Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]3[C:14]4[C:19]([C:20](=[O:21])[C:10]=23)=[C:18]([NH:22]C(=O)C)[CH:17]=[CH:16][CH:15]=4)=[CH:5][CH:4]=1.Cl>CO>[NH2:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:20](=[O:21])[C:10]1[C:11]2=[N:12][N:13]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2[nH]nc3c2C(=O)c2c(NC(C)=O)cccc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2c3c(nn2-c2ccccc2)-c2cccc(N)c2C3=O)cc1
Reaction time: 2 h
Yield: 81 %

Procedure:
A suspension of N-[3-(4-Methoxy-phenyl)-4-oxo-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-acetamide (as produced according to Nugiel, D. A.; Etzkorn, A. M.; Vidwans, A.; Benfield, P. A.; Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.; Doleniak, D.; Seitz, S. P. J. Med. Chem. 2001, 44, 1334-1336) (1.0 g, 3.0 mmol) in MeOH (10 mL) was treated with concentrated HCl (1 mL) and heated to reflux. After stirring the mixture for 2 h the reaction was cooled and the product was collected by filtration and obtained as a greenish solid (0.7 g, 81%). mp 273° C.; NMR (DMSO-d6) δ13.6 (bs, 1 H), 8.3 (d, J=8.4 Hz, 1 H), 8.1 (d, J=8.8 Hz, 2 H), 7.5 (t, J=7.7 Hz 1 H), 7.2 (d, J=7.0 Hz, 1 H), 7.1 (d, J=8.8 Hz, 2 H), 3.8 (s, 3 H); HRMS m/e calc'd for C17H14N3O2 (M+H): 292.1086, found: 292.1080.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:12][C:13]([F:30])([F:29])[C:14]1[C:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[F:30][C:13]([F:12])([F:29])[C:14]1[C:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=3)=[O:25])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(-c2ncccc2C(F)(F)F)cc1
Reactant: C[Si](C)(C)c1ccc(N)cc1
Product: C[Si](C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3C(F)(F)F)cc2)cc1
Yield: 68.3 %

Procedure:
Compound A-04 can be synthesized according to method 2. Just R1 and R3 of Scheme 2 are, respectively, CF3 and p-SiMe3. namely: compound 6 is 4-trimethylsilyl aniline (compound 6a 35 mg); compound 10 is 4-(3-trifluoromethylpyridine-2-yl)benzoic acid (compound 10b); compound 12 is compound A-04 (60 mg, yield 68.3%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[S:12][CH2:11][CH2:10][C:5]21OCC[O:6]2.C1COCC1.O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[C:5](=[O:6])[CH2:10][CH2:11][S:12]1
Reactant: COCC1SCCC12OCCO2
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCC1SCCC1=O
Yield: 114 %

Procedure:
A solution of 0.16 g (0.84 mmol) of compound from Step C, 3.2 ml THF, 3.2 ml H2O, and 4.8 ml acetic acid was heated at 70° C. for 48 hours. The cooled mixture was concentrated and the residue was dissolved in ethyl acetate, (50 ml) washed with saturated sodium bicarbonate solution (10 ml) and brine, dried, filtered, and concentrated to give 0.14 g of an oil. The oil was flash chromatographed on silica gel eluting with hexane:ether (3:1) to give 0.090 g (75%) product as an oil; NMR (deuteriochloroform): δ 3.7 (m, 2H), 3.5 (m, 1H), 3.37 (S, 3H), 2.05 (m, 1H), 1.95 (m, 1H), 2.65 (t, 2H).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15](C)[CH2:16]Cl)=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:16])[CH2:1][N:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)=[CH:12][CH:11]=1
Reactant: CC(CCl)Oc1ccc(F)cc1
Reactant: O=CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CN1CCNCC1)Oc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Formyl piperazine (2.8 g) and 2-(4-fluorophenoxy)propyl chloride (4.7 g) were dissolved in dimethylformamide (60 ml), and sodium iodide (3.2 g) and triethylamine (4.4 ml) were added thereto, and the mixture was stirred overnight at 50 to 70° C. The organic layer was partitioned by adding water and ethyl acetate, washed with brine, dried over sodium sulfate anhydrous, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (ethyl acetate). The resulting yellow oil (12.3 g) was dissolved in methanol (20 ml), and 5N aqueous sodium hydroxide (10 ml) was added thereto and then stirred for 1 hour under reflux. The reaction mixture was evaporated, then the organic layer was partitioned by adding water and ethyl acetate, washed with brine, and dried over sodium sulfate anhydrous. The residue obtained by evaporation was purified by Cromatorex NH silica gel column chromatography (ethyl acetate/methanol system), whereby the title compound (2.2 g, 38%) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cnc2nc(Cl)nc(Cl)c2c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2nc(Cl)nc(N3CCOCC3)c2c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
2,4-Dichloro-6-nitro-pyrido[2,3-d]pyrimidine (5.8 g; 23.8 mmol) was dissolved in dichloromethane (100 mL), and chilled in a dry ice bath. To the cold solution was added morpholine (2.07 g; 23.8 mmol), and diisopropylethylamine (3.07 g; 23.8 mmol) and it was allowed to warm gradually to room temperature. The solution was washed with a saturated ammonium chloride solution (2×50 mL), dried over magnesium sulfate, and evaporated to give 2-chloro-4-morpholino-6-nitro-pyrido[2,3-d]pyrimidine (6.7 g.).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C(=O)C>[CH3:14][N:15]([CH3:17])[CH:16]=[N:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1
Reactant: CCn1c(N)cc(=O)[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: CC(=O)N(C)C
Product: CCn1c(N=CN(C)C)cc(=O)[nH]c1=O
Temperature: 40 °C

Procedure:
A suspension of 6-amino-1-ethyl-1,3-dihydropyrimidine-2,4-dione (0.77 g, 5 mmol) in anhydrous N,N-dimethylacetamide (25 ml) and N,N-dimethylformamide dimethylacetal (2.7 ml, 20 mmol) and was warmed at 40° C. for 90 minutes. Solvent was then removed under reduced pressure, and the residue triturated with ethanol, filtered, and washed with ethanol, to provide 6-[2-(dimethylamino)-1-azavinyl]-1-ethyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (6).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[N:20]=[N:19][C:18](=[S:21])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].I[CH3:23].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[NH:20][N:19]=[C:18]([S:21][CH3:23])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C2=NC(=S)N=N2)cc(C(C)(C)C)c1O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.00 g (19.64 mmol) of triazolethione (Example 19) and 9.1 g (60.0 mmol) of iodomethane in 50 ml of absolute ethanol is stirred at 50° to 60° C. for 0.5 hour, then cooled to room temperature. The reaction is treated with 300 ml aqueous 0.7N NaOH, stirred for 30 minutes, and filtered. Recrystallization of the resulting solid from ethanol-water gives 5.26 g (6.27 g theor., 84%) of the S-methylated product as a fluffy, white solid, mp 271°-272° C.
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN1CCCC1=O>[CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Reactant: Nc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCn1c(Nc2ccccc2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 150 °C
Yield: 48 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in N-methyl-pyrrolidone (1 ml) was added aniline (0.20 g, 2.14 mmol) and the mixture was heated at 150° C. overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 5% methanol in dichloromethane to give the product (0.034 g, 47%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([Cl:15])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)ccc1C

Procedure:
A mixture of 10.0 g (60.17 mmol) of 3-methoxy-4-methylbenzoic acid, 15 ml (210 mmol) of thionyl chloride and 10 ml of toluene was stirred at reflux for 2 hours. The solvents were then evaporated and the residue was distilled bulb-to-bulb at 60°-70° C. at a pressure of 0.04 mm of Hg to give the title compound as a colorless liquid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.[Li]C(CC)C.CN([CH:30]=[O:31])C>CCOCC>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:30]=[O:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1C=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A solution of N-Boc-Piperidine (6.0 g, 32.4 mmol) in ether (65 mL) was cooled to −60° C. and treated with TMEDA (4.9 mL, 32.4 mmol) followed by sec-BuLi (54.8 mL, 71.2 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 10 min and then cooled to −78° C. The mixture was treated with a solution of DMF (3.8 mL, 48.6 mmol) in 6 mL of ether via syringe, stirred for 10 min, and then quenched with 60 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted three times with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an orange oil. Purification by column chromatography on silica gel with hexanes:EtOAc (4:1) afforded 4.2 g (67%) of the product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 9.58 (s, 1H), 4.69-4.51 (br. m, 1H), 4.12-3.85 (br. m, 1H), 2.85 (br. s, 1H), 2.19-2.13 (d, 1H), 1.72-1.23 (m, 15H); 13C NMR (75 MHz) 201.4 (s), 80.4 (s), 43.0 (br. s), 28.3 (s), 24.7 (s), 23.6 (s), 20.9 (s) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C(OC)(OC)[O:15]C>CO>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)([OH:15])=[O:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: COC(OC)OC
Solvent: CO
Product: O=C(O)C=Cc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 37.0 g of 4-formylcinnamic acid in 22 ml of trimethyl orthoformate and 600 ml of methanol was heated under reflux for 17 hrs. with stirring. At the end of this time, 100 ml of methanol was added and the reaction mixture was heated under reflux for an additional 5 hrs. and then allowed to cool to room temperature. The precipitate was collected, washed with methanol and dried at 75°-80° overnight to give 7.36 g of 4-carboxycinnamic acid.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[OH:46][C@@H:47]([CH3:93])[CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55]2[N:60]=[CH:59][C:58]([C:61]3[CH:62]=[C:63]4[C:69]([C:70]5[CH:71]=[N:72][N:73]([CH2:75][C:76]6[CH:77]=[C:78]([OH:82])[CH:79]=[CH:80][CH:81]=6)[CH:74]=5)=[CH:68][N:67](S(C5C=CC(C)=CC=5)(=O)=O)[C:64]4=[N:65][CH:66]=3)=[CH:57][CH:56]=2)[CH2:51][CH2:50]1.[OH-].[Li+]>C1COCC1.CO.O>[OH:46][C@@H:47]([CH3:93])[CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55]2[N:60]=[CH:59][C:58]([C:61]3[CH:62]=[C:63]4[C:69]([C:70]5[CH:71]=[N:72][N:73]([CH2:75][C:76]6[CH:77]=[C:78]([OH:82])[CH:79]=[CH:80][CH:81]=6)[CH:74]=5)=[CH:68][NH:67][C:64]4=[N:65][CH:66]=3)=[CH:57][CH:56]=2)[CH2:51][CH2:50]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(O)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(O)c6)c5)c4c3)cn2)CC1
Yield: 8.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-3-((4-(5-(6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)methyl)phenol (180 mg, 0.271 mmol) was hydrolyzed with lithium hydroxide (34 mg, 0.813 mmol) in THF/methanol/water (2/2/0.5 mL) to yield 12 mg (9% yield) of desired product. 1H NMR (CD3OD, 400 MHz): δ 8.51-8.45 (m, 2H), 8.32-8.31 (m, 1H), 8.16 (s, 1H), 7.99-7.92 (m, 2H), 7.20-7.16 (t, 1H), 7.06-6.97 (m, 1H), 6.78-6.69 (m, 3H), 5.36 (s, 2H), 4.70-4.60 (m, 1H), 4.26-4.20 (t, 1H), 4.10-4.05 (q, 1H), 3.78-3.70 (m, 4H), 3.58-3.49 (m, 2H), 2.92-2.61 (m, 2H), 2.63-2.61 (m, 1H), 1.22-1.21 (m, 3H). MS: m/z=510.2 (M+1), HPLC: 98.41% in method A.
Reaction SMILES: CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[NH:22][C:21]1=O.CCN=C=NCCCN(C)C.Cl[C:44]1[S:54][C:47]2[NH:48][C:49]([C:51](O)=[O:52])=[CH:50][C:46]=2[CH:45]=1>CN(C=O)C.O>[F:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH:20]([NH:19][C:51]([C:49]1[NH:48][C:47]3[S:54][CH:44]=[CH:45][C:46]=3[CH:50]=1)=[O:52])[CH2:29]2
Reactant: NC1Cc2cc(F)ccc2NC1=O
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CNc2ccc(F)cc2C1)c1cc2ccsc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Et3N (184 μL, 1.32 mmol), HOBT (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4-dihydro-2(1H)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and EDAC (127 mg, 0.66 mmol) were added to a solution of 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (133 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40° C., to give the title compound (203 mg, 84%) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:43]=[C:34]6[CH2:35][N:36]([CH:39]7[CH2:42][O:41][CH2:40]7)[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:43]=[C:34]6[CH2:35][N:36]([CH:39]7[CH2:42][O:41][CH2:40]7)[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
To a suspension of 166a (250 mg, 0.41 mmol) in methanol (20 mL) was added sodium borohydride (47 mg, 1.23 mmol) at 0° C. The mixture was stirred for 30 minutes. It was then quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 166 (20 mg, 6.6%). MS-ESI: [M+H]+ 615.6. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=5.0 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J=5.0 Hz, 1H), 5.75 (s, 1H), 4.95 (t, J=6.5 Hz, 1H), 4.76-4.74 (m, 2H), 4.69-4.65-4.67 (m, 3H), 4.46-4.44 (m, 1H), 4.35-4.33 (m, 1H), 4.10-4.08 (m, 4H), 3.38-3.35 (m, 2H), 3.69 (s, 3H), 3.58-3.56 (m, 2H), 2.84-2.82 (m, 2H), 2.58-2.53 (m, 4H), 1.89-1.84 (m, 2H), 1.77-1.76 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[N:5]([C:18](=[O:19])[CH2:17][O:16][CH3:15])[NH:4][C:3]([O:2][CH3:1])=[O:14]
Reactant: COCC(=O)Cl
Reactant: COC(=O)NNc1c(C)cccc1C
Solvent: ClCCl
Product: COCC(=O)N(NC(=O)OC)c1c(C)cccc1C
Temperature: 25 °C

Procedure:
3 g of methyl-3-(2,6-dimethylphenyl)-carbazate were dissolved in 40 ml of methylene chloride (CH2Cl2). While stirring at room temperature, 1.7 g of methoxyacetyl chloride were gradually dropped into the solution. The reaction mixture was stirred at room temperature for 3 hours. It was then washed with 20 ml of H2O, 30 ml of a solution of NaHCO3 at 5% and 30 ml of H2O. It was anhydrified on anhydrous Na2SO4 and the solvent was removed by evaporation.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[SH:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([S:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[C:15]([F:14])[CH:16]=1)#[N:19]
Reactant: Sc1cccs1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Sc2cccs2)c(F)c1
Temperature: 25 °C

Procedure:
Sodium hydride (1.80 g 60% dispersion in oil, 0.045 mol) was washed with petroleum ether then suspended in freshly degassed DMF (50 ml). Thiophene thiol (5.22 g, 0.045 mol) was added dropwise under nitrogen and the mixture was stirred until gas evolution ceased. 3,4-Difluorobenzonitrile (5.0 g, 0.036 mol) was added portionwise and the mixture was refluxed about 1.5 hours, after which the mixture was cooled to room temperature. The reaction mixture was poured into cold H2O and extracted with 3×100 ml ether. The ether extracts were washed with water and brine, then treated with decolorizing carbon and magnesium sulfate. After filtration and evaporation of the solvent the residual (8.46 g) oil crystallized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:20])([CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:23])=[C:4]([C:9]([CH3:19])([CH3:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CI
Reactant: CCCCCCCCCC(C)(C)c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(C)c1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained above in part (a), (30.85 g, 90 mmoles), is dissolved in 100 ml of dry THF and then treated with 2.7 g (90 mmoles) of sodium hydride (80% in oil) which is added in small fractions. At the end of the addition, the mixture is stirred for 30 minutes at ambient temperature. 12.8 g (90 mmole) of methyl iodide are then added and this mixture is stirred for 2 hours at 20° C. The solvent is evaporated and the residue is purified by chromatography on a silica column (eluant: a mixture of dichloromethane, 40% and hexane, 60%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][C:3]1[CH:2]=[CH:11][C:10]([N:9]2[C:12]3[C:13](=[CH:14][C:15]([F:18])=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:17]=3)[C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8]2)=[CH:5][CH:4]=1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 1(e), the above acid (7) R6 =H, R=p-fluorophenyl), after reacting with the piperazine, can give the desired 1-p-fluoro-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (9) ##STR17## R=p-fluorophenyl) and its hydrochloride salt.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]([N:31]([CH3:39])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][CH3:38])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:40](N)([NH2:43])(=[O:42])=[O:41]>O1CCOCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]([N:31]([CH3:39])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][N:37]([CH3:38])[S:40](=[O:42])(=[O:41])[NH2:43])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNCCOCCN(C)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1C
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)N(C)CCOCCN(C)S(N)(=O)=O)n(C)c2c1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of intermediate 6 (620 mg, 1.16 mmol) and sulfamide (900 mg, 9.36 mmol) in dioxane (10 mL) was heated at 100° C. in a microwave oven for 60 minutes. The reaction mixture was cooled down to room temperature, and then evaporated under vacuum. The residue was triturated in water, filtered and washed with water. The powder was reconstituted in AcOEt. The solution was dried over anhydrous Na2SO4, filtered and the filtrate evaporated to yield 610 mg (86%) of methyl 3-cyclohexyl-1-methyl-2-(2-{2-[methyl(2-{2-[methyl(sulfamoyl)amino]ethoxy}ethyl)amino]-2-oxoethoxy}phenyl)-1H-indole-6-carboxylate 7 as a yellowish powder: m/z=615 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5](/[CH:6]=[CH:7]/[C@@H:8]2[CH:13]([N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])NC(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]([CH3:31])([CH3:30])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].BrCC(OC)=O>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C@@H:8]2[CH:13]([NH:14][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[CH2:12][CH2:11][C:10]([CH3:31])([CH3:30])[O:9]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1CCC(C)(C)O[C@@H]1/C=C/c1ccc(Cl)cc1
Agent: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCC(C)(C)O[C@@H]1/C=C/c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 83 %

Procedure:
To a suspension of 1,3-ketal-2-hydrazino (8C) (117 mg, 0.24 mmol) and Cs2CO3 (199 mg, 0.61 mmol) in 2.5 mL CH3CN, was added methyl bromoacetate (75 mg, 0.48 mmol) in 1.0 mL CH3CN. The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was then refluxed until the intermediate was consumed as indicated by TLC. The reaction mixture was quenched with saturated NH4Cl (aq.) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (83%) (Magnus et al., Org. Lett. 2009, 11, 5646).