Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([OH:6])[CH2:4]O.C(C1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[CH:11][CH:10]=1)#N>O>[N:15]1([C:12]2[CH:13]=[CH:14][C:4]([C:3]([OH:6])=[O:1])=[CH:10][CH:11]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: OCCO
Reactant: N#Cc1ccc(-n2ccc3ccccc32)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(-n2ccc3ccccc32)cc1
Yield: 95 %

Procedure:
A mixture of 180 ml of 6N NaOH, 360 ml ethylene glycol and 39.3 g (180 mmole) of 1-p-cyanophenylindole [Misbahul Ain Khan and J. B. Polya, J. Chem. Soc., 85 (1970)] is refluxed for 3 hours at 150°. The basic solution is diluted with 450 ml of H2O and extracted with diethyl ether to remove neutrals. The aqueous solution is acidified with 200 ml of 6N HCl. The solid is filtered washed with hot water and dried in a vacuum oven at 50° to yield 45.8 g (95%) of p-(indol-1-yl)benzoic acid, m.p. 224°-226°.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([C:9]3[C:14]4[O:15][CH2:16][CH2:17][NH:18][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([C:9]3[C:14]4[O:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Clc1cc2nc(-c3cccc4c3OCCN4)[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc2nc(-c3cccc4c3OCCN4CCN3CCOCC3)[nH]c2cc1Cl
Yield: 92.3 %

Procedure:
4.5 g (14 mmol) of 8-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 1a) obtained in Example 5 was dissolved in 100 mL of dimethylformamide. 1.3 g (7 mmol) of 4-(2-chloroethyl)morpholine, 0.58 g (3.5 mmol) of potassium iodide and 0.97 g (7 mmol) of K2CO3 were added thereto, followed by irradiation of microwave at 110° C. for 10 min. The reaction mixture was concentrated under reduced pressure, followed by dilution with ethyl acetate. The resulting product was washed with distilled water and saturated sodium chloride solution, followed by drying over magnesium sulfate and concentrating under reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate/hexane=1/1) to obtain the title compound (2.8 g, yield: 91%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([N:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[Br:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([OH:54])[CH:49]=1>C1COCC1.O>[Br:47][C:48]1[CH:53]=[CH:52][N:51]([CH:43]2[CH2:44][CH2:45][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)[C:50](=[O:54])[CH:49]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(Br)cc2=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.9 %

Procedure:
To an ice cold solution of triphenylphosphine (0.17 g, 0.63 mmol) in THF (10.0 mL) was added DIAD (0.12 mL, 0.63 mmol) and the resulting solution was stirred at the same temperature for 15 min. after which a yellow precipitate was formed. 1-Boc-3-hydroxypyrrolidine (0.10 g, 0.53 mmol) was then added to the reaction mixture and allowed to stir for 20 min followed by addition of 4-bromo-2-hydroxypyridine (0.093 g, 0.53 mmol). The resulting reaction mixture was stirred for 16 h at room temperature. After completion of reaction (TLC monitoring), the reaction mixture was diluted with water and extracted with EtOAc (3×50 ml). The combined organics was dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 0.5% MeOH-DCM) to obtain the desired product (0.20 g, quantitative yield). MS: 343.10 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])=[O:17])[CH2:14][CH2:15]2)=[N:8][CH:9]=1
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)COC(=O)N1CCN(c2ccc(N)cn2)CC1
Reaction time: 14 h
Yield: 80.9 %

Procedure:
0.24 g of 10% palladium on charcoal is added to a suspension of 0.64 g (1.98 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-nitro-2-pyridyl)-1-piperazinecarboxylate, prepared in step 5.3, in 90 ml of ethyl acetate. Stirring is continued at room temperature under a hydrogen atmosphere of 60 psi for 14 hours. After filtering off the catalyst, the filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.47 g of product is obtained in the form of a violet-colored oil, and is used without further purification in the following step.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]2[CH:45]=[C:46]([C:48]([OH:50])=O)[N:47]=[C:41]2[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[N:51]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:62][CH2:61][C:60]3([CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[CH2:59][CH2:58]2)=[CH:53][CH:52]=1>C(Cl)Cl>[N:51]1[CH:52]=[CH:53][C:54]([N:57]2[CH2:62][CH2:61][C:60]3([CH2:63][CH2:64][N:65]([C:48]([C:46]4[N:47]=[C:41]5[CH2:40][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:43][N:42]5[CH:45]=4)=[O:50])[CH2:66][CH2:67]3)[CH2:59][CH2:58]2)=[CH:55][CH:56]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
DIPEA (5.96 mmol, 4.0 equiv.), EDCl (2.24 mmol, 1.5 equiv.) and HOBt (2.24 mmol, 1.5 equiv.) were added at 0° C. to a solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (1.49 mmol, 1.0 equiv.) in DCM (20 ml), and the mixture was stirred for 30 min. A solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (F-19) (1.49 mmol, 1.0 equiv.) in DCM (5 ml) was added at 0° C., and then the reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with DCM (100 ml) and washed with sat. sodium carbonate solution (65 ml), sat. ammonium chloride solution (65 ml), water (50 ml) and sat. sodium chloride solution (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 63%
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([Mg]Br)=C.[CH2:21]1[CH2:25][O:24]CC1.[NH4+].[Cl-]>CCOCC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)([CH:21]2[CH2:25][O:24]2)[OH:7])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1CO1
Reaction time: 0.33 h

Procedure:
To a solution of 6 g of 4,4'-dichlorobenzophenone in 200 mL of ether was added 30 mL of 1.4M vinylmagnesium bromide/THF at 0°. After being stirred at 25° for 20 minutes, the mixture was poured onto aqueous NH4Cl, partitioned, washed with brine, dried (MgSO4), filtered, and concentrated. The crude adduct was allowed to stand in 50 mL of methylene chloride with 5.8 g of m-chloroperbenzoic acid for 3 days at 25°. The mixture was diluted with CH2Cl2, washed with aqueous NaHSO3, aqueous NaHCO3, brine, dried (Na2SO4), concentrated, and chromatographed (150 mL SiO2 /30% CH2Cl2 in hexane) to provide 2.9 g of the title compound (after washing the concentrated fractions with pentane), m.p. 87°-88°.
Reaction SMILES: CO[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].C([O:15][CH2:16][C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1)(=O)C(C)=C.C(O)(=[O:27])C(C)=C.C(S)CCCCCCCCCCC.CC(N=NC(C#N)(C)C)(C#N)C.COCNC(=O)C(C)=C.C(OCC1C=CC=CC=1)(=O)C(C)=C.C(O)(=O)C(C)=C>COCCO>[C:16]([C:17]1[CH:22]=[CH:21][C:3]([NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[CH:19][CH:18]=1)([OH:15])=[O:27]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: C=C(C)C(=O)NCOC
Reactant: C=C(C)C(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCCCCCCS
Solvent: COCCO
Product: C=C(C)C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl cellosolve (199.8 g), N-methoxymethyl methacrylamide (18 g), benzyl methacrylate (11.4 g), methacrylic acid (3 g), dodecyl mercaptan (0.075 g), and Vazo-64 (0.6 g) were added to 500 ml 4-neck ground glass flask, equipped with a heating mantle, temperature controller, mechanical stirrer, condenser, pressure equalized addition funnel and nitrogen inlet. The reaction mixture was heated to 80° C. under nitrogen atmosphere. Then, a pre-mixture of N-methoxymethyl methacrylamide (55 g), benzyl methacrylate (34 g), methacrylic acid (9 g), dodecyl mercaptan (0.225 g), and Vazo-64 (1.2 g) were added over two hours at 80° C. The reaction was continued another eight hours and Vazo 64 (0.35 g) was added two more times. The polymer conversion was >99% based on determination of percent of non-volatiles. The weight ratio of N-methoxymethyl methacrylamide/benzyl methacrylate/methacrylic acid in the polymer was 56/34.8/9.2. The resin solution was precipitated in powder form using DI water/Ice (3:1) and a Lab Dispersator (4000 RPM) and then filtered. The resulting powder was dried at room temperature for 24 hours. The next day, a tray containing the polymer was placed in oven at 110° F. (43° C.) for two additional days. The yield was 95% and polymer acid number was 58 (actual) versus 58.8 (theoretical).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][C:14]([OH:17])([CH3:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][C:14]1([OH:17])[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC1(O)CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-hydroxy-3-methyl-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.09 g, 0.37 mmol) in DCM/TFA (2 mL/2 mL). The reaction mixture was stirred for 90 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Methyl-[1,3′]biazetidinyl-3-ol as a colourless oil (0.04 g, 76%). 1H NMR (300 MHz, CDCl3): δ 3.68-3.51 (m, 6 H), 3.25 (d, J=7.6 Hz, 2 H), 3.15 (d, J=7.6 Hz, 2 H), 1.49 (s, 3 H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[N:24]1[C:33]2[C:28](=CC=C[C:32]=2O)[CH:27]=[CH:26][CH:25]=1.[C:35](=[O:38])([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O.[Cu]I>[OH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH:21]=[CH:22][C:17]([O:16][CH:13]4[CH2:14][CH2:15][N:10]([C:7]5[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=5)[CH2:11][CH2:12]4)=[CH:18][C:19]3=[O:23])=[N:24][C:33]=2[CH3:32])[C:35]1=[O:38]
Reactant: Oc1cccc2cccnc12
Reactant: O=C([O-])[O-]
Reactant: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Agent: [Cu]I
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(N5CCC(O)C5=O)c(C)n4)c(=O)c3)CC2)nc1
Temperature: 140 °C
Yield: 98 %

Procedure:
A 25 mL round bottom flask was charged with 4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (116 mg, 0.369 mmol) (prepared according to the procedure described in patent application WO-2009/012275), Intermediate 4 (120 mg, 0.443 mmol), quinolin-8-ol (21.4 mg, 0.148 mmol), potassium carbonate (66.3 mg, 0.480 mmol), copper(I) iodide (28.1 mg, 0.148 mmol) and DMSO (3 mL). The mixture was heated under Ar to 140° C. for 5 hours and then allowed to cool to room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and washed with H2O (100 mL). The organic layer was concentrated in vacuo to a brown oil, which was purified by flash chromatography (SiO2, 0 to 70% Acetone in CH2Cl2) to give example 5 (73.2 mg, 39% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.82 (dd, J=8.1, 5.5 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 6.09 (dd, J=7.8, 2.6 Hz, 1H), 6.02 (d, J=2.5 Hz, 1H), 5.75 (d, J=5.7 Hz, 1H), 4.69-4.84 (m, 1H), 4.28-4.38 (m, 1H), 4.11-4.26 (m, 2H), 3.57-3.74 (m, 2H), 3.40-3.54 (m, 2H), 2.40-2.47 (m, 1H), 2.31-2.40 (m, 5H), 1.91-2.07 (m, 3H), 1.45-1.65 (m, 4H), 0.87 (t, J=7.3 Hz, 3H). MS (ESI) 505 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]2)[O:4][N:3]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:15][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:7]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(c2cc(C)no2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2onc(C)c2Br)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (9.49 g, 48.6 mmol) in anhydrous DMF (50 mL) was added N-bromosuccinimide (10.31 g, 57.9 mmol). The reaction mixture was stirred at room temperature for 24 h. To the orange mixture was added water and the aqueous layer was extracted with MTBE (3×). The combined organic layers were washed with aqueous 10% sodium thiosulfate, water (2×) and dried to provide the product ethyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate (12.5 g, 45.6 mmol, 94% yield) as a light yellow oil. The product was used directly in the subsequent reaction without further purification. LC/MS m/z 274 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 40 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3-chloro-4-methylphenyl isocyanate (0.26 g, 1.6 mmol) and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at this temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.35 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.22 (s, 3H), 2.36-2.43 (m, 1H), 2.57-2.64 (m, 1H), 2.86-2.98 (m, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.40 (d, J=17.3 Hz, 1H), 4.54 (d, J=17.3 Hz, 1H), 5.15 (dd, J=13.1 Hz, J=5.0 Hz, 1H), 6.77 (t, J=5.6 Hz, 1H), 7.09-7.19 (m, 2H), 7.48-7.57 (m, 2H), 7.61-7.64 (m, 2H), 8.72 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.7, 22.6, 31.2, 39.7, 46.2, 51.6, 116.5, 117.7, 121.6, 127.5, 128.3, 130.4, 131.0, 131.7, 133.0, 135.5, 139.5, 139.9, 155.1, 168.1, 171.0, 172.8; Anal. calcd for C22H21ClN4O4.0.2H2O: C, 59.45; H, 4.85; N, 12.60. Found: C, 59.28; H, 4.83; N, 12.39.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:15]([Cu])#[N:16]>CN1CCCC1=O>[C:15]([C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)[nH]c1cnccc12
Yield: 6.7 %

Procedure:
A dark solution of example 1 (190 mg, 0.62 mmol) and CuCN (110 mg, 1.22 mmol) in N-methyl 2-pyrrolidone (1.5 ml) was heated in a sealed reaction tube at 200° C. for 48 h. The mixture was filtered and the filtrate was diluted with water (50 ml). A brown solid that precipitated was filtered, washed with water, saturated aqueous NaHCO3, and then methanol. This material was dissolved in DMSO and diluted with aqueous HCl. This homogeneous dark solution was decolorized with charcoal, filtered and concentrated to give a concentrated solution in DMSO. This DMSO solution was partitioned in (1:1) EtOAc-THF and saturated aqueous NaHCO3. The organic solution was dried (MgSO4) and concentrate to give 8 mg of 7-cyano-β-carboline.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.F[C:34](F)(F)[C:35]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:34]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:4]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1)[CH3:35]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1

Procedure:
4-[3-(3-Trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=463.3 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [NH4+:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:6]=[CH:7][S:8]([N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:10])=[O:9]>C1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:6]=[CH:7][S:8]([NH:11][C:12](=[NH:1])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: COc1ccc(C(Cl)=NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(=N)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Yield: 96 %

Procedure:
Ammonium gas is bubbled through a solution of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride (8.7 g., 0.02 mole) in 100 ml. of dry benzene for a period of 1 hr. The solvent evaporated under reduced pressure and the solid residue stirred with 50 ml. of water and filtered affords 8.0 g. (96% yield) of N-(3,4-DICHLOROSTYRYLSULFONYL)-3,4-DIMETHOXYBENZAMIDINE, m.p. 205°-210° C. A sample crystallized from acetonitrile has a melting point of 208°-211° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9]([O:11][CH2:12][CH2:13]OCCOCC)[CH3:10].C1(C(=CC=CC=1)O)O.C1(O)C=CC=CC=1>>[CH2:9]([O:11][CH:12]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:13])[CH3:10]
Reactant: Oc1ccccc1O
Reactant: CCOCCOCCOCC
Solvent: Oc1ccccc1
Product: CCOC(C)Oc1ccccc1O

Procedure:
127 parts by weight of pyrocatechol-[(1-ethoxy)-ethyl]-ether and 55 parts by weight of pyrocatechol are reacted and processed as described in Example 3(c). The yield is 179 parts of the phenol compound. The boiling point is 79° to 80° C. at 1 mm.
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2.[OH-].[K+]>CO.O>[O:4]=[C:5]1[CH2:3][CH:6]2[CH2:7][C:8]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9][CH:10]([CH2:11][CH:12]1[CH2:13]3)[CH2:14]2
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of diazomethane (Diazald, 3.97 mmol) was added dropwise to a cold (0° C.) solution of ketone 1C (0.886 mmol) and KOH (40 mmol) in MeOH (10 mL) and water (2 mL) over a period of 3 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The resulting white-grey suspension was concentrated and the residue was partitioned between water (10 mL) and DCM (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated to yield ketone 1D in 90% yield. The ketone was used in the next step without further purification. Data: LC/MS (ESR) m/z 280 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([OH:6])=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:4](=[O:6])[C:3]1[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:8][N:9]=[CH:10][C:2]=1[F:1]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Yield: 55.6 %

Procedure:
100 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (0.266 mmol, 1 eq.; Intermediate 1A) were suspended in 2 mL of DMF and then 28,754 mg 1,2-diaminobenzene (0.266 mmol, 1 eq.), 215,339 mg of HATU (0.566 mmol, 2.13 eq.) and 73,196 mg of N,N-Diisopropylethylamine (0.566 mmol, 2.13 eq.) were added and stirring was continued at 50° C. temperature for 18 h. The reaction mixture was partitioned between 20 ml of ethyl acetate and 20 ml of brine. The aqueouse layer was reextracted twice with 20 ml of ethyl acetate each. The combined organic layers were dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to afford 69 mg of the target compound in 72% UV-purity. This material was used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[C:4]=2[N:3]=[N:2]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[CH:23][N:24]([CH3:26])[CH3:25])[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[C:4]=2[N:3]=[N:2]1
Reactant: O=C(Cc1cccc2[nH]nnc12)c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cccc2[nH]nnc12

Procedure:
2-benzotriazolyl-1-(2,4-dichlorophenyl)ethan-1-one was dissolved in dimethyl-formamide dimethyl acetal (5 mL) and the solution refluxed for 8 h. Evaporation of the solvent gave 2-benzotriazolyl-1-(2,4-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one as an air sensitive red solid which was used in the next step without further purification.