Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:31]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:47]>C1COCC1.CCOCC>[ClH:47].[ClH:47].[CH3:7][N:8]([CH3:30])[CH2:9][CH:10]=[C:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:41][CH2:42]1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(CCOc2ccccc2)CC1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CC=C1CCN(CCOc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (9.13 ml, 2.5M solution in hexanes) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide (9.46 g) in dry THF (60 ml) under nitrogen at 0° C. over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then 1-(2-phenoxyethyl)-4-piperidone (5.0 g) in THF (15 ml) was added dropwise over 5 minutes. The mixture was warmed to ambient temperature and then heated at 60° C. for 5 hours. The mixture was left at ambient temperature for 18 hours and then quenched with water and diluted with ethyl acetate. 2M Hydrochloric acid was added and the mixture was separated. The organic layer was extracted with 2M hydrochloric acid and the combined acidic layers were basified and extracted with dichloromethane to give an oil. The oil was purified by flash column chromatography on silica using dichloromethane and then dichloromethane/methanol (1:1) as the mobile phase. The oil obtained after chromatography was dissolved in ether and treated with ethereal hydrogen chloride. The ether was decanted off and the residual semi-solid was triturated with acetone/ether (1:1) and filtered to give a solid which was recrystallised from IMS to give 4-(2-dimethylaminoethylidene)-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 234°-235° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.C1N2CCN(CC2)C1.[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])[CH2:23][CH2:22][CH2:21][CH:20]=1>C(Cl)Cl>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:35])(=[O:31])=[O:32])[CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1C1=CCCC1
Reactant: COc1cc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C2=CCCC2)n1

Procedure:
A mixture of 2-amino-4-methoxy-6-methylpyrimidine (0.45 g, 3.2 mmol), methylene chloride and DABCO (ca. 10 mg) was contacted with 2-(1-cyclopentenyl)benzenesulfonyl isocyanate in methylene chloride solution at ambient temperature. After approximately 20 minutes the product crystallized from the reaction mixture and was collected by filtration and rinsed with ether. In this manner, 0.35 g of product was obtained, m.p. 235°-236°. The infrared spectrum exhibited a carbonyl absorption at 1710 cm-1 indicating the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH:7]2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>C1(P[C-]2C=CC=C2)C=CC=CC=1.[C-]1(PC2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][C:8]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7]3)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(I)cccc2c1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
8-Iodo-3-phenylsulfonyl-quinoline (D6) (190 mg, 0.48 mmol), N-methyl-piperazine (48 mg, 0.48 mmol), sodium tertbutoxide (65 mg, 0.68 mmol), di-palladium tetrakis-(dibenzylidine acetone) [Pd2(dba)3] (88 mg, 0.1 mmol) and 1,1′-diphenylphosphino ferrocene (161 mg, 0.3 mmol) were suspended in degassed dry dioxan (2 ml). The mixture was stirred under argon at 40° C. for 16 hours. The solvent was removed and the residue subjected to flash chromatography on silica gel (eluting with dichloromethane—methanol aq. ammonia) to give the title compound (E1), identical spectroscopically to that prepared by the earlier methods.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:30]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C21H25FN6O2, 412.2
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>O>[Cl:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: Nc1ccc(CCO)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)cccc1Nc1ccc(CCO)cc1
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 2,6-dichloronitrobenzene (Norman, M. H.; Chen, N.; et al. PCT Int. Appl., WO 9940091 (1999)., Spada, A. P.; Fink, C. A.; Myers, M. R. PCT Int. Appl., WO 9205177 (1992)., 6.3 g, 32.8 mmol), 4-aminophenylethyl alcohol (4.9 g, 36 mmol) and sodium acetate (3.2 g, 39.3 mmol) was placed in a sealed tube and heated at 160° C. for 3 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 4.57 g (72%) of the title compound as a red oil: 1H-NMR (CDCl3) δ 7.09–7.28 (6H, m), 6.91 (1H, dd, J=2.0, 7.1 Hz), 3.87 (2H, t, J=6.6 Hz), 2.86 (2H, t J=6.6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Cl-].[C:29]([O:33][C:34](=[O:37])[CH2:35][Zn+])([CH3:32])([CH3:31])[CH3:30]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2].O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[N:10]=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:27]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Product: COC(OC)c1nc2c(cc1CC(=O)OC(C)(C)C)CCCN2C(=O)Nc1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A tube was charged with 6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2H, 41.7 mg, 0.096 mmol), Pd(dba)2 (2.8 mg, 4.8 μmol) and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (3.4 mg, 4.8 μmol), flushed with argon, then THF (1 ml) was added followed by 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in Et2O, 0.386 ml, 0.193 mmol) and the reaction mixture was stirred at 70° C. under argon for 1 h. The reaction mixture was poured into water and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 95:5 to 50:50) followed by a reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 95:5 to 5:95) to give the title compound as a red resin. (UPLC-MS 3) tR 1.33 min; ESI-MS 468.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[CH3:30][C:31]1([CH3:47])[C:40]2[C:35]3=[C:36]([C:41]([CH2:43][C:44]([NH2:46])=[O:45])=[CH:42][N:34]3[CH2:33][CH2:32]1)[CH:37]=[CH:38][CH:39]=2>>[CH:26]([Si:19]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[O:18][CH2:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]2[C:4]1[C:3](=[O:2])[NH:46][C:44](=[O:45])[C:43]=1[C:41]1[C:36]2=[C:35]3[C:40](=[CH:39][CH:38]=[CH:37]2)[C:31]([CH3:47])([CH3:30])[CH2:32][CH2:33][N:34]3[CH:42]=1)([CH3:27])[CH3:28]
Reactant: CC1(C)CCn2cc(CC(N)=O)c3cccc1c32
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Product: CC(C)[Si](OCCCc1cccc2c(C3=C(c4cn5c6c(cccc46)C(C)(C)CC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-((triisopropylsilyloxy)propyl)indole-3-glyoxylic acid methyl ester and 2-(6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)(C)(C)C.[CH:23]1(C(Cl)=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(CC)CC.Cl>C(Cl)Cl>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:12]2[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:6]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:13]=2)[CH2:19][CH2:18]1)[CH3:21]
Reactant: CCN1CCN(c2cc(NC(=O)OC(C)(C)C)ncn2)CC1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(c2cc(NC(=O)C3CCCC3)ncn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
A mixture of 1.6 g (7.75 mmol) 6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-ylamine (intermediate 4), 2.03 g (9.3 mmol) di-tert-butyl dicarbonate and 1.17 g (11.6 mmol) NEt3 in 30 mL DCM was stirred at 50° C. in a sealed tube for 16 h. After evaporation of all volatiles the residue was purified with flash column chromatography on silica. The combined product fractions were evaporated to dryness to yield [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester. MS(m/e): 308.4 (MH+). A mixture of 31 mg (0.1 mmol) [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester, 20 mg (0.15 mmol) cyclopentanecarbonyl chloride and 30 mg (0.3 mmol) NEt3 in 2 mL DCM was shaken at room temperature for 6 h. Subsequently, 3 mL HCl (4N) was added, the mixture was shaken at 50° C. for 4 h and all volatiles removed under reduced pressure. The residue was taken up in methanol/NEt3 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 20 mg (66%) of the title compound as white solid. MS (m/e): 344.1 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].Cl.C[CH2:14][O:15]CC>[C-]#N.[Zn+2].[C-]#N>[OH:11][C:10]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([OH:6])[CH:7]=[CH:8][C:9]=1[CH:14]=[O:15]
Reactant: CCOCC
Reactant: CCCc1c(O)cccc1O
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCc1c(O)ccc(C=O)c1O
Reaction time: 0.5 h

Procedure:
Zinc cyanide (24 g) was added to a stirred suspension of 2-propylresorcinol (32.4 g) in dry ether (150 ml) and the resulting mixture saturated with hydrogen chloride. After being left to stand at room temperature for 30 minutes the ether was decanted and the remaining solid heated on the steam bath with water for 30 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:4]=2[N:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Si:24]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][C:5]2[N:6]([CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[C:2]([NH2:1])=[N:3][C:4]=2[CH:16]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Nc1nc2cc(CO)ccc2n1C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)nc(N)n2C1CCCCC1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of (2-Amino-1-cyclohexyl-1H-benzoimidazol-5-yl)methanol (0.650 g, 0.00265 mol) and 1H-Imidazole (0.4149 g, 0.006094 mol) in N,N-Dimethylformamide (10 mL) was added tert-Butyldimethylsilyl chloride (0.4393 g, 0.002914 mol) and the mixture stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated socium bicarbonate, dried and concentrated. The residue was taken up in methylene chloride containing 0.1% triethylamine and purified by flash chromatography with a gradient of from 0 to 10 percent methanol. The product fractions were concentrated to give 539 mg of the product.
Reaction SMILES: N([O-])=O.[Na+].[CH:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2N)[CH2:7][CH2:6]1.[I-:21].[K+]>O.Cl>[CH:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[I:21])[CH2:7][CH2:6]1
Reactant: Nc1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
An ice-cooled solution of sodium nitrite (3.55 g, 51 mmol) in water (10 mL) was added dropwise to a stirred, cooled (0° C.) solution of 2-cyclopropoxy-5-(trifluoromethoxy)benzeneamine (Description 7, 4.8 g, 20.6 mmol) in aqueous hydrochloric acid (5M, 300 mL), maintaining the internal temperature at 0° C. The mixture was stirred at 0° C. for 30 min., then potassium iodide (8.55 g, 51.5 mmol) in water (10 ml,) was added dropwise, maintaining the internal temperature at 0° C. The mixture was stirred at 0° C. for 30 min., then allowed to warm up to room temperature and stirred until nitrogen evolution ceased. The mixture was extracted with ether, the organic fraction was washed with aqueous sodium thiosulfate (10%), dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (98:2 increasing to 95:5), to give the title compound as a colourless oil (6.23 g, 88%). 1H NMR (360 MHz, CDCl3) δ7.62 (1H, d, J 2.4 Hz), 7.20 (1H, dd, J 9.1, 2.4 Hz), 7.15 (1H, d, J 9.1 Hz), 3.80 (1H, m), and 0.83 (4H, m).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[O:4][CH2:3][CH2:2]1.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl>ClC1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2c1OCCO2
Agent: Cl
Solvent: Clc1ccccc1
Product: c1cc2c(c(N3CCNCC3)c1)OCCO2

Procedure:
A stirred mixture of 1,4-benzodioxan-5-amine (21.6 g; prepared by basification of the above hydrochloride salt), bis(2-chloroethyl)amine monohydrochloride (25 g) and chlorobenzene (250 ml) was heated under reflux for 72 hours, then the solvent was removed in vacuo. The residue was diluted with water (250 ml), basified by the addition of 5M aqueous sodium hydroxide solution, and the product was extracted into ethyl acetate (5×100 ml). The extracts were dried (MgSO4), and the solvent removed in vacuo to give 1-(1,4-benzodioxan-5-yl)piperazine as a brown oil (29.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:11][CH2:12][O:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][N:15]=1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:11][CH2:12][O:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([NH2:22])=[CH:16][N:15]=1)[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CCOc1ncc([N+](=O)[O-])c(OC)n1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CCCN(CCOc1ncc(N)c(OC)n1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a mixture of crude [2-(4-methoxy-5-nitro-pyrimidin-2-yloxy)-ethyl]-propyl-carbamic acid tert-butyl ester (1.76 g, 4.94 mmol) and 10% palladium on charcoal (200 mg) in water (15 ml) was slowly added a solution of ammonium formate (3.12 g, 49.44 mmol) in water (10 ml) at 80° C. After stirring for 1 h at 80° C. the mixture was filtered and concentrated under reduced pressure. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography with toluene/THF/MeOH (4:1:1)/2.5% triethylamine to give 720 mg (44.7%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.Cl>C1(C)C=CC=CC=1>[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=2)=[CH:34][CH:33]=1
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)cc1

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.6 mmol, prepared according to the procedure described in PCT/IB03/02879) was heated to reflux with tetra-kis triphenyl palladium (0) (0.068 g, 0.058 mmol), aqueous solution of potassium carbonate (0.16 g in 0.6 ml water), 4-(methylthio)benzene boronic acid (0.168 g, 1 mmol) and toluene (20 ml) under a nitrogen atmosphere overnight. The reaction mixture was acidified with dilute hydrochloric acid 10 ml and extracted with ethyl acetate. The organic layer was concentrated; the crude material obtained was triturated with ether and filtered to yield the title compound. 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H), 7.13-7.15 (m, 4H), 7.23-7.34 (m, 8H), 7.61 (d, 2H); MS m/z: 423.1 (M++1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:39])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:81]1[CH:85]=[CH:84][CH:83]=[C:82]1[C:86](O)=[O:87]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:39])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:12][NH:13][C:86]([C:82]1[S:81][CH:85]=[CH:84][CH:83]=1)=[O:87]
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 26.3 %

Procedure:
To a solution of (S)-3-Amino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-phenyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester trifluoro-acetic acid salt (0.27 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.1 mL, 0.81 mmol), HBTU (0.15 g, 0.40 mmol), HOBT (0.044 g, 0.32 mmol), and 2-Thiophenecarboxylic acid (0.038 g, 0.30 mmol). The mixture was stirred at room temperature 1.25 h, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (50-80% EtOAc in hexane) to give 0.040 g (26%) colorless oil product. MS m/e 564.0 (M+H+).
Reaction SMILES: O1C=CCCC1.[N+:7]([C:10]1[S:24][C:13]2[S:14][C:15]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][C:17](=[O:18])[C:12]=2[CH:11]=1)([O-:9])=[O:8].[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[CH2:26].O.O.O.C([O-])(=O)C.[Na+]>CO.O>[N+:7]([C:10]1[S:24][C:13]2[S:14][C:15]3([CH2:19][CH2:20][N:21]([CH2:26][CH2:25][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:22][CH2:23]3)[CH2:16][C:17](=[O:18])[C:12]=2[CH:11]=1)([O-:9])=[O:8]
Reactant: O=C1CC2(CCNCC2)Sc2sc([N+](=O)[O-])cc21
Reactant: C=Cc1ccccn1
Agent: C1=COCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CC2(CCN(CCc3ccccn3)CC2)Sc2sc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A solution containing 660 mg (2.05 mmol) of 2'-Nitro-spiro(piperidine-4,6'-(6H)thieno[2,3-b]thiopyran)-4'(5'H)-one dihydropyran, 430 mg (4.1 mmol) of 2-vinylpyridine and 557 mg (4.1 mmol) of sodium acetate trihydrate in 10 ml of 1:1 methanol/water was heated at reflux for 4 hours. The reaction was cooled to room temperature and a solid separated. The solid was collected and dissolved in methanol and treated with excess ethanolic HCl. The dihydro chloride separated and was collected and dried over night in vacuo to give 482 mg of the product.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:21]([O-])=O)=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2].C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[NH2:21][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[C:13]1[CH:14]=[C:15]([CH3:20])[N:16]=[C:17]([CH3:19])[CH:18]=1)[N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:25]([OH:27])=[O:26])[C:6]2=[O:24]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc([N+](=O)[O-])c(-c3cc(C)nc(C)c3)cc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(N)c(-c3cc(C)nc(C)c3)cc21
Reaction time: 1 h

Procedure:
A 35 g portion of 1-ethyl-1,4-dihydro-6-nitro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid was suspended in a mixture of 350 ml of hot dimethylformamide, 280 ml of saturated NaHCO3 and 70 ml of water and the suspension was heated on a steam bath with stirring. A mixture of 58 g of sodium hydrosulfite in 100 ml of water was added in portions over a period of 20 minutes, during which time the reaction mixture became a clear solution and then darkened. More saturated NaHCO3 solution (50 ml) was added and the reaction mixture was heated for 16 hours, after which time reduction was not complete. More sodium hydrosulfite (12 g) was added directly to the reaction mixture and heating continued for 1 hour after which time the reduction appeared to be complete (by TLC). Water (100 ml) was added, redissolving some of the material which had come out of solution; and, the mixture was heated an additional 90 minutes to insure completion of the reduction. A 1.15 g sample, m.p. 288°-290° C. with decomposition, was recrystallized from ethanol and dried for 16 hours at 130° C. under high vacuum to yield 0.9 g of 6-amino-1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid as its monohydrate, m.p. >300° C.