propanoyl]amino}benzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate from Step A above in 1 mL of glacial acetic acid under an atmosphere of nitrogen was heated to 100° C. for 1 h. The resulting solution was allowed to cool to ambient temperature and then concentrated in vacuo to afford the title compound as a light brown gum that was used without further purification. LC/MS: m/z (ES) 644.5 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9]C)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][CH2:19][C:20]#[CH:21]>C(#N)C.C(OCC)C>[CH3:9][O:8][C:7]1[C:2]([C:21]#[C:20][CH2:19][O:18][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1cccnc1Cl
Reactant: C#CCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COCC#Cc1ncccc1OC
Temperature: 25 °C

Procedure:
To a solution of commercially available 2-chloro-3 ethoxy pyridine (1 eq.) in acetonitrile (1.9M) was added PdCl2(CH3CN)2 (0.015 eq.), Cs2CO3 (2.4 eq.) and 2-(dicyclohexylphosphino)-2′-6′-dimethoxy-1-1′-biphyl (S—PHOS; 0.044 eq.). The suspension was sonicated for 5 min then 3-methoxyprop-1-yne (1.7 eq.) was added. The final mixture was stirred 12 h at 100° C., cooled down to room temperature, diluted with diethylether. The organic fraction was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/Acetone 5% afforded the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[N:3]1.[CH:13]([OH:16])(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:16][CH:13]=[N:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:18]
Reactant: CCO
Reactant: OC(O)O
Reactant: CCOC(=O)c1cnn(C)c1N
Product: CCOC=Nc1c(C(=O)OCC)cnn1C
Yield: 87 %

Procedure:
84.6 g. of 1-methyl-4-carboethoxy-5-aminopyrazole and 74.1 g. of orthoformic acid triethyul ester are heated together until the splitting off of ethanol has ended. The oily residue is distilled under oil pump vacuum to obtain 5-[(ethoxy-methylene)amino]-1-methyl-1h-pyrazole-4-carboxylic acid, ethyl ester b.p. 98°-102°; m.p. 32°-34° (yield87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].Cl[CH2:18][CH2:19]Cl.[C:21](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:18]([CH3:19])[CH3:21])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: ClCCCl
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(C)C)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.2 g, 0.89 mmol) in 1,2-dichloroethane (3 ml) acetone (6.6 ml, 89.6 mmol) and acetic acid (0.053 g, 0.89 mmol) were added. The reaction mixture was cooled to 0° C. Sodium triacetoxyborohydride (0.266 g, 1.25 mmol) was added and stirred at r.t. for 24 h. The reaction mixture was quenched with saturated NaHCO3 and extracted in DCM (20 ml), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. Purification on silica gel (MeOH:CHCl3) yielded 0.14 g (60%) of 2-(3-Isopropylamino-phenoxy)-2-methyl-propionic acid ethyl ester which was hydrolyzed using a typical procedure A1 and used as such for the next step.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([N:43]=[C:44]=[S:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][C:44]([NH:43][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)=[S:45])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)Nc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), phenyl isothiocyanate (113 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was recrystallized from a mixture of ethanol and ethyl acetate (5:1) to afford the title compound (347 mg, mp 129.6-130.9° C.).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH2:19][O:20][C:21]2[CH:26]=CC(O)=[CH:23][CH:22]=2)[CH:11]=1)#N.O.Cl.[N:30]1C=CC=C[CH:31]=1>>[C:5]([O:4][C:1]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:12]2([C:31]#[N:30])[CH:11]=[CH:10][CH:18]=[CH:17][CH:13]2[C:14]([OH:16])=[O:15])=[CH:26][CH:2]=1)(=[O:7])[CH3:6]
Reactant: N#Cc1ccc(C(=O)O)c(COc2ccc(O)cc2)c1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: CC(=O)Oc1ccc(OCC2(C#N)C=CC=CC2C(=O)O)cc1

Procedure:
Under ice cooling and stirring, 5.5 ml of acetic anhydride was added to 5.2 g of 4-cyano-2-(4-hydroxyphenoxy)methylbenzoic acid obtained in Reference example 23 dissolved in 15.6 ml of pyridine and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture and the mixture was adjusted to about pH 2 with conc. hydrochloric acid and extracted with ethyl acetate. Then, the organic layer was washed with a saturated saline solution, 1N-hydrochloric acid and further a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was removed to obtain 5.36 g of a crude product of the title compound.