Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2]([C:5](O)=O)[CH2:3][SeH].[CH3:8][Si:9]([CH3:29])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])Cl.[OH:30][Ge:31][OH:32].[CH:33]1[CH:34]=[CH:35][C:36]2[C:37](=[C:39]3[N:71]=[C:70]4[N:72]=[C:63]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][C:69]=54)[N:62]=[C:60]4[NH:61][C:53]([C:54]5[CH:55]=[CH:56][CH:57]=[CH:58][C:59]=54)=[N:52][C:50]4=[N:51][C:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=54)=[N:42][C:41]=2[NH:40]3)[CH:38]=1>N1C=CC=CC=1>[CH3:8][Si:9]([CH3:29])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:30][Ge:31][O:32][Si:9]([CH2:3][CH2:2][CH2:5][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH3:63])([CH3:11])[CH3:8].[CH:34]1[CH:33]=[CH:38][C:37]2[C:36](=[C:41]3[N:42]=[C:43]4[N:51]=[C:50]([C:49]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=54)[N:52]=[C:53]4[NH:61][C:60]([C:59]5[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=54)=[N:62][C:63]4=[N:72][C:70]([C:69]5[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=54)=[N:71][C:39]=2[NH:40]3)[CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(C)Cl
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: O[Ge]O
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC[Si](C)(C)O[Ge]O[Si](C)(C)CCCCCCCCCCCCCCCCCC

Procedure:
[In analogy to a procedure by Wheeler et. al., J. Am. Chem. Sec. 106, 7404 (1984)] 3.3 g (9.5 mmol) of dimethyl-octadecyl-chlorosilane and 0.5 g (0.8 mmol) of dihydroxygermanium-phthalocyanine in 50 ml of pyridine are stirred for 2 hours at 50°. The solution is cooled and filtered using a suction filter. The solvent is removed in vacuo, and 250 ml of hexane are added to the residue. The resulting precipitate is filtered off with suction and washed first with hexane, then in portions with 200 ml of acetone/water (1:1). The residue is dried overnight under a high vacuum, then extracted with toluene in a Soxhlet, freed of solvent and dried, yielding bis(dimethyl-octadecyl-siloxy)germanium-phthalocyanine; NMR (pyridine-d5): δ=9.8-9.9 (m, 8H); 8.3-8.5 (m,8H): aromatic H's; 0.75-1.46 (various m's); 0.45(m); -0.03 (m); -0.88 (m); -1.91 (m); -2.48 (m, 4×CH3 : silyl side chains) ppm.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CN(/[CH:12]=[N:13]/[C:14]1[C:23]([C:24]([O:26]C)=O)=[CH:22][C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:28][CH3:29])[CH:20]=2)[N:15]=1)C.C(O)(=O)C>O1CCCC1>[CH3:29][O:28][C:19]1[C:18]([O:30][CH3:31])=[CH:17][C:16]2=[N:15][C:14]3[NH:13][CH:12]=[C:2]([C:1]#[N:3])[C:24](=[O:26])[C:23]=3[CH:22]=[C:21]2[CH:20]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3nc2cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
Acetonitrile (1.3 mL, 24.9 mmol) is added to a −78° C. solution of 9.0 mL of 2.5 M n-butyllithium (22.5 mmol) in 40 mL of tetrahydrofuran. After stirring at −78° C. for 15 min, a solution of 2.86 g (9.02 mmol) of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate in 100 mL of tetrahydrofuran is added dropwise over 30 minutes. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to room temperature and then stirred at room temperature for 1 hour. The reaction mixture is cooled to −78° C. and 3.0 mL of acetic acid is added. The mixture is then stirred at room temperature for 40 min. The solids are collected by filtration washing with water, methanol and ethyl acetate to provide 1.11 g (44%) of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile as a light yellow solid, mp>300° C. MS 281.9 (M+H)+ Analysis for C15H11N3O3.0.65H2O Calcd: C, 61.49; H, 4.23; N, 14.34. Found: C, 61.40; H, 4.40; N, 14.70.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:18]([NH:17][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[S:19])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cccc(Br)n1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cccc(Br)n1)c1ccccc1
Temperature: 65 °C
Yield: 99.5 %

Procedure:
2.604 g (14.75 mmol) 2-amino-6-bromopyridine was dissolved in 20 mL acetone, and 2.02 mL (14.75 mmol) undiluted benzoyl isothiocyanate was then added dropwise. The solution turned a brown color. The reaction mixture was then heated for 2 hr at 65° C. (oil bath temperature) with stirring. The light yellow solid which formed was filtered under vacuum and washed with pentane. The solvent of the mother liquor was also removed under vacuum. The resulting solids from the crystallizate (1.338 g) and from the mother liquor (3.595 g) were identical according to thin-layer chromatography (silica gel, eluents: dichloromethane/methanol (9:1)). A total of 4.933 g (14.67 mmol, 99.5%) N-{[(6-bromopyridin-2-yl)amino]carbonothioyl}benzamide was isolated.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Br:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Br:15])=[CH:24][C:23]=3[Br:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: COC[C@@H](C)n1cc(Cl)nc(Cl)c1=O
Product: COC[C@@H](C)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 119-120° C.; 1H NMR (300 MHz, CDCl3): δ 7.47 (d, J=1.8 Hz, 1 H), 7.27 (d, J=1.8 Hz, 1 H), 7.06 (s, 1 H), 5.14-5.09 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.62-3.52 (m, 2 H), 3.34 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.40 (d, J=7.0 Hz, 3 H); HRMS (CI) calcd for C16H16N3O2Br2Cl (M+H)+: 474.9298; found m/z 474.9285.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[C:4]([OH:6])=[O:5])#[N:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[C:4]([O:6][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:5])#[N:2]
Reactant: O=C1CCC(=O)N1O
Reactant: N#CC(=Cc1ccccc1F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: N#CC(=Cc1ccccc1F)C(=O)ON1C(=O)CCC1=O
Yield: 44.2 %

Procedure:
The same procedures as in Example 119 were carried out from α-cyano-2-fluorocinnamic acid (12.0 g), N-hydroxysuccinic acid imide (10.8 g), WSC.HCl (18.1 g), and methylene chloride (300 mL), to give the captioned compound (8.0 g, 44%) as crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:30]=[CH:29][C:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[N:9]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:14][C:13]1[C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[N:9][C:10]([NH:15][C:16]2[CH:30]=[CH:29][C:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:24][C:18]=3[CH:17]=2)=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4N)n3)cc2CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
To a solution of N*4*-((1S,2R)-2-Amino-cyclopentyl)-5-chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine (132 mg, 0.298 mmol) in DCM (2 mL) was added Et3N (62.0 μL, 0.447 mmol) at 0° C. under argon. Stirred reaction for 10 min. before adding methanesulfonyl chloride (34.6 μL, 0.447 mmol) dropwise via syringe. Reaction stirred for 20 minutes at 0° C. The reaction mixture was diluted with DCM and washed with 1N NaOH (2×). Dried organic layer over MgSO4, filtered and concentrated. The residue was purified by column chromatography to yield (58 mg, 38%). mp: 73-74° C., MS (ESI+): 509 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.14 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 1.33 (d, J=7.5 Hz, 1H), 7.32 (s, 1H), 6.96 (d, J=8 Hz, 1H), 6.40 (d, J=7 Hz, 1H), 4.34 (m, 1H), 3.89 (br s, 1H), 3.44 (t, J=6 Hz, 2H), 3.23 (s, 3H), 2.75 (br s, 8H), 2.62 (m, 8H), 2.50 (m, 5H), 2.02 (m, 2H), 1.76 (m, 2H), 1.66 (m, 1H), 1.54 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])([CH3:7])[CH3:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 32 %

Procedure:
To a stirring solution of ethyl-2-bromoisobutyrate (2.65 g, 13.6 mmol) in anhydrous acetonitrile (25 mL) at room temperature was added tert-butyl-1-piperazinecarboxylate (2.48 g, 13.3 mmol) followed by potassium carbonate (1.88 g, 13.6 mmol). The mixture was heated to 85° C. overnight. The cooled reaction mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, separated and dried (MgSO4). The crude product was purified by column chromatography to yield 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester as a colourless oil (1.28 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCCCCC.[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1.ClCCCI.C([O-])([O-])=O.[K+].[K+].[CH2:33]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]>O1CCCC1.O>[CH2:33]([CH:37]1[CH2:42][CH2:41][N:40]([CH2:1][CH2:2][CH2:3][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]
Reactant: c1ccc2c(c1)CCCN2
Reactant: [Li]CCCC
Reactant: CCCCC1CCNCC1
Agent: ClCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1CCN(CCCN2CCCc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of n-butyllithium in hexane (1.5M, 7.3 mL, 11 mmol) was added drop wise to a solution of 1,2,3,4-tetrahydro-quinoline (1.256 mL, 10 mmol) in tetrahydrofuran (10 mL) at −78° C. under an atmosphere of argon. The reaction mixture was stirred for ½ h then 1-chloro-3-iodopropane (1.0 mL, 9.5 mmol) was added. The reaction mixture was stirred at −78° C. for ½ h then stirred for additional 16 h at room temperature. Tetrahydrofuran was evaporated off and the solid was dissolved in acetonitrile (10 mL). KI (1.83 g, 11 mmol), K2CO3 (2.76 g, 20 mmol) and 4-butylpiperidine (1.66 mL, 10 mmol) were added. The slurry was stirred at 50° C. for 48 h then water (10 mL) was added and the product was extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: ethyl acetate) to give the title compound (1.11 g, 35%) Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=315.1 (MS (%)=95). 1H NMR (400 MHz, CDCl3): δ=0.89 (3H, t), 1.18-1.34 (9H, m), 1.64-1.70 (2H, m), 1.79 (2H, quin.), 1.85-1.98 (4H, m), 2.36 (2H, t), 2.74 (2H, t), 2.92 (2H, broad d), 3.24-3.31 (4H, m), 6.54 (1H, ddd), 6.60 (1H, dd), 6.93 (1H, dd), 7.03 (1H, ddd). 13C NMR (CDCl3): δ 14.3, 22.5, 23.1, 24.2, 28.4, 29.3, 32.7, 36.0, 36.5, 49.6, 49.8, 54.4, 56.7, 110.9, 115.5, 122.5, 127.3, 129.3, 145.6.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[O:19]1[C:23]2([CH2:28][CH2:27][N:26]([C:16]([C:13]3[S:14][CH:15]=[C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])[N:12]=3)=[O:17])[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC4(CC3)OCCO4)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 1,4-Dioxa-8-azaspiro[4.5]decane (Aldrich) (0.06 ml; 0.53 mmol; 1 eq.) and triethylamine (0.15 ml; 1.06 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by precipitation in MeOH, affording Compound (38) as a beige solid (64.9 mg, 30%). 1H NMR (DMSO-d6, 300 MHz) δ 1.73 (m, 4H), 2.13 (s, 3H), 2.48 (s, 3H), 3.72 (m, 2H), 3.93 (m, 4H), 4.28 (m, 2H), 7.99 (s, 1H), 12.16 (s, 1H). M− (ESI): 407.10; M+ (ESI): 409.21. HPLC (method A), Rt: 2.86 min (purity: 94%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[C:5]1(C)[CH:10]=[CH:9][C:8]([S:11](O)(=O)=O)=[CH:7][CH:6]=1.[OH2:16]>>[OH:16][C:5]1[CH:6]=[CH:7][C:8]([S:11][C@H:2]([CH3:3])[C:1]([O:4][CH2:1][CH2:2][CH3:3])=[O:4])=[CH:9][CH:10]=1
Reactant: CCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Product: CCCOC(=O)[C@@H](C)Sc1ccc(O)cc1
Yield: 83 %

Procedure:
A solution of HPTPA (0.06 mole, 11 g) in an molar excess of 1-propanol (45 ml), containing a crystal of p-toluene sulphonic acid, was heated at reflux while allowing water to distil from the reaction mix. When no acid remained, as shown by IR-spectroscopy, the excess solvent was allowed to distil out and the cold residue taken into ether and washed with saturated NaHCO3 solution, dried (MgSO4) and the crude product isolated by evaporation. This was purified by distillation under reduced pressure (yield: 83%; SOR: +98°,c=2). The properties of the product determined by IR, 1H-NMR and mass spectroscopy and elemental analysis were consistent with the assigned structure.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O:14][C:15](=O)/[CH:16]=[C:17](/[O:20][C:21]1[C:26]2[N:27]=[C:28]([CH3:30])[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1)\[CH2:18]Br)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:18][C:17]([O:20][C:21]2[C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[CH:16][C:15]1=[O:14])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc2oc(C)nc12
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3oc(C)nc23)=CC1=O
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.570 g, 3.14 mmol), (E)-4-bromo-3-(2-methyl-benzooxazol-4-yloxy)-but-2-enoic acid ethyl ester (0.970 g, 2.85 mmol) and N,N-diisopropylethylamine (0.809 g, 6.21 mmol) in acetonitrile (20 mL) in a sealed tube was heated at 100° C. for 5 h. The reaction mixture was then cooled to room temperature and ethyl acetate was added. The mixture was then filtered. The filtrate was washed successively with aqueous saturated ammonium chloride, water, and brine and then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and microwaved in an Emry Optimizer microwave reaction vessel at 160° C., for 3 h. The mixture was then cooled and concentrated in vacuo and the residue was purified by ISCO Combiflash chromatography (40 g Silicycle, 5% to 50% ethyl acetate/hexanes) to afford (S)-4-methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.570 g, 56%) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:15][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-(4-nitrophenoxy)pyridin-2-amine [US Pat Appl 2008319188, Production Example 53] (0.60 g, 2.60 mmol) and DIPEA (0.680 μL, 3.89 mmol) in DCM (15.0 mL) under nitrogen at 0° C. was added 2-methoxyacetyl chloride (225 μL, 3.89 mmol) dropwise over 5 min. The reaction was maintained at RT for 16 hr and was quenched by the addition of a 1% solution of NH3 in MeOH (10 mL). The mixture was evaporated in vacuo and the residue was taken up into DCM (50 mL) and was washed with water (25 mL) and brine (25 mL), and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in DCM, 0-30%, gradient elution) to afford 2-methoxy-N-(4-(4-nitrophenoxy)pyridin-2-yl)acetamide as a white solid (0.73 g, 92%); Rt 1.88 min (Method 2); m/z 304 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCO)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCS(C)(=O)=O)CC1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of methanesulfonyl chloride 0.374 g, 3.3 mmol in ethyl acetate (3 ml was added to a mixture of 1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (1.0 g, 3 mmol) and triethylamine. The resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give an oily residue. The residue was chromatographed on silica gel (290 g; ethyl acetate/hexane: 1:4) to yield 1-(2-methanesulfonylethyl)-4-methoxycarbonyl-4-(N'-phenyl-propionamido)piperidine (0.53 g, 43%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Cl)Cl.BrN1[C:28](=O)[CH2:27][CH2:26][C:25]1=O>>[C:16]([O:15][C:13]([N:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:28]2[CH2:20][CH:25]1[CH:26]=[CH:27]2)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NNC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Reactant: ClCCl
Product: CC(C)(C)OC(=O)N1C2C=CC(C2)N1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 54 %

Procedure:
To a stirred mixture of 1 g (4.34 mmol) of 1-benzyloxycarbonyl-2-t-butoxycarbonylhydrazine (Dutta et al., J.C.S. Perkin I, 1975, 1712-1720) in 30 ml of anhydrous methylene chloride 1.55 g (8.7 mmol) of N-bromosuccinimide was added at 0° C. and the stirring was continued for 1 hour with external cooling in an ice bath. The reaction mixture was washed with 10% aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residue was redissolved in 15 ml of anhydrous ether, 0.57 g (8.7 mmol) of freshly distilled cyclopentadiene was added and the mixture was allowed to stay for I hour at room temperature. Evaporation to dryness under reduced pressure gave 0.77g (54% yield) of the title product as a colorless syrup; NMR (CDCl3) 1.44 (s, 9H, t-butoxy CH3); 1.7 (m, 2H, CH2 -7); 5.06 (m, 2H, CH-1,4); 5.15 (s, 2H, methoxy CH2); 6A (m, 2H, CH-5,6); 7.24 (m, 5H, aromatic).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH2:34][C:32](=[O:33])[N:31]([CH2:35][C:36]([OH:38])=[O:37])[C:29]1=[S:30].[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:34]2[S:28][C:29](=[S:30])[N:31]([CH2:35][C:36]([O-:38])=[O:37])[C:32]2=[O:33])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2+:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C1CCNCC1
Solvent: CCO
Product: C1CC[NH2+]CC1
Product: O=C([O-])CN1C(=O)C(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 7 h
Yield: 101.4 %

Procedure:
A mixture comprising 2.5 g of 2-tritylaminothiazole-4-carbaldehyde, 0.81 g of rhodanine-3-acetic acid, 1.1 g of piperidine and 25 ml of ethanol was stirred at room temperature for 7 hours. The crystalline product which precipitated out was collected by filtration and washed with methanol, to obtain 2.7 g of the desired compound as a yellowish-brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.6 %

Procedure:
To a solution of 3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol) and 4-bromochlorobenzene (0.77 g, 4 mmol) was added sodium tert-butoxide (0.96 g, 10 mmol), palladium(1H) dibenzylideneacetone (Pd2DBA3, 0.09 g, 0.1 mmol), and BINAP (0.19 g, 0.3 mmol). The suspension was stirred at 120° C. for 10 hours. The reaction was filtered through celite and evaporated in vacuo. The residue was purified by silica gel chromatography (hexane→ethyl acetate) to yield 0.84 g (68%) of the title compound. 1H-NMR (CDCl3): δ 1.00 (3H, m), 1.74 (9H, s), 3.10 (3H, m), 3.30 (1H, m), 3.80 (2H, m), 4.10 (1H, brs), 6.85 (2H, d), 7.20 (2H, d).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.O.[N+]([O-])([O-])=[O:15].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C>[O:15]=[C:12]1[C:2]2[S:1][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cc2c(s1)CCCC2
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5 mmol), acetic acid (40 mL) and water (40 mL). A solution of ammonium cerium(IV) nitrate (36.1 g, 65.9 mmol) in acetic acid (40 mL) was added dropwise, and the reaction was stirred at room temperature for 1 h. After this time, the reaction mixture was poured into water (200 mL) and extracted with methylene chloride (3×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to afford 16 in 72% yield (2.35 g) as a yellow solid: mp 174-175° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.60 (bs, 1H), 7.68 (s, 1H), 2.86 (t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.08 (quintet, 2H, J=6.0 Hz).