Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:18][CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
TFA (55.30 mL, 717.76 mmol, 15.0 eq) is added at 0° C. to a stirred solution of (tert-butoxy)-N-{4-[(fluoren-9-ylmethoxy)carbonylamino]phenyl}carboxamide (20.60 g, 47.85 mmol, 1.0 eq) in CH2Cl2 (900 mL). The resulting solution is allowed to warm to room temperature. After stirring overnight at room temperature, the reaction mixture is concentrated to dryness and the residue is triturated in water. Then the mixture is filtered to afford 15.80 g of the expected crude product as a white powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH2:19])[C:6]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:7][CH:8]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].O>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])[C:20](=[O:21])[NH:19][C:5]=2[CH:4]=1
Reactant: COc1ccc(Cl)cc1Nc1ccc(Cl)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Chloro-N1-(5-chloro-2-methoxy-phenyl)-benzene-1,2-diamine hydrochloride (6.3 g, 20 mmol) in tetrahydrofurane (70 ml) was added carbonyldiimidazole (9 g 55 mmol). The reaction mixture was stirred at 60° C. overnight, poured into water (app. 200 ml) and extracted with ethylacetate, and the organic phase was washed with brine and evaporated to an oil. The title compound was crystallized from toluene.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2].[CH3:28][C:29]1[C:33](I)=[C:32]([CH3:35])[O:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:33]2[C:29]([CH3:28])=[N:30][O:31][C:32]=2[CH3:35])[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)ccc1Cl
Reactant: Cc1noc(C)c1I
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2c(C)noc2C)ccc1Cl

Procedure:
By carrying out the operation analogously to example 58, starting from 5-bromo-2-chlorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 3,5-dimethyl-4-iodoisoxazole, the expected compound is obtained in the form of a crude product used without further purification in the deacetylation stage.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)([O-])O.[Na+]>CO.O>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1N

Procedure:
A solution of 2,3-diaminobenzoic acid (0.2 g, 1.32 mmol) in methanol (40 ml) was saturated with hydrogen chloride as described above, and the mixture was subsequently heated under reflux for 2 hours. The solid residue obtained on evaporation of the solvent was dissolved in water, and the solution was adjusted to pH 7.0 with sodium hydrogen carbonate. After extraction with ethyl acetate (2×30 ml), the combined organic layers were dried (MgSO4), and the solvent was removed to give methyl 2,3-diaminobenzoate as a brown oil which solidified on trituration with petrol (40/60) (121.6 mg, 56%), m.p. 62-63° C. Found: C, 58.35; H, 5.80; N, 16.69. C8H10N2O2 requires C, 57.83; H, 6.02; N, 16.87%; δH (d6 -DMSO), 200 MHz) 3.87 (3H, s, OCH3). 4.90 (2H, br s, Ar-2-NH2), 6.32 (2H, br s, Ar-3-NH2), 6.46-6.54 (1H, t, Ar-5H), 6.80-6.84 (1H, dd, Ar-4H), 7.18-7.23 (1H, dd, Ar-6H); m/z (EI) 166 (M+), 134, 106, 79.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>CCOCC>[Br:34][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1)[CH3:12]
Reactant: CC(C)Cc1cccc(C(C)O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)Cc1cccc(C(C)Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of 1-(3-isobutylphenyl)ethanol (1.1 g), triphenylphosphine (3.24 g) and carbon tetrabromide (4.09 g) in ether (20 ml) was stirred at 25° C. for 1 hour. The precipitates were filtered off, and the liltrate was evaporated to give 1-(1-bromoethyl)-3-isobutylbenzene (1.49 g) as an oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16](O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.C1C=CC(P([N:81]=[N+:82]=[N-:83])(C2C=CC=CC=2)=O)=CC=1>C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>[N:81]([C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:35]([O:37][CH3:38])=[O:36])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:25][C:19]=2[O:18][CH2:17]1)=[N+:82]=[N-:83]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1cc(OCc2ccccn2)ccc1-3
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N=[N+]=[N-])COc1cc(OCc2ccccn2)ccc1-3
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Methyl (7S)-14-cyclohexyl-7-hydroxy-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved in THF (60 mM) and PPh3 (1.2 eq) was added. The solution was cooled to 0° C. and treated with DIPEA (1 eq), followed by slow addition of DIAD (1.2 eq). The mixture was left stirring at this temperature for 5 min, then a solution of DPPA in THF (1.2 eq) was added dropwise. After complete addition the mixture was stirred at 0° C. for further 30 min, then stirring was continued at RT. Since no reaction was observed after 1 h more PPh3 in THF (1.2 eq), DIAD in THF (1.2 eq) and DPPA in THF (0.6 eq) were added at RT. The formation of a precipitate was observed. Stirring was continued for 1 h at RT after which time HPLC-MS indicated complete conversion. The mixture was used without further treatment in the next reaction (quant). (ES+) m/z 538 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C@@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.C(=O)([O-])O.[Na+].ClCCl.[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([N:2]1[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C@@H:5]2[C@@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)(=[O:24])[CH3:23]
Reactant: O=C(O)[C@@H]1CC2CCCCC2CN1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2CCCC[C@@H]2C[C@H]1C(=O)O
Reaction time: 22 h
Yield: 33.4 %

Procedure:
A mixture comprising (4aR,8aS) isomer, (4aR,8aR) isomer and trans isomer of decahydroisoquinoline-3(S)-carboxylic acid was dissolved in 72 ml of water, followed by the addition of 60.9 g (725 mmol) of sodium hydrogencarbonate and 72 ml of dichloromethane at room temperature. Thereafter, 27.4 ml (290 mmol) of acetic anhydride was slowly dropwise added thereto, followed by stirring for 22 hours. Insolubles were separated by filtration. After 6N hydrochloric acid was poured thereinto to adjust to pH3, common salt was added thereto up to saturation. Extraction with chloroform was conducted and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in a reduced pressure. Dichloromethane was added thereto to thereby obtain 5.45 g of a crystal of the title compound. Yield 33.4% (two steps).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:17][C:18]1[CH:22]=[C:21]([CH:23]2[CH2:25][CH2:24]2)[NH:20][N:19]=1>>[CH:23]1([C:21]2[NH:20][N:19]=[C:18]([NH:17][C:1]3[NH:2][C:6](=[O:7])[C:5]4[C:4]([CH:3]=3)=[CH:12][C:11]([O:13][CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=4)[CH:22]=2)[CH2:25][CH2:24]1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1OC
Reactant: Nc1cc(C2CC2)[nH]n1
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)[nH]c(=O)c2cc1OC

Procedure:
Similar procedure as described in example 2c was used, starting from 2-cyanomethyl-4,5-dimethoxy-benzoic acid and 3-amino-5-cyclopropylpyrazol to give 3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dimethoxy-2H-isoquinolin-1-one. LC-MS: m/e 327 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](OS(C)(=O)=O)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:5][CH:4]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([S:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:32][CH:31]=2)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CS(=O)(=O)OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Yield: 84 %

Procedure:
A mixture of 1-[4-(4-chlorophenyl)-2-methanesulfonyloxy-n-butyl]imidazole hydrochloride (2.0 g), 4-acetylaminothiophenol (1.2 g) and anhydrous potassium carbonate (2.0 g) in 30 ml of acetone and 10 ml of methanol was stirred and refluxed overnight under nitrogen. The solvent was evaporated and the residue treated with water (50 ml) and ether (20 ml) and the mixture stirred until crystallization was complete. Filtration of the product and recrystallization from ethyl acetate gave 1.84 g of 1-[4-(4-chlorophenyl)-2-(4-acetylaminophenylthio)-n-butyl]imidazole as a pale cream solid, m.p. 165.5°-166.5° C. B. Similarly, proceeding as above substituting the appropriate thiophenol for 4-acetylaminothiophenol the following compounds are prepared:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[N+:12]([C:15]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>COCCOC.O>[F:11][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 45.3 %

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (660 mg, 2.50 mmol) and K2CO2 (940 mg, 6.81 mmol) were suspended in DME-H2O (4:1, 15 mL) and purged with nitrogen. The solution was degassed by sonication before Pd(dppf)Cl2 (185 mg, 10 mol %) was added. The mixture was heated to 130° C. for 10 min under microwave irradiation. The cooled mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resulting black solid was absorbed onto silica and purified by column chromatography (4:1 to 1:1 petrol-EtOAc) to give the product as an orange solid (285 mg, 45%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:24]([O-:27])(=[O:26])[CH3:25].[K+]>CC#N.CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][O:27][C:24](=[O:26])[CH3:25])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)OCc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)N(C(C)=O)CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (7.0 g) was dissolved in a mixed solvent (50 ml) of CH3CN/DMF=1/1. Potassium acetate (12.0 g) was added and the mixture was stirred at 60° C. for 1 hr. CH3CN was evaporated under reduced pressure and AcOEt (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=1/0−10/1) to give 7.5 g of N-(1-acetyl-5-acetoxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].O.[NH3:18]>O1CCOCC1>[NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([NH2:18])=[O:8]
Reactant: N
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cc1OC
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(N)cc1C(N)=O
Reaction time: 40 h

Procedure:
To a solution of 5.66 g of methyl 5-amino-2-methoxy-4-nitrobenzoate in 200 ml of dioxane was added 50 ml of 28 % ammonia water, and then the mixture was allowed to stand at room temperature for 40 hours. The solvent was evaporated under reduced pressure, and the residue was recrystallized from dioxane to give the title compound, m.p. 250°-257° C., yield of 4.30 g.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:14]>>[CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]cnc12
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Product: Cc1cccc2c1ncn2CC(=O)Nc1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
The title compound was synthesized in 39% yield (65 mg) according to a procedure described in Example 92, using 4-methyl-1H-benzoimidazole (66 mg, 0.5 mmol) and 2-bromo-N-(3-trifluoromethyl-phenyl)-acetamide (Example 92, part A) (141 mg, 0.5 mmol). Calculated for C17H14F3N3O m/z: 333.11, found 334.07 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 5.18 (s, 2H), 7.01 (d, J=7.6 Hz, 1H), 7.12 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.18 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: O.ON1C2C=CC=C[C:6]=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([C:35]([O-:37])=[O:36])=[N:32][CH:31]=2)=[CH:26][CH:25]=1.[Li+]>CO>[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([C:35]([O:37][CH3:6])=[O:36])=[N:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: On1nnc2ccccc21
Reactant: O=C([O-])c1ncc(-c2ccncc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncc(-c2ccncc2)s1
Reaction time: 96 h
Yield: 53.8 %

Procedure:
1-Hydroxybenzotriazole monohydrate (805 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g) were added to a solution of lithium 5-(4-pyridyl)thiazole-2-carboxylate (632 mg) in methanol (5.0 ml) at room temperature. After stirring for 4 days, the reaction mixture was concentrated under reduced pressure, and dichloromethane (20 ml), a saturated aqueous solution (100 ml) of sodium hydrogencarbonate and water (100 ml) were added to the residue to separate an organic layer. The water layer was then extracted with dichloromethane (2×20 ml). After the resultant organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was then purified by column chromatography on silica gel (dichloromethane:acetone=5:1→2:1) to obtain the title compound (353 mg) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, p-nitroaniline (138 g) was dissolved in a mixed solution of tetrahydrofuran (200 ml) with pyridine (140 ml) in a nitrogen atmosphere. To the solution, octadecanoyl chloride (333 g) was added through the dropping funnel over a time span of 20 minutes, while stirring the reaction mixture. After the completion of the dropwise addition, the reaction mixture was stirred for 2 hours. The resultant solid product was removed by filtering, and the filtrate was concentrated under reduced pressure, to produce crystals. The crystals were collected and recrystallized from ethanol. 4'-nitro-n-octadecaneanilide (364 g) was obtained at a yield of 90%.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OS([O-])=O.[Na+].Cl.Cl.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:24]([NH2:26])=[NH:25].C(O)C>O>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]2[NH:30][C:29]3[CH:28]=[CH:27][C:23]([C:24](=[NH:25])[NH2:26])=[CH:22][C:21]=3[N:20]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc3cc(C(=N)N)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-tert-butylbenzaldehyde (0.4000 g, 0.00247 mol) was added 3 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzamidine dihydrochloride (0.56 g, 0.0025 mol) and ethanol (8 mL) were added. The mixture was refluxed for 3 h. The reaction was then poured into water. The precipitate filtered and recrystallized from 2N HCl to afford 1H-benzimidzole-5-carboximidamide, 2-[4-(1,1-dimethylethyl)phenyl]- (400 mg, 44%) as a white solid: 1H NMR (DMSO-d6) δ9.47 (bs, 2 NH), 9.15 (bs, 2 NH), 8.30 (d, 2 arom-H, J=8 Hz), 8.21 (s, 1 arom-H), 7.88 (d, 1 arom-H, J=8 Hz), 7.73 (d, 1 arom-H, J=9 Hz), 7.68 (d, 2 arom-H, J=8 Hz), 1.35 (s, 9 tert-butyl-H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:23]([CH:24]=[CH2:25])=[CH:22][N:21]=[C:20]([CH3:26])[CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:28][C:17]([F:16])([F:27])[C:18]1[CH:19]=[C:20]([CH3:26])[N:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)cc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=1
Reactant: BrCC1CC1
Reactant: O=c1ccc(Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Cl)nn1CC1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Cyclopropylmethyl bromide (0.82 mL) was added to a mixture of 6-chloro-2H-pyridazin-3-one (1.0 g) and K2CO3 (2.10 g) in dimethylformamide (10 mL). The resulting mixture was stirred at 60° C. overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:1:0.1) to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([CH2:15][C:16](=[O:20])[C:17](O)=[O:18])[CH2:14][CH2:13]1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:27](=[O:28])[O:26][CH2:25]2>>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([CH2:15][C:16](=[O:20])[C:17]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:27](=[O:28])[O:26][CH2:25]3)=[O:18])[CH2:13][CH2:14]1
Reactant: O=C(O)C(=O)CC1(c2cccc(C(F)(F)F)c2F)CC1
Reactant: Nc1ccc2c(c1)COC2=O
Product: O=C(CC1(c2cccc(C(F)(F)F)c2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
Preparation from 3-[1-(2-fluoro-3-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionic acid and 5-aminophthalide analogously to the preparation of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionylamino}-phthalide (cf. Example 1a)). M.p. 157-158° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CN1CCN(c2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(4-methylpiperazin-1-yl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Phenomenex Luna C18 100A, 10 m silica, 21 mm diameter, 150 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.