Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]=[C:12]([CH3:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28]I.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:26][C:27]([F:31])([F:30])[CH2:28][N:10]1[C:9](=[O:25])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:12]([CH3:24])=[N:11]1
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC(F)(F)F)c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 48.7 %

Procedure:
The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (3 mL) and treated with 1,1,1-trifluoro-2-iodoethane (27.5 mL, 280 mmol) in presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50–60° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 48%). 1HNMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 3.10 (s, 3H), 4.85 (q, J=9 Hz, 2H), 6.90 (m, 2H), 7.10 (dd, J=6 Hz, J=9 Hz, 2H), 7.25 (m, 2H), 7.95 (d, J=9 Hz, 2H). MS (DCI/NH3) 458 (M+NH4)+ Anal. calc. for C20H16N2F4SO3: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.41; H, 3.56; N, 6.35.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@H:20]([O:35][CH3:36])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1.[N:37]12[CH2:44][CH2:43][N:40]([CH2:41][CH2:42]1)[CH2:39][CH:38]2[CH2:45][NH2:46].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[N:37]12[CH2:44][CH2:43][N:40]([CH2:41][CH2:42]1)[CH2:39][CH:38]2[CH2:45][NH:46][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@@H:20]([O:35][CH3:36])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Reactant: NCC1CN2CCN1CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1cnc(NCC2CN3CCN2CC3)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 20.7 %

Procedure:
Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 330 mg, 0.57 mmol) was added to a solution of 1-(1,4-diazabicyclo[2.2.2]oct-2-yl)methanamine (EP748807, 407 mg, 2.88 mmol) and N,N-Diisopropylethylamine (0.38 mL, 2.88 mmol) in N-methyl 2-pyrrolidinone (5 mL) and the resulting reaction mixture was stirred for 20 h at 80° C. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduce pressure to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform) to afford 80 mg (20.5%) of ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate as an off-white solid.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[CH3:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][N:17]=[C:7]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 2-amino-5-methylphenyl phenyl ketone (2.0 g, 9.5 mmol) in HCl (45 mL of a 6M solution) at 0° C. was added sodium nitrite (NaNO2) (719 mg, 10.4 mmol) in water (2 mL). The reaction was stirred for 30 min when the homogeneous solution was added dropwise to a solution of SnCl2 (5.88, 26 mmol) in concentrated HCl (15 mL) at room temperature. The reaction was stirred for 30 min when it was filtered. The solid was then taken up in ethyl acetate (80 mL) and saturated sodium bicarbonate (80 mL). The suspension was then filtered and the ethyl acetate layer dried (Na2SO4) and concentrated to give the product (1.59 g, 80% yield). (1H NMR (DMSO-d6) δ 7.96 (d, 2H), 7.85 (br s, 1H), 7.54–7.46 (m, 3H), 7.39 (t, 1H), 7.24 (d, 1H), 2.45 (s, 3H); ES-MS (m/z) 209 [M+1]+.
Reaction SMILES: [OH-].[K+].Br[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6].Cl.[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6])[CH3:24]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 16 h

Procedure:
Under inert atmosphere 8.4 g (150 mmol) of potassium hydroxide is dissolved in 150 ml of ethanol. After adding 10.0 g (31 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone in portions at room temperature stirring is continued for 16 hours. Then the reaction mixture is acidified with 10% HCl and extracted with ethylacetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 3.8 g of compound 113, m.p. 73-75° C.
Reaction SMILES: [C:1]([CH:4]([C:14](=O)[CH3:15])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])(=O)[CH3:2].O.[NH2:18][NH2:19].O>C(O)(=O)C>[CH3:2][C:1]1[C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[C:14]([CH3:15])[NH:19][N:18]=1
Reactant: NN
Reactant: CC(=O)C(C(C)=O)C(=O)Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c(C)c1C(=O)Nc1ccccc1
Yield: 88 %

Procedure:
The foregoing diacetyl acetanilide (2.2 g) in glacial acetic acid (30 ml) was treated with hydrazine hydrate (1.5 g) and the mixture boiled under reflux for 30 min. The mixture was then poured into water and the product collected and crystallised from ethanol. 3,5-dimethyl-N-phenyl-4-pyrazolecarboxamide (1.9 g, 86%) was obtained as colourless plates, m.p. 244-5° C (Found: C, 66.8 H, 6.0 N, 19.3 C12H13N3O requires C, 66.9; H, 6.1; N, 19.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](SC)=[NH:15])=[CH:9][C:8]=2[O:18][CH3:19])[CH:6]=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[C:26](O)=O.[NH2:36][NH2:37]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:37][N:36]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH:6]=[C:2]([Cl:1])[N:3]=[CH:4]3)=[C:8]([O:18][CH3:19])[CH:9]=2)[N:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1ccccc1F
Reactant: NN
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccccc3F)n2)ccc1-n1cnc(Cl)c1
Yield: 100 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate (1.5 g, 5.05 mmol, from preparation A) and 6-chloro-2-(2-fluorophenyl)hexanoic acid (1.24 g, 5.05 mmol, from preparation AQ) were coupled and then reacted with hydrazine (0.635 mL, 20.2 mmol) using a procedure analogous to Step A of Example 13. The crude product, 5-(5-chloro-1-(2-fluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.68 g, 100% yield), was used in the subsequent step without purification. LC-MS (M+H)+ 489.2.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH2:12][CH3:13])[CH:6]=1)C.[NH3:15]>CO>[CH2:12]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=1)[C:4]([NH2:15])=[O:3])[CH3:13]
Reactant: N
Reactant: CCOC(=O)c1cc(C)nc(CC)c1
Solvent: CO
Product: CCc1cc(C(N)=O)cc(C)n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 2-ethyl-6-methyl-isonicotinic acid ethyl ester (3.90 g, 20.2 mmol, prepared in analogy to the corresponding tert.-butyl ester) in 7 N NH3 in methanol (50 mL) is stirred in a sealed vessel at 60° C. for 20 h. The solvent is evaporated and the residue is suspended in diethyl ether. The solid material is collected, washed with additional diethyl ether and dried under HV to give 2-ethyl-6-methyl-isonicotinamide (2.85 g) as a white powder; LC-MS: tR=0.26 min, [M+1]+=165.05; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.5 Hz, 3H), 2.49 (s, 3H), 2.75 (q, J=7.8 Hz, 2H), 7.44 (s, 2H), 7.59 (s br, 1H), 8.11 (s br, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[CH:10][C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C=O)C.C(Cl)(Cl)Cl>[F:32][C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]([S:41]([CH3:40])(=[O:43])=[O:42])[CH:2]([NH2:1])[NH:3][C:4]=3[CH:10]=2)=[CH:17][CH:16]=1)=[O:20]
Reactant: Nc1nc2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1c2ccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)cc2NC1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a mixture of 2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol) (prepared according to similar procedures as described for Intermediates 4, 5, and 6 and Example 22) and triethylamine (30 mg, 0.30 mmol) in DMF/CHCl3 (3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26 mmol). After stirring for 3 h at rt, the reaction mixture was washed with water and extracted with CHCl3. The organic layer was dried over MgSO4 and evaporated. The crude material was purified with silica gel column chromatography (AcOEt) to give the product of Example 23 (11.0 mg, 11%) and the title compound (34 mg, 25%): 1H NMR (DMSO-d6) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.51 (d, 1H), 7.47 (d, 1H), 7.46 (d, 2H), 7.38 (m, 1H), 7.02 (brs, 2H), 6.97 (d, 2H), 6.82 (d, 1H), 6.70 (dd, 1H), 3.49 (s, 3H); MS m/e 524 (M+1).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][S:55]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH3:67])[CH:59]=2)(=[O:57])=[O:56])=[C:50]([CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=2)[CH:49]=1>O1CCCC1>[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH3:67])[CH:59]=2)(=[O:57])=[O:56])[C@@H:35]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]2)=[C:50]([CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=2)[CH:49]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2ccccn2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2Cc2ccccn2)[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Reaction time: 0.5 h
Yield: 162.3 %

Procedure:
0.91 ml of diisopropylazodicarboxylate is added at room temperature to 1.21 g of triphenylphosphine in solution in 25 ml of tetrahydrofuran. After 30 minutes, 0.86 g of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate is introduced. After 30 minutes, 1.29 g of N-[4-chloro-2-(pyridin-2-ylmethyl)phenyl]-3,4-dimethoxybenzene-sulfonamide are added and the mixture is left for 18 hours at room temperature. The reaction medium is concentrated and chromatographed on silica gel in order to obtain 2.94 g of the expected product.
Reaction SMILES: Cl.C(C1[CH:14]=[C:13]([SH:15])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)(O)=O.[C:17](=O)([O-])[O-].[Cs+].[Cs+].[C:23]([O:26][CH2:27]C)(=[O:25])[CH3:24]>CN(C=O)C>[CH3:27][O:26][C:23]([C:24]1[CH:14]=[C:13]([S:15][CH3:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:25]
Reactant: O=C(O)c1cc(S)c2ccc(Cl)cc2n1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SC)c2ccc(Cl)cc2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCI (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[S-:12][C:13]#[N:14].[K+].II>C(#N)C>[CH2:7]([N:11]1[C:3]2[CH2:2][O:1][CH2:5][C:4]=2[S:12][C:13]1=[NH:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: N#C[S-]
Reactant: O=C1CCOC1
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CCCCn1c2c(sc1=N)COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of dihydrofuran-3(2H)-one (0.5 g, 6.0 mmol, Small Molecules Inc.) in acetonitrile (10 mL) were added molecular sieves (0.5 g) and butan-1-amine (0.4 g, 5.5 mmol, Aldrich). The reaction mixture was stirred at room temperature overnight and then filtered. To the filtrate was added potassium thiocyanate (0.7 g, 7.3 mmol, Aldrich). The temperature was adjusted to 50° C. and the mixture was stirred until the solids were dissolved. Then, iodine (2.8 g, 10.9 mmol, EMD Chemicals) was added to the mixture and stirred at 50° C. overnight. The reaction mixture was cooled, concentrated and dissolved in EtOAc (15 mL). The solution was washed with Na-meta-bisulfite 20% (15 mL) by mixing the layers for 30 minutes. The organic layer was washed twice with 1N HCl (15 mL). The aqueous layers (metabisulfite and HCl) were combined and the pH was adjusted to pH ˜9 by adding NH4OH. The product was extracted with EtOAc (4×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to obtain the crude product (0.22 g) of the title compound. MS (ESI+) m/z 199 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[CH3:24][C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:26]([C:25](=[O:30])[CH3:24])[C:27](=[O:29])[CH3:28])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(C)=O
Yield: 59.1 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (3.07 g, 10 mmol) synthesized according to the method described in WO95/18125 in toluene (40 ml) were added 2,4-pentanedione (1.2 g, 12 mmol), acetic acid (300 mg) and piperidine (425 mg). While removing water through Dean-Stark trap, the mixture was refluxed under heating. Five hours later, toluene was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) and the fraction containing the objective substance was concentrated under reduced pressure to give the title compound (2.3 g, yield 60%) as a yellow oil.
Reaction SMILES: [N:1]([CH:4]([C:25]1[O:29][C:28]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)[CH2:5][C:6]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[C:8]([Cl:24])[CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.C(OCC)(=O)C>[CH2:17]([O:16][C:15]1[C:6]([CH2:5][CH:4]([C:25]2[O:29][C:28]([CH2:30][N:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[NH2:1])=[CH:7][C:8]([Cl:24])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)N=[N+]=[N-])o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(5-{1-azido-2-[8-(benzyloxy)-5-chloroquinolin-7-yl]ethyl}-2-furyl)-N,N-dimethylmethanamine (0.1.451 mmol) in tetrahydrofuran (5 mL) and water (1.5 mL) in a round bottom flask equipped with a reflux condenser was added triphenylphosphine (1.596 mmol, 1.1 eq.) (CAUTION: vigorous gas evolution, do not seal reaction vessel) and the resulting mixture was then warmed to 70° C. and stirred 2 h. The reaction mixture was then allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and was washed with 1N HCl (3×25 mL). The aqueous layers were combined, backextracted with ethyl acetate (25 mL) and then adjusted to pH=12 by addition of 5N NaOH resulting in a precipitate. The aqueous solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated a yellow oil that was used directly in the ensuing step. MS (ESI) m/z 436.4; HRMS: calcd for C25H26ClN3O2+H+, 436.17863; found (ESI, [M+H]+ Obs'd), 436.1788.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:33]4[CH2:32][CH2:31][NH:30][CH:29]([C:25]5[O:24][CH:28]=[CH:27][CH:26]=5)[CH2:34]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1coc(C2CNCCN2)c1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Temperature: 95 °C
Yield: 95.7 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.96 g), (RS)-2-(2-furyl)piperazine (0.6 g) and sodium carbonate (0.38 g) in dimethyl sulphoxide (20 cc) is heated to approximately 95° C. for 5 hours and a half. After cooling to approximately 20° C., the mixture is poured into water (50 cc) at a temperature in the region of 5° C. and extracted with dichloromethane (3×100 cc). The combined organic extracts are washed with water (3×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 40° C. The residue obtained is taken up with ethanol (20 cc), drained and washed with ethanol (2×20 cc) and ethyl ether (3×30 cc). (RS)-3-Ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) is obtained in the form of a yellow solid, m.p. 198°-200° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CNC2
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2Cc3ccccc3C2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added isoindoline (5.9 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C19H16N2O2: 304.1212, found 304.1222.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH:8][C:7]=12
Reactant: CCCCCC(=O)O
Reactant: Cc1ccnc(N)c1N
Product: CCCCCc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and hexanoic acid (0.25 ml, 2 mmols) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (9:1) to give the pure product (0.28 g, 69%) as a tan colored solid.