Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[O:30]=[C:26]1[N:27]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[C:16]4[C:10]([CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:29][O:25]1
Reactant: O=C1NCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(Br)cc3)nc2CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCOC4=O)cc3)nc2CC1
Temperature: 100 °C

Procedure:
A mixture of 1,1-dimethylethyl 2-(4-bromophenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 12) (160 mg, 0.41 mmol), 2-oxazolidinone (71 mg, 0.82 mmol), potassium carbonate (170 mg, 1.23 mmol), copper (I) iodide (24 mg, 0.12 mmol) and N,N′-dimethyl-1,2-ethanediamine (13 μl, 0.12 mmol) in dioxane (10 ml) was heated at reflux overnight. The same amounts again of 2-oxazolidinone, copper (I) iodide and N,N′-dimethyl-1,2-ethanediamine were added and the mixture heated for 6 hours. The reaction mixture was transferred to a microwave vial, the same amounts again of 2-oxazolidinone, copper (I) iodide and N,N′-dimethyl-1,2-ethanediamine were added and the mixture heated at 100° C. in microwave for 1 hour. The same amounts again of 2-oxazolidinone, copper (I) iodide and N,N′-dimethyl-1,2-ethanediamine were added and the mixture heated at 100° C. in microwave for a further 2 hours. Crude mixture was filtered through a celite pad washing with methanol. The solvent was evaporated in vacuo, the residue was taken up into ethyl acetate, washed with water and brine, then dried over magnesium sulphate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel, eluting with a 50% mixture of ethyl acetate in hexane to afford the title compound (D26). MS (ES+) m/e 343 [M-tBu]+.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH2:17]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Br)([Br:21])=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH2:17][Br:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc2ccccc2c1-c1ccccc1
Solvent: Cc1ccccc1
Product: BrCc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above alcohol (2.3 g) was dissolved in toluene (10 ml) and thionyl bromide (1.0 ml) was added. The mixture was stirred at ambient temperature for 1 h, heated at reflux for 10 minutes and finally stirred at ambient temperature for 30 minutes. The reaction mixture was diluted with toluene (75 ml), washed with a 10% sodium bicarbonate solution and dried (MgSO4). The solvent was evaporated in vacuo to give crude (1-phenyl-2-naphtyl) methylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]2[CH2:37][O:36][B:35]([OH:38])[C:34]=2[CH:39]=1.ClC1C=C(C2(C(F)(F)F)ON=C(C3C=CC(C(NC4C=CC5COB(O)C=5C=4)=O)=C(C)C=3)C2)C=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]5[CH2:37][O:36][B:35]([OH:38])[C:34]=5[CH:39]=4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccc2c(c1)B(O)OC2
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc2c(c1)B(O)OC2
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2

Procedure:
The title compound was prepared from 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid and 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol by the same method as described for 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-methylbenzamide. It was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1 H), 8.94 (m, 1 H), 7.37-7.82 (m, 9 H), 4.95 (s, 2 H), 4.49 (m, 2 H), 4.34 (m, 2 H), 2.37 (s, 3 H) ppm; MS: m/z=563 (M+1, ESI+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:35][CH:36]=5)=[CH:26][CH:27]=4)[CH2:22]C[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB(C2C=CC3C4C(=CC(B5OC(C)(C)C(C)(C)O5)=CC=4)CC=3C=2)O1>>[C:45]([O:44][C:42]([N:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[C:34]1[NH:33][C:32]([C:25]2[CH:26]=[CH:27][C:28]3[C:29]4[C:30](=[CH:31][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[CH2:22][C:23]=3[CH:24]=2)=[CH:36][N:35]=1)=[O:43])([CH3:47])([CH3:46])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1
Agent: CC1(C)OB(c2ccc3c(c2)Cc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)Cc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1

Procedure:
Followed the procedure used to prepare compound 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-fluoren-2-yl]-[1,3,2]dioxaborolane was used instead of 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane. m/z 637.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=1)[CH3:2].C([Li])(CC)C.[C:22](=[O:24])=[O:23].S(=O)(=O)(O)O>O1CCCC1.O>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[C:6](=[C:7]2[O:8][CH2:9][O:10][C:11]2=[CH:12][CH:13]=1)[C:22]([OH:24])=[O:23])[CH3:16]
Reactant: O=C=O
Reactant: CCN(CC)C(=O)c1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc2c(c1C(=O)O)OCO2
Temperature: 0 °C

Procedure:
A solution of N,N-diethylpiperonylamide 10.0 g, 45.0 mmol) in tetrahydrofuran is added dropwise at -65° C. to -55° C. to a mixture of sec-Butyllithium (500 mL, 50.0 mmol, 1M in cyclohexane) in tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is poured over tetrahydrofuran saturated with dry ice, allowed to warm to 0° C., treated slowly with water and acidified to pH 3 with concentrated sulfuric acid. The tetrahydrofuran is removed in vacuo and the aqueous residue is extracted with ethyl acetate. The organic extract is dried (MgSO4) and concentrated in vacuo to a yellow-orange gum, NMR and mass spectrographic analysis show it to be a mixture of starting material and the title product. The above aqueous layer is acidified further to pH 2, extracted with ethyl acetate, and the organic extract is dried (MgSO4) and concentrated in vacuo to yield the title product as a yellow foam, 4.00 g (33.6%) identified by NMR spectral analysis.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[NH2:15][CH2:16][CH2:17][OH:18]>O>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:15][CH2:16][CH2:17][OH:18])[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(Cl)nccc2o1
Reactant: NCCO
Solvent: O
Product: NS(=O)(=O)c1cc2c(NCCO)nccc2o1
Temperature: 110 °C
Yield: 76.7 %

Procedure:
A mixture of 2-sulfamoyl-4-chloro-furo[3,2-c]pyridine (1.75 g, 7.5 mmol) in 2-aminoethanol (5.5 ml, 91 mmol) was heated at 110° C. for 5 hours. This solution was diluted with water and the product was extracted into ethyl acetate. The ethyl acetate extract was evaporated and the residue was triturated with diethyl ether to give solid product (1.48 g). This material was recrystallized from ethyl acetate to give pure product (1.38 g, 71% yield), m.p. 192°-195° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].CC([N:35]([CH2:39][CH2:40][N:41]1[CH:45]=[C:44](I)[N:43]=[CH:42]1)[C:36](=[O:38])[O-:37])(C)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:44]3[N:43]=[CH:42][N:41]([CH2:40][CH2:39][NH:35][C:36]([O:37][C:16]([CH3:11])([CH3:7])[CH3:15])=[O:38])[CH:45]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3]
Reactant: CC(C)(C)N(CCn1cnc(I)c1)C(=O)[O-]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 12 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (333 mg, 0.80 mmol), 1,1-dimethylethyl[2-(4-iodo-1H-imidazol-1-yl)ethyl]carbamate (for a preparation see Intermediate 80) (270 mg, 0.8 mmol), potassium carbonate (443 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) in toluene (10 ml) and ethanol (10 ml) was refluxed under nitrogen for 16 h then cooled to room temperature and the insoluble were filtered off. Potassium carbonate (443 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) were added to the filtrate and the resulting mixture refluxed for 7 h then cooled to room temperature and the insoluble filtered off. The resulting solution was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-imidazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (47 mg, 0.094 mmol, 12%) as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:36][O:37][CH2:38][C@@H:39]([NH:46][C:47]([NH2:49])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CC(N(C)C)=O>[CH3:36][O:37][CH2:38][C@@H:39]([NH:46][C:47]([NH:49][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Reactant: Cn1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cn1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1cnn(C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a vial were added 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (47.6 mg, 0.100 mmol), (S)-1-(2-methoxy-1-phenylethyl)urea (38.8 mg, 0.200 mmol), cesium carbonate (0.024 ml, 0.300 mmol), CHLORO[2-(DICYCLOHEXYLPHOSPHINO)-3,6-DIMETHOXY-2′,4′,6′-TRI-I-PROPYL-1,1′-BIPHENYL][2-(2-AMINOETHYL)PHENYL]PALLADIUM(II) (15.98 mg, 0.020 mmol) and DMA (1.0 ml). The mixture was Vac/N2 purged 6 times and heated at 100° C. for 2 h. LC-MS showed complete conversion. The mixture was diluted with EtOAc and washed with water and brine. After dried over Na2SO4 the solution was concentrated to yield (S)-1-(2-methoxy-1-phenylethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (63.4 mg, 0.100 mmol, 100% yield) without purification.
Reaction SMILES: [C:1]([N:3]([CH2:23][CH2:24][CH2:25][CH3:26])[C:4](=[O:22])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1)[CH3:6])#[N:2].[H][H]>O1CCOCC1.[Pd]>[C:1]([N:3]([CH2:23][CH2:24][CH2:25][CH3:26])[C:4](=[O:22])[CH:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH3:6])#[N:2]
Reactant: [H][H]
Reactant: CCCCN(C#N)C(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCN(C#N)C(=O)C(C)Oc1ccc(O)cc1
Yield: 60.8 %

Procedure:
16.5 g (0.047 mole) of 2-(4-benzyloxyphenoxy)propionic acid N-cyano-N-butylamide, prepared according to Example b), are hydrogenated with hydrogen in 170 ml of dioxan, in the presence of 1.7 g of 5% palladium on carbon catalyst. The catalyst is then removed by filtration and the filtrate is concentrated by evaporation. The residue is chromatographed through silica gel eluted with ethyl acetate/hexane (1:3), affording 7.5 g (61% of theory) of 2-(4-hydroxyphenoxy)propionic acid N-cyano-N-butylamide as a colourless oil. nD25 : 1.5132.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[BH4-].[Na+].O.Cl>[OH-].[Na+]>[OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:17])[CH:14]([OH:16])[CH3:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CC(=O)C(C)=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(C)O
Temperature: 25 °C

Procedure:
1.8 g of the product obtained in Example 6 was dissolved in 20 ml of 1N NaOH-solution and 4.0 g of sodium borohydride in small amount of water wasadded. The mixture was stirred over night at room temperature, acidified with hydrochloric acid and extracted with ether. The solvent was evaporated in vacuo and the residue purified in a silica gel column by using toluene-acetic acid dioxane (18:1:1). The product was crystallized from dichloromethane petroleum ether. Yield 0.80 g (44%), m.p. 102°-104° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[CH:34]1([CH2:37][NH:38][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:32])([F:33])[F:1])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)=[CH:24][CH:25]=2)[CH2:36][CH2:35]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)O)cc4)ccc32)c1
Reactant: NCC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)NCC5CC5)cc4)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid (20.0 mg, 0.0440 mmol) and cyclopropylmethylamine (6.3 mg, 0.088 mmol, Aldrich, Cat. No. 359521) in N,N-dimethylformamide (1 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (23 mg, 0.053 mmol, Adv. ChemTech. Cat. No. RC8105) and N,N-diisopropylethylamine (23 μL, 0.13 mmol). The reaction mixture was stirred at r.t. for 2 h, then diluted with MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=508.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:33][C:34](=[O:46])[NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:45])[CH2:43]Br)=[CH:38][CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O.C(OCC)(=O)C.CO>[CH2:26]([O:33][C:34](=[O:46])[NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:42](=[O:45])[CH2:43][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=2)=[CH:40][CH:41]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(Nc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
To a stirred solution of 11.1 g of 3-[4-(1H-benzoimidazol-2-yl)-furazan-3-ylamino]-propionitrile (95%, 41.5 mmol, 1 eq) in 90 ml of N,N-dimethylformamide are added 7.84 g of potassium carbonate (56.8 mmol, 1.3 eq), followed by 23.25 g of [4-(2-bromo-acetyl)-phenyl]-carbamic acid benzyl ester (75%, 50.1 mmol, 1.2 eq). The reaction mixture is stirred for 4 h at room temperature. Then 700 ml of water are added and the resulting suspension is extracted with 3×800 ml of ethyl acetate. The combined organic layers are washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product as dark brown solid. This crude product is suspended in 150 ml of a 2/1 ethyl acetate/methanol mixture. Filtration provides 12.63 g of the desired product as light brown powder.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[OH:25][CH2:26][CH:27](CO)[OH:28].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH:26]([CH2:27][OH:28])[OH:25])=[O:6]
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCC(=O)OCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
1.0 g (3.0 mmol) of methyl 4,8,12,16-tetramethylheptadec-3-enoate was slowly added dropwise to a solution of 0.68 g (7.4 mmol) of glycerol and 0.61 g (4.4 mmol) of potassium carbonate in dry N,N-dimethylformamide (3.5 mL) at 100° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The reaction solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 347 mg of the title compound (29% yield) as a yellow viscous product.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1OC
Yield: 68.8 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (20.2 g, 0.077 mol) and o-anisidine (15 ml, 0.11 mol) were heated under reflux in 1,4-dioxan (150 ml) for 1 hour. The solvent was evaporated and the residue dissolved in dichloromethane and washed with dilute hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried, filtered and evaporated to a yellow solid, which was triturated with ether to give 3-butyryl-4-(2-methoxyphenylamino)-8-methoxyquinoline (18.55 g, 68.75%) m.p. 159°-161°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[C:23]([CH2:24]O[Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=[CH:20][N:19]=1)([OH:17])[CH2:13]2.[F-].C([N+:45](CCCC)(CCCC)CCCC)CCC>>[NH2:45][CH2:24][C:23]1[C:18]([C:12]2([OH:17])[CH2:11][CH:10]3[N:9]([CH:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:39])[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Agent: [F-]
Product: NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
Follow the procedure of Step 4 of Example 15, using the product from Step 3 (12.3 g, 21.1 mmol) and tetrabutylamonium fluoride (11 g, 42.2 mmol) to give the desired compound.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5](Cl)(=[O:7])=[O:6]>N1C=CC=CC=1>[CH3:1][N:2]([S:5]([CH3:4])(=[O:7])=[O:6])[N:3]([S:5]([CH3:4])(=[O:7])=[O:6])[S:5]([CH3:4])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: CNN
Solvent: c1ccncc1
Product: CN(N(S(C)(=O)=O)S(C)(=O)=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 18.2 %

Procedure:
To an ice-cold stirred solution of methylhydrazine (4.6 g, 0.1 mol) in dry pyridine (30 ml) was added methanesulfonyl chloride (44.6 g, 0.39 mol) dropwise, while maintaining the temperature between 0° and 10° C. The reaction mixture was left in a freezer (-10° C.) for 2 days. It was then triturated with a mixture of ice and concentrated hydrochloric acid (1:1, v/v, 100 ml). The precipitate that formed was collected, washed with cold water and dried. This product was stirred with chloroform (200 ml) and filtered. The undissolved material, consisting mainly of 1,2-bis(methylsulfonyl)-1-methylhydrazine, was discarded and the filtrate was treated with decolorizing carbon, filtered and evaporated to dryness in vacuo to give a yellow solid, which was crystallized twice from ethanol (Norit A) to give 5.1 g (18%) of the title compound: m.p. 123°-124° C.; anal. (C4H12N2O6S3) C,H,N; 1H NMR (acetone-d6) δ 3.6 [s, 6H, N2 (SO2CH3)2 ], 3.5 (s, 3H, N-CH3), 3.2 (s, 3H, N1SO2CH3).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([OH:19])=O)=[CH:3][CH:2]=1.ClS(O)(=O)=O>O>[CH3:20][C:1]1[CH:2]=[C:3]2[C:4]([S:7][C:8]3[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:9]=3[C:17]2=[O:19])=[CH:5][CH:6]=1
Reactant: Cc1ccc(Sc2cc(C(=O)O)ccc2C(=O)O)cc1
Agent: O=S(=O)(O)Cl
Solvent: O
Product: Cc1ccc2sc3cc(C(=O)O)ccc3c(=O)c2c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
The 2-(p-tolylthio)benzene-1,4-dicarboxylic acid is transferred slowly to a flask, containing 100 ml of chlorosulfonic acid. The temperature is maintained between the 5 and 10° C. with an ice-bath. At the end of the addition, the solution is left to rest for maturation and after 1 hour is poured in water and ice. The precipitate is filtered, washed with water and dried in a vacuum oven obtaining 19.69 g (yield: 96.7%) of 7-methyl-9-oxo-thioxanthene-3-carboxylic acid as a yellow solid. Melting point>250° C.