Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(Br)n2)cc1
Reactant: COCCN
Solvent: CN1CCCC1=O
Product: COCCNc1cccc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)n1
Temperature: 190 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-({4-[(6-bromo-2-pyridinyl)methoxy]benzoyl}amino)benzamide (100 mg, 0.21 mmol), 2-methoxyethylamine (500 μL) and NMP (500 μL) was heated to 190° C. in the microwave for 90 min. The cooled reaction mixture was eluted through a silica cartridge with isohexane then ethyl acetate to give the crude product which was triturated with diethyl ether to give the title compound as a solid (36 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 3.28 (m, 2H), 3.31 (m, 3H), 5.08 (s, 2H), 6.47 (d, 1H), 6.61 (d, 2H), 7.14 (d, 2H), 7.32 (m, 2H), 7.40 (m, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (m, 2H), 8.37 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M+H+ 475.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1SC)=[C:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]([F:19])=[CH:6][C:5]=2Br>[Ni].C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[C:7]([F:19])=[CH:6][CH:5]=2
Reactant: CSc1c(C)[nH]c2c(Br)cc(F)c(N3CCOCC3)c12
Agent: [Ni]
Solvent: CCO
Product: Cc1cc2c(N3CCOCC3)c(F)ccc2[nH]1
Yield: 72.4 %

Procedure:
Raney nickel (1.5 kg) was added to a solution of 214 g of 2-methyl-3-methylthio-4-morpholino-5-fluoro-7-bromoindole in 3 l of ethanol and the mixture was refluxed for 3 hours. After completion of reaction the reaction mixture was cooled and Raney nickel was removed by filtration. Concentration of the filtrate gave 101 g of 2-methyl-4-morpholino-5-fluoroindole.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].[Cl:5][C:6]([Cl:12])([Cl:11])[C:7](=[NH:10])OC>>[Cl:5][C:6]([Cl:12])([Cl:11])[C:7]([NH:4][NH:3][CH:1]=[O:2])=[NH:10]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: NNC=O
Product: N=C(NNC=O)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of 4.2 g (0.07 mole) formylhydrazine and 20 ml (28.5 g, 0.16 mole) methyl 2,2,2-trichloroacetimidate was stirred at room temperature. After 10 minutes a vigorous reaction occurred and the temperature rose to 65° C. The beige solid that formed was washed with petroleum ether and dried to give 11.0 g [77%, mp 124°-126° C. (decomposed)] of product. An analytical sample was recrystallized from toluene [mp 128°-130° C. (decomposed)]. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].Cl.[OH-].[K+].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl>O.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]1[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: NC(CO)c1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(c2ccccn2)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.4 %

Procedure:
To a solution of 2-amino-2-(pyridin-2-yl)ethanol (3.8 g, 28 mmol) (as the bis HCl salt) in water (50 mL) cooled to 0° C. was added potassium hydroxide (11 g, 19 mmol) followed by THF (50 mL) and the reaction stirred for 20 minutes at 0° C., followed by addition of bis(trichloromethyl) carbonate (8.2 g, 28 mmol) as the solid and stirring at 0° C. for 2 hours. The reaction was next poured into water and extracted with EtOAc and the combined organic layers were washed with 1N NaOH, brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using EtOAc as eluent to yield 4-(pyridin-2-yl)oxazolidin-2-one (1.4 g, 8.5 mmol, 31% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][C:27]([NH2:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CN(C)C=O.O>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9 %

Procedure:
A mixture of 6.1 g (0.020 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 4.9 g (0.040 mole) of 4-chlorobutanamide, 8.5 g (0.080 mole) of anhydrous sodium carbonate and 0.4 g (0.002 mole) of potassium iodide in 100 mL of N,N-dimethylformamide was stirred at ambient temperature for 24 h. The mixture was poured into 1.5 L of water and extracted twice with 500 mL portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4), and concentrated under reduced pressure to give a dark oil. The oil was purified by column chromatography using 250 g of silica gel on a 65 cm×4 cm column eluted with methanol-methylene chloride (1:2). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was partitioned between methylene chloride and water. The methylene chloride layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a glass. The glass was converted to the oxalic acid salt, and the solid was recrystallized from ethyl acetate/2-propanol to yield 0.7 g (9%) of the title compound as a white solid containing 0.25 mole H2O, mp 177°-179° C.
Reaction SMILES: O1CCCC1.[CH3:6][C@@:7]12[C:13](=O)[CH2:12][C@@H:11]1[CH2:10][CH:9]=[CH:8]2.CP([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(C)=O.[H-].[Na+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:6][C@@:7]12[C:13](=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C@@H:11]1[CH2:10][CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)CP(C)(C)=O
Reactant: C[C@]12C=CC[C@H]1CC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@]12C

Procedure:
An anhydrous tetrahydrofuran solution (2 mL) of (±)-(1S,5R)-5-methylbicyclo[3.2.0]hept-3-en-6-one (800 mg, 6.55 mmol) was added dropwise with stirring under ice cooling to a reaction solution prepared in advance from an anhydrous tetrahydrofuran solution (10 mL) of tert-butyl dimethylphosphorylacetate (1.28 g, 6.55 mmol) and sodium hydride (>63% oil, 245 mg, 6.55 mmol), and the mixture was then stirred for 1 hour in this bath and further stirred at room temperature for 2 hours. The reaction solution was diluted with an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (389 mg).
Reaction SMILES: [CH:1]1([OH:12])[CH:6]([OH:7])[CH:5]([OH:8])[CH:4]([OH:9])[CH:3]([OH:10])[CH:2]1[OH:11].C(O)[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O>>[O:7]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:11])[OH:10])[OH:9])[OH:8]
Reactant: OC1C(O)C(O)C(O)C(O)C1O
Agent: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Comparing to the growth of the strain A34030 on a D-glucose-supplemented medium as a positive control, addition of L-arabinose, D-fructose, sucrose, D-xylose and D-mannitol gave a similar growth of the strain A34030, respectively. On the other hand, addition of myo-inositol gave lesser growth of the strain, and on rhamnose-supplemented medium, the growth was not observed. Addition of raffinose gave better growth of the strain A34030 than that of D-glucose.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.O.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:34][NH:35]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
To N-{(3R,5R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-3-piperidinyl}-N,3,3-trimethylbutanamide (82 mg, 0.187 mmol) in ethanol (4 mL) was added hydrazine monohydrate (1 mL, 20.4 mmol), and the reaction mixture was stirred for 4 hours at 120° C. into a sealed vessel. The reaction was allowed to cool down to room temperature, and poured onto water (˜120 mL). The resulting aqueous mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (36 mg) as an off-white solid as a 3:2 mixture of rotamers. LC-MS (ES) m/z=451 [M+H]+. 1H NMR (400 MHz, DMSO-d6+1 drop D2O): δ 0.98 (m, 12H), 1.41 and 1.52 (m, 1H), 1.87-2.41 (m, 4H), 2.76 and 2.90 (s, 3H), 2.99-3.25 (m, 2H), 3.84-3.99 (m, 1H), 4.01-4.26 (m, 1H), 4.39-4.66 (m, 1H), 6.57-6.62 (s, 1H), 7.50-7.60 (m, 1H), 7.70 (m, 1H), 7.92 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[C:15]2[N:20]=[C:19]([N:21]3[C:25]([C:26]([F:29])([F:28])[F:27])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[N:22]3)[CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:45]2[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH:50]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[CH2:33]([O:32][C:30]([C:24]1[CH:23]=[N:22][N:21]([C:19]2[N:20]=[C:15]([C:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:35]=[CH:36][C:2]([C:45]4[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=4)=[CH:3][CH:4]=3)[CH:16]=[CH:17][CH:18]=2)[C:25]=1[C:26]([F:29])([F:28])[F:27])=[O:31])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A vial was charged with the title compound from Example 12 Step C (375 mg, 0.669 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (310 mg, 1.00 mmol; Tetrahedron Lett, 2000, 41, 3705-3708) and trans-dichlorobis(triphenylphosphine)palladium (II) (47 mg, 0.067 mmol). Acetonitrile (2.2 mL) and sodium carbonate (1.7 mL, 1.0 M aqueous, 1.7 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 15 h, then was allowed to cool to ambient temperature and was loaded directly onto a silica gel column. Purification by chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 663.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.16 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.08-6.02 (m, 1H), 5.11 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 4.08-4.06 (m, 2H), 3.65-3.63 (m, 2H), 2.54-2.50 (m, 2H), 2.35 (s, 3H), 1.49 (s, 9H), 1.41 (q, J=7.0 Hz, 3H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.17 mmol), glycine (3.07 g, 41 mmol) and NaOMe solution (61 mL, 31 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 62 mg of the title compound. MS: (+) m/z 455.11 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl.Cl[CH2:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:39][N:35]1[CH:36]=[CH:37][N:38]=[C:34]1[CH2:33][N:7]1[C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:2]1=[O:1]
Reactant: Cn1ccnc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.16 g, compound B50) and 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (500 mg, compound D31) in dry DMF (15 ml) is added potassium carbonate (753 mg). The mixture is stirred for 3 h at 50° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo. The residue is taken up in EtOAc, filtered off and dried in vacuo to afford the title compound as a solid
Reaction SMILES: [CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:19]1(=[O:30])[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1>C1(C)C=CC=CC=1>[CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2csc(C3CCC3)n2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2csc(C3CCC3)n2)c1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of 0.13 g of (E)-3-[2-[2-cyclobutyl-4-thiazolyl]ethenyl]phenylamine, 0.094 g of homophthalic anhydride and 10 ml of toluene was heated on a steam bath for 1 hr and then allowed to cool to room temperature. Filtration of the reaction mixture yielded 0.1 g of (E)-2-[2-[3-[2-(2-cyclobutyl-4-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 198°-199° C. from acetonitrile.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:12])[CH:10]=[CH2:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:13]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:19]1)C[C:14]2=O>ClCCl.COC(OC)(C)C>[CH:10]([CH:9]1[O:12][C:13]([CH3:19])([CH3:14])[O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8]1)=[CH2:11]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: C=CC(O)CC(O)CC(=O)OC
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: C=CC1CC(CC(=O)OC)OC(C)(C)O1
Reaction time: 8 h

Procedure:
The crude β,δ-dihydroxy-6-heptenoic acid, methyl ester from the previous step was dissolved in a mixture of 30 ml of dichloromethane and 10 ml of 2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and the mixture was stirred overnight. Concentration of the reaction mixture and flashchromatography of the residue yielded 1.1 g of 6-ethenyl-2,2-dimethyl-1,3-dioxane-4- acetic acid, methyl ester which was employed in the subsequent step without further purification.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:3].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[NH4+]>O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:1]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1sc([N+](=O)[O-])cc1N=NN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
Methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (2 g, 9.38 mmol) was added slowly for 15 min at 0 to −5° C. to concentrated sulfuric acid (20 mL). Then concentrated nitric acid (0.54 mL, 70%, 10.7 mmol) was added to the above reaction mixture for 10 min and stirred at the same temperature for 1 h and rt for 16 h. The mixture was poured into ice cooled water and basified with ammonium hydroxide. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (80:20) as eluents to give the product as a yellow color solid (450 mg, 26%), mp 128-130° C.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[Br:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].CN(CC1C=CN=CC=1)C>ClCCl.ClCCl.CO>[CH3:1][O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([CH2:17][Br:16])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: CN(C)Cc1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
A solution of dicyclohexylcarbodiimide (DCC, 0.95 g, 4.61 mmol, 1.2 equiv) in 10 mL of dichloromethane (DCM) was added dropwise to a stirred mixture of 4-bromomethyl-3-nitro-benzoic acid 1 (1.0 g, 3.84 mmol, 1.0 equiv) and 4-dimethylaminomethylpyridine (DMAP) (0.020 g, 0.19 mmol, 0.05 equiv) in 10 mL of dichloromethane-methanol (10%) at room temperature. The mixture was stirred for 6 hours to obtain 4-bromomethyl-3-nitro-benzoic acid methyl ester 2. Dicyclohexyl urea (DCU) thus obtained was removed by filtration and the solvent in the filtered solution was removed under vacuum. The residue was purified by column chromatography using hexane-ethyl acetate (15%) as an eluant to give ester 2 as a light yellow oil.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.[Br:31]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[Br:31][C:30]1[C:17]([F:16])=[C:18]([CH:27]=[CH:28][CH:29]=1)[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CN1CCC(Oc2ccccc2F)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(Br)c2F)CC1
Reaction time: 0.25 h

Procedure:
Add n-butyl lithium (1.6 M in hexane, 7.4 mL) to a solution of 2,2,6,6-tetramethyl-piperidine (1.67 g) in THF (30 mL) at −78° C. and stir. After 15 min., add dropwise a solution of 4-(2-fluoro-phenoxy)-1-methyl-piperidine preparation 17, 1.65 g) in THF (20 mL) and stir. After 1 hr., add dropwise 1,2-dibromo-1,1,2,2-tetrachloro-ethane (2.57 g) in THF (15 mL) and stir. After 30 min. at −78° C. and 1 hr. at room temperature, partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give the title compound (1.25 g). Mass spectrum (electric spray) m/z=288 (M+1), 290 (M+2+1); 1H NMR (CDCl3): 7.12 (m, 1H), 6.92 (m, 2H), 4.30 (m, 1H), 2.69 (m, 2H), 2.30 (s, 3H), 2.28 (m, 2H), 1.97 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: C(O)(C)(C)C.CC(C)([O-])C.[K+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:33]([CH2:34][C:35]#[CH:36])[C:32]3[C:31](=[O:37])[N:30]([CH3:38])[C:29](=[O:39])[N:28]([CH3:40])[C:27]=3[N:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>CS(C)=O.O.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:33]([CH:34]=[C:35]=[CH2:36])[C:32]3[C:31](=[O:37])[N:30]([CH3:38])[C:29](=[O:39])[N:28]([CH3:40])[C:27]=3[N:26]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C=Cn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
Tert-butanol (0.1 ml) and potassium tert-butoxide (0.015 g) were added to a solution of 4-[1,3-dimethyl-2,6-dioxo-7-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (0.402 g) in dimethyl sulfoxide (5 ml), and the reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous solution of ammonium chloride (5 ml) was added, and the reaction solution was poured into ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with 10% aqueous solution of acetic acid (50 ml), saturated aqueous solution of sodium bicarbonate (50 ml), and saturated aqueous solution of sodium chloride (50 ml) in order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.176 g of the title compound from a fraction eluted with hexane-ethyl acetate (3:7).