Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].F[C:25](F)(F)[C:26]([OH:28])=[O:27].Cl.[C:32]([O:35]CC)(=[O:34])[CH3:33]>O.O1CCCC1>[C:26]([OH:28])(=[O:27])/[CH:25]=[CH:33]\[C:32]([OH:35])=[O:34].[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(C)=O
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\C(=O)O
Product: OC1CN(CCCOCCc2ccc3sccc3c2)C1

Procedure:
To tetrahydrofuran (5 mL) suspension of 1.00 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol was added 0.37 g of sodium borohydride, and dropwise added tetrahydrofuran (1 mL) solution of 0.75 mL of trifluoroacetic acid for 30 minutes, which was then refluxed for 2 hours. After cooling, thereto was dropwise added 3.27 mL of 6.0 mol/L hydrochloric acid, which was then refluxed for 1.5 hours. To the reaction mixture were added water and ethyl acetate, and the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the pH was adjusted to 10.0 with 20% (w/w) sodium hydroxide aqueous solution. The organic layer was separated, washed sequentially with water and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After insoluble matter was filtered off, the solvent was distilled off under reduced pressure. To the resultant residue was added 0.36 g of maleic acid, which was solidified from a mixed solvent (5 mL) of ethyl acetate:2-propanol (4:1) to provide 0.62 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate as colorless crystal form.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.C(O)(=O)C.[NH:41]1[CH2:44][CH:43]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:42]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:41]2[CH2:44][CH:43]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])[CH2:42]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1ncc(NC(=O)N2CC(NC(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 88.8 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (711 mg) and tert-butyl 3-azetidinylcarbamate acetic acid salt (418 mg) in methylene chloride (8 ml) was added N-ethyldiisopropylamine (0.62 ml), and the mixture was stirred under reflux for 16 hours. To the reaction mixture was added methylene chloride, and the solution was washed successively with 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of ethyl acetate and hexane to give tert-butyl [1-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-azetidinyl]carbamate (735 mg) as a solid;
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[N:5]1[NH:6][N:7]=[N:8][C:9]=1[C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][CH2:3][N:7]1[N:6]=[N:5][C:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1
Reactant: COc1ccc(CC(=O)Nc2sccc2-c2nn[nH]n2)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1nnc(-c2ccsc2NC(=O)Cc2ccc(OC)cc2)n1
Reaction time: 72 h

Procedure:
Chloromethyl methyl ether (0.20 ml, 2.63 mmol) was added to a heterogeneous mixture of N-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide (Example 8.1., 580 mg, 1.84 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in DMF (10 ml). After stirring for 72 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was directly purified by HPLC to yield N-(3-(2-(methoxymethyl)-2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide. Method [7] Retention time 6.60 min by HPLC (MH+ 360). 1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 7.47 (d, J=5.7 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (d, J=5.7 Hz, 1H), 5.77 (s, 2H), 3.87 (s, 3H), 3.86 (s, 2H), 3.37 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (2.37 g) (STEP 11A) in dry methylene chloride (25 ml) was added a solution of 10% p-toluenesulfonic acid in methanol (25 ml), and the mixture was stirred at room temperature. After 10 minutes, the mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (2.1 g). 1H NMR consistent with the desired structure.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7](OCC)=[CH:6][C:3]=1[C:4]#[N:5].N([O:19][CH2:20][CH2:21]C(C)C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:20]([O:19][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:21]
Reactant: CC(C)CCON=O
Reactant: CCOc1cc(C#N)c(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(F)(F)F)ccc1C#N
Yield: 84.9 %

Procedure:
To a solution of 2-amino-5-ethoxy-4-trifluoromethyl-benzonitrile (31.62 g, 137.4 mmol, 1.0 equiv) in anhydrous THF (410 mL) was added isoamyl nitrite (40.4 mL, 302 mmol, 2.2 equiv) and the mixture was heated to reflux for 16 h. The solvent was removed by evaporation under reduced pressure to give an orange oil which was dissolved in a sat. solution of NaHCO3 and extracted three times with diethyl ether. The combined organic phases were washed with 1 N HCl and a sat. solution of sodium chloride and the organic phases dried over Na2SO4. Removal of the solvent by evaporation under reduced pressure left an orange oil which was purified by double Kugelrohr distillation (up to 160° C. bath temperature at 1.5 mbar) yielding 25.1 g (85%) of the title compound as a light yellow solid upon solidification. MS (EI): 185.1 [M]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][O:14][CH3:15].CN(C=O)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COCCNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
Potassium carbonate (262 mg) and bis(2-methoxyethyl)amine (840 mg) were added to a DMF (2 ml) solution containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 5 hours. Water (15 ml) was added to the reaction solution, followed by stirring at room temperature for 1 hour. Insoluble matter was collected by filtration, and a white solid of N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine (117 mg) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7].[C:16]12([C:26](O)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[CH3:1][C:2]1[N:3]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:4](=[N:8][C:26]([C:16]23[CH2:25][CH:20]4[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]4)[CH2:23]2)[CH2:17]3)=[O:27])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(=N)n(CC2CCOCC2)c1C
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(CC2CCOCC2)c1C
Yield: 13.1 %

Procedure:
The product of Example 58A (0.11 g, 0.49 mmol) and adamantane-1-carboxylic acid (97 mg, 0.54 mmol) were processed as described in Example 3B. Purification by column chromatography (SiO2, 0-20% methanol/methylene chloride gradient) afforded 25 mg (13%) of the title compound. MS (DCI/NH3) m/z 389 (M+H)+. Anal. Calculated for C22H32N2O2S: C, 68.00; H, 8.30; N, 7.21. Found: C, 67.61; H, 8.67; N, 7.17.
Reaction SMILES: [CH:1](=O)[C:2]1C=CC=CC=1.CO[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>CCO>[CH:15]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:18][CH:17]=2)[CH:2]=[CH:1][N:16]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: c1ccc2cnccc2c1
Temperature: 25 °C

Procedure:
To a stirred solution of benzaldehyde AB (2.0 g, 11.13 mmol) in EtOH (25 mL) were added 4-methoxybenzylamine (PMBNH2; 1.91 g, 13.92 mmol) and a catalytic amount of trifluoroacetic acid (TFA; 5 mol %) at RT, and the mixture was gradually heated to reflux temperature under inert atmosphere. After completion of reaction (8 h, monitored by TLC), the reaction mixture was cooled to RT and concentrated under reduced pressure. The obtained solid residue was subjected to crystallization (50% CH2Cl2/pentane) to afford colorless crystalline isoquinoline derivative AC (2.0 g, 6.69 mmol, 60%). 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 7.72 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.32 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 6.46 (s, 1H), 5.02 (br s, 1H), 4.43 (s, 2H), 3.80 (s, 3H). MS (ESI): m/z 299 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([CH3:23])[C:19](=O)[CH2:20]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([C:19]1[N:7]=[C:3]2[CH:4]=[CH:5][CH:6]=[N:1][N:2]2[CH:20]=1)[CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccnn1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)CBr
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)c1cn2ncccc2n1
Temperature: 25 °C

Procedure:
A mixture of pyridazin-3-ylamine (2 g, 21.05 mmol) and (3-bromo-1-methyl-2-oxopropyl)-carbamic acid benzyl ester (7.5 g, 25.26 mmol) in EtOH (25 mL) was heated to reflux overnight. After completion, the reaction mixture was cooled to rt. EtOH was removed in vacuo. The residue was dissolved in EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide (1-imidazo[1,2-b]pyridazin-2-yl-ethyl)-carbamic acid benzyl ester: LC-MS (ESI) m/z 297.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:29][CH2:30][CH2:31][O:32][CH3:33])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH2:31][O:32][CH3:33])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH3:28]
Reactant: CCNCCOC
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CCN(CCOC)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and ethyl-(2-methoxy-ethyl)-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 480.4 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89.0 mg) and phenylboronic acid (48.8 mg) were dissolved in DME (0.8 mL). A solution of 2M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as an off-white powder. HPLC (Condition 4) tR=5.09 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=444.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (m, 1H) 1.74-1.85 (m, 1H) 2.85 (d, J=11.34 Hz, 1H) 3.10-3.26 (m, 2H) 3.32-3.45 (m, 1H) 4.15 (m, J=2.30 Hz, 1H) 4.80 (d, J=3.13 Hz, 1H) 7.25-7.51 (m, 7H) 7.78-7.88 (m, 2H) 7.96 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.30 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:31][CH:32]=2)=[O:27])[CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57.8 mg, 50%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:14][C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:47]([O:51][NH2:52])([CH3:50])([CH3:49])[CH3:48].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:47]([O:51][NH:52][C:15](=[O:17])[CH2:14][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccc3ccccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetic acid hydrochloride (1.49 g, 3.35 mmol), 1-hydroxybenzotriazole (0.539 g, 3.52 mmol), 4-methylmorpholine (1.55 mL, 14.9 mmol), and O-t-butylhydroxyl amine hydrochloride (0.464 g, 3.70 mmol) are dissolved in methylene chloride (50.0 mL),and the reaction is cooled to 0° C. To this solution is added N- [dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.35 g, 7.04 mmol), and the reaction is allowed to warm up to room temperature and stir overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with saturated sodium bicarbonate, brine, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (1% methanol/methylene chloride) to give N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2].C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[CH2:1]([NH:3][C:4]1[C:9]([C:10]([F:24])=[O:11])=[CH:8][N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCNc1nc(SC)ncc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNc1nc(SC)ncc1C(=O)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution containing 3.0 g (14.0 mmol) of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylic acid and 2.1 mL (15.0 mmol) of triethylamine in 50 mL of CH2Cl2 are added 2.3 mL (28.0 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution is diluted with 250 mL of CH2Cl2 and 75 mL of ice-cold water. After separation of the phases by settling, the organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 3.0 g of expected product are obtained in the form of a greenish gum. The yield is quantitative.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6]([C:8]1[N:9]=[N:10][C:11]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:12][CH:13]=1)=[S:7])[CH3:4].N1C=CC=CC=1.NOS(O)(=O)=O>C(O)C.CO>[CH3:4][C:3]1[N:5]=[C:6]([C:8]2[N:9]=[N:10][C:11]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:12][CH:13]=2)[S:7][N:2]=1
Reactant: CC(=NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CCO
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nsc(-c2ccc(SCCCCOc3cccc(C(F)(F)F)c3)nn2)n1
Yield: 26.1 %

Procedure:
A mixture of intermediate 13 (0.009 mol) and pyridine (0.02 mol) in ethanol (80 ml) was stirred. A mixture of hydroxylamine-O-sulfonic acid (0.01 mol) in methanol (20 ml) was added. The mixture was stirred overnight. The solvent was evaporated. The residue was taken up in DCM. The organic solution was washed with a diluted NaOH solution and with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:DCM). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried, yielding 1 g (26%) of 3-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[[4-[3-(trifluoromethyl)phenoxy]butyl]thio]pyridazine (compound 94).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=S.[N-:21]=[N+:22]=[N-:23].[Na+]>C1COCC1>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]1[C:19]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])=[N:23][N:22]=[N:21]1
Reactant: Cc1ccccc1CN
Reactant: [N-]=[N+]=[N-]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1CNc1nnnn1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methylbenzylamine (89.1 mg, 0.735 mmol) in 8 ml of dry THF was treated with 2,3-dichlorophenylisothiocyanate (150 mg, 0.735 mmol). After stirring at room temperature for 1 hour, the mixture was treated with mercuric acetate (234.2 mg, 0.735 mmol) and sodium azide (143.3 mg, 2.21 mmol) and stirred at room temperature for 16 hours. The mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile to ammonium acetate (10 mM) over 15 minutes at a flow rate of 70 mL/min to provide the title compound. MS (ESI+) m/z 334 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.46 (d, J=5.42 Hz, 2H), 7.16 (m, 3H), 7.26 (m, 1H), 7.57 (t, J=5.42 Hz, 1H), 7.60 (t, J=8.14 Hz, 1H), 7.71 (dd, J=7.97, 1.53 Hz, 1H), 7.93 (dd, J=8.14, 1.70 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:21]([O:23]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21](=[O:23])[C:12]2=[CH:13][NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1
Reactant: CCOC(=O)c1cnc2ccccc2c1NNc1ccc(Cl)cc1Cl
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
The mixture of 3.5 g of ethyl 4-(2,4-dichlorophenyl-hydrazino)-quinolin-3-carboxylate and 40 ml of eutectic diphenyl ether-biphenyl is heated to 175° for 4 hours, cooled to room temperature and diluted with diethyl ether. The resulting suspension is filtered, the residue washed with diethyl ether and dissolved in N aqueous sodium hydroxide. The solution is washed with diethyl ether, its pH adjusted to 8.5 with ammonium chloride and the precipitate formed collected. It is washed successively with hot water, methanol and diethyl ether, to yield the 2-(2,4-dichlorophenyl)-pyrazolo[4,3-c]-quinolin-3(5H)-one, showing peaks in the IR-spectrum at 890, 867, 845, 832, 816, 796, 775, 767, 756, 730 and 701 cm-1.