Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:61])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:60])[CH2:30][N:31]([CH2:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([N:55]4[CH:59]=[N:58][N:57]=[CH:56]4)=[CH:51][CH:50]=3)S(C3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)(=O)=O)([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C(N)CC>>[CH:4]12[N:7]([C:8](=[O:61])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:60])[CH2:30][NH:31][CH2:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([N:55]4[CH:59]=[N:58][N:57]=[CH:56]4)=[CH:51][CH:50]=3)([CH3:11])[CH3:10])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN(CCc2ccc(-n3cnnc3)cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Solvent: CCCN
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNCCc2ccc(-n3cnnc3)cc2)c1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To a solution of (S)-N-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}-2,4-dinitro-N-[2-(4-[1,2,4]triazol-4-yl-phenyl)ethyl]benzenesulfonamide (0.246 g in 5.5 mL dry methylene chloride) was added 0.72 mL of n-propylamine and the mixture stirred at room temperature. After 35 minutes the volatiles were removed in vacuo and the concentrate purified by flash chromatography on silica gel (methylene chloride:methanol, 90:10; then 85:15) to give the title compound (0.180 g). MASS: 615 (M+H)
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(Cl)nc(Cl)n2)c(C)c1
Reaction time: 3 h

Procedure:
Cyanuric chloride (1.84 g) was allowed to react with 1.9 eq of m-xylene and 2.5 eq (3.35 g) of AlCl3 in 25 mL of chlorobenzene at 5° C. for 0.5 h and then at room temperature for 3 h. Analysis by HPLC, after 2.5 h, showed that less than 8% of cyanuric chloride had reacted to form only 2,4-dichloro-6-(2,4-dimethylphenyl)-1,3,5-triazine, no 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine or 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine were present. The reaction was allowed to continue at room temperature. After 24 hours, HPLC analysis showed about 51% cyanuric chloride conversion and formation of 2,4-dichloro-6-(2,4-dimethylphenyl)-1,3,5-triazine and 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine in the ratio of 95:5, respectively. No 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine was detected.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.O>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(I)cc2)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of n-butyllithium (2.59M, in hexane) (8.76 ml) was added dropwise to a solution of 1,4-diiodobenzene (7.49 g) in anhydrous THF (50 ml) at −78° C., and the resulting mixture was stirred at −78° C. for 30 minutes. Tetrahydro-4H-pyran-4-one (2.09 ml) was added dropwise thereto and the resulting mixture was stirred at −78° C. for 1.5 hours. After stirring the mixture for another 3 hours at room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from cyclohexane/ethyl acetate mixed solvent to obtain tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (4.12 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][N:4]=1.FC(F)(F)C1C=CC(C(O)=O)=CN=1.ClCC1OC(C2(C)CCCCC2)=NC=1C.ClCC1SC(C2CCC(F)(F)CC2)=NC=1COC.[CH3:60][O:61][C:62](=[O:70])[CH:63](Cl)[C:64](=O)[CH2:65][O:66][CH3:67]>C(O)C>[CH3:60][O:61][C:62]([C:63]1[S:8][C:7]([C:6]2[CH:5]=[N:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:11][CH:10]=2)=[N:9][C:64]=1[CH2:65][O:66][CH3:67])=[O:70]
Reactant: NC(=S)c1ccc(C(F)(F)F)nc1
Reactant: COCC(=O)C(Cl)C(=O)OC
Agent: COCc1nc(C2CCC(F)(F)CC2)sc1CCl
Agent: Cc1nc(C2(C)CCCCC2)oc1CCl
Agent: O=C(O)c1ccc(C(F)(F)F)nc1
Solvent: CCO
Product: COCc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(=O)OC
Yield: 11.2 %

Procedure:
10.5 g 6-Trifluoromethyl-thionicotinamide (derived from 6-Trifluoromethyl-nicotinic acid according to the method described for 5-Chloromethyl-4-methyl-2-(1-methyl-cyclohexyl)-oxazole and 5-Chloromethyl-2-(4,4-difluoro-cyclohexyl)-4-methoxymethyl-thiazole) and 10.0 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 100 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by RP-HPLC to obtain 1.9 g 4-Methoxymethyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[Cl:9]
Reactant: Clc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reaction time: 1 h

Procedure:
2723 gm (15.0 mols) of 1,2,4-trichlorobenzene were added to 7350 gm (105 mols) of 90% fuming nitric acid at 40° C. over a 3 hour period. The reaction mixture was held at 40° C. for one hour and worked up by the addition of 3700 ml of H2O while maintaining a temperature of 55°-60° C., and separating the waste acid. Two additional washes with 2000 ml of hot (55° C.) water and 1000 ml of 10% sodium bicarbonate solution followed by a phase separation gave 3316 gm (14.64 mols) of crude 1,2,4-trichloro-5-nitrobenzene. An additional 33 gm product was recovered from the waste acid when cooled and filtered.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[C:39]([C:33]1[CH:34]=[N:35][C:36]2[C:31]([C:32]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1)=[CH:30][C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:38][CH:37]=2)#[N:40]
Reactant: O=C(O)C#CCN1CCCCC1
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CCN4CCCCC4)cc23)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Partially dissolved 1.21 (7.22 mmol) 4-piperidino-2-butynoic acid in 100 ml THF and chilled to 0° C. under N2. Added 955 μl (8.67 mmol) N-methylmorpholine and 750 μl (5.78 mmol) isobutyl chloroformate. Stirred for 40 minutes and added a solution of 840 mg (2.89 mmol) 6-amino-4-[(3-methoxyphenyl)amino]-3-quinolinecarbonitrile dissolved in 10 ml hot pyridine. At 2 hours, poured into ice water and made basic with saturated sodium bicarbonate. Extracted with ethyl acetate, dried with sodium sulfate, and stripped down to a small volume, which was loaded onto a column of silica gel. Eluted with 10% methanol/ethyl acetate, stripped solvent of desired fractions, and dried in vacuo, giving 970 mg of green solid: mass spectrum (electrospray m/e): M+H=440.1.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][C@H:4]2[CH3:23].[OH:24][CH2:25][C@@:26]12[C@@H:43]3[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[C:38](=[O:44])[CH2:37][CH2:36]4)[CH2:33][C@H:32]([CH3:45])[C:31]1=[CH:30][C:29](=[O:46])[CH2:28][CH2:27]2.[CH3:47]OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2>>[CH3:25][O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][C@H:4]2[CH3:23].[CH3:47][O:24][CH2:25][C@@:26]12[C@@H:43]3[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[C:38](=[O:44])[CH2:37][CH2:36]4)[CH2:33][C@H:32]([CH3:45])[C:31]1=[CH:30][C:29](=[O:46])[CH2:28][CH2:27]2
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Product: COC[C@@]12C(=CC(=O)C[C@H]1C)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COC[C@]12CCC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Using essentially the same procedure but substituting 19-hydroxy-1β-methyl-4-androstene-3,17-dione and 19-hydroxy-6α-methyl-4-androstene-3,17-dione for the 19-hydroxyandrost-4-ene-3,17-dione above results in the formation of 19-methoxy-1β-methyl-4-androstene-3,17-dione and 19-methoxy-6α-methyl-4-androstene-3,17-dione.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:63]([O:67][C:68]([C:70]1[N:71]([CH3:76])[C:72]([NH2:75])=[CH:73][CH:74]=1)=[O:69])([CH3:66])([CH3:65])[CH3:64]>>[C:63]([O:67][C:68]([C:70]1[N:71]([CH3:76])[C:72]([NH:75][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:73][CH:74]=1)=[O:69])([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Cn1c(N)ccc1C(=O)OC(C)(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC(C)(C)C
Yield: 35.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with 5-amino-1-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester prepared in Example 193 (0.15 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester as a yellow solid (Yield 0.12 g, 36%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[N+:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Yield: 70.5 %

Procedure:
To 20 g (0.1 mole) of 4-phenylmethoxy-phenol in 200 ml acetic acid were added, dropwise at room temperature, 7.26 ml of nitric acid (d=1.4, 0.105 mole). 2 Hours after completion of the addition the reaction medium was poured onto cold water and extracted twice with 250 ml of methylene chloride. The organic phase was washed twice with 200 ml of water and dried over sodium sulfate. Then the solvent was evaporated and the residue flash chromatographed using ethyl acetate/heptane 30/70 as eluting solvent to give 17.3 g (Yield=70.6%) of 2-nitro-4-phenylmethoxy-phenol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
70.4 mg of the target compound (0.21 mmol, 47.7%) was obtained using 1-(4-methylphenyl)piperazine (155 mg, 0.88 mmol), biphenyl-2-carbaldehyde (80 mg, 0.44 mmol) and NaBH(OAc)3 (284 mg, 1.32 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[I:22]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([I:22])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(I)n1-2
Temperature: 0 °C

Procedure:
A stirred mixture of 0.339 gm (1 mmol) of 8-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 25 ml of benzene was treated with 0.242 gm (1.1 mmol) of N-iodosuccinimide and refluxed under nitrogen for 12 hr and 40 min. The mixture was cooled and was then mixed with ice water containing sodium bicarbonate and sodium chloride and was finally extracted with methylene chloride. The extract was washed with dilute sodium chloride, dried with sodium sulfate and concentrated in vacuo. The residue was crystallized from methylene chloride-methanol to yield one batch of 0.252 gm, which melted with decomposition between 209° and 212.5° C. and another batch of 0.020 gm which melted with decomposition between 196° and 198.5° C. A portion of the first batch was recrystallized twice by being dissolved in almost pure methylene chloride to which methanol was slowly added during concentration. After this recrystallization, the title product melted with decomposition between 200° and 207° C. Another sample for analysis was prepared by essentially the same procedure and, after recrystallization from methylene chloride-methanol, molded with decomposition between 216° and 219° C. Analysis of the product for carbon, hydrogen and nitrogen showed C: 41.04%, H: 2.11%, N: 12.10%. Calculated values for such an analysis of the product are: C: 41.31%; H: 2.16% and N: 12.05%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: BrCCCCCCCCCBr
Product: CN1CCN(CCCCCCCCCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)CC1

Procedure:
The compound was prepared by a method similar to Example 2 from 6-hydroxyflavone, 1,9-dibromononane and 4-methyl piperazine: mp 77°-80° C.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:23]([O-:25])=[O:24])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl.[CH3:47][NH:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl>[CH:49]1([N:48]([CH3:47])[C:6](=[O:8])[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: N#CC(CCC(=O)O)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CNC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Reaction time: 16 h

Procedure:
4-cyano-5-(2-nitro-5-phenoxy-phenyl)-pentanoic acid (0.230 g, 0.68 mmol) was dissolved in dichloromethane (1.5 mL) followed by addition of HOBt (0.103 g, 0.68 mmol), triethylamine (0.170 mL, 0.68 mmol), EDC (0.194 g, 1.01 mmol) and N-methyl-cyclohexylamine (0.09 mL, 0.68 mmol). The reaction was allowed to proceed for 16 h after which time, the solvent was removed under reduced pressure. The resulting mixture was dissolved in ethyl acetate and washed 3 times with 10% sodium carbonate solution, one time with saturated brine solution, 3 times with 1N HCl and then again one time with brine wash. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield a residue. The residue was purified with flash chromatography using a mixture of 65:35 heptanes:ethyl acetate as the mobile phase to yield a residue.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)([CH3:14])[CH2:12][OH:13].C[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:25]1([S:28]([O:13][CH2:12][C:11]([CH3:10])([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH3:14])(=[O:30])=[O:29])[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(CO)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)c1ccccc1)c1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
710 μl (4.07 mmol) of N,N-diisopropylethylamine and 33.13 mg (0.27 mmol) of 4-dimethyl amino pyridine are added to a solution of 410 mg (2.71 mmol) of 2-methyl-2-pyrid-4-ylpropan-1-ol in 10 mL of dichloromethane. The mixture is cooled to 0° C. and a solution of 775.42 mg (4.07 mmol) of 4-methylbenzene-1-sulfonyl chloride in 2 mL of dichloromethane is then added. After allowing the reaction medium to warm to room temperature and stirring overnight, it is washed with water and with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 660 mg of 2-methyl-2-pyrid-4-ylpropyl benzenesulfonate, corresponding to the following characteristics:
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3]C.[CH:7](=O)[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C.Cl[CH2:20]Cl>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:20][O:6][CH:1]([O:2][CH3:3])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7]
Reactant: CCCCCCCCC=CC=O
Reactant: CCOC([O-])[O-]
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCCCCCCCCC(OC)OC
Yield: 97 %

Procedure:
37.78 g of ethyl orthoformate (13.09 ml, 356 mmol, 2 eq.) and 1.691 g of para-toluenesulfonic acid (catalytic amount: 8.9 mmol, 0.051 eq.) are added to a solution of 30.05 g of 97% undecenal (37.10 ml, 173 mmol) dissolved in 500 ml of methanol. The reaction takes place over 12 hours and at reflux of the methanol. After addition of 500 ml of dichloromethane, the reaction mixture is washed successively with a 1% sodium carbonate solution (two times) and with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated to give 36.39 g of a brown liquid with a yield of 97%.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH3:2].[CH3:9][S:10]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][C:20]=1[NH2:29])(=[O:12])=[O:11].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:18]([CH2:17][CH2:16][O:15][CH2:14][CH2:13][S:10]([CH3:9])(=[O:12])=[O:11])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1
Reactant: COC(C)(OC)OC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Yield: 70.9 %

Procedure:
Trimethyl orthoacetate (1 g, 8.1 mmol) was added to a mixture of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (˜2.3 g, ˜7.4 mmol) and toluene (45 mL). Pyridine hydrochloride (0.25 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. Pyridine was added to help solubilize the starting material. After 2 hours the reaction mixture was concentrated under reduced pressure to provide a dark oil. This material was purified by column chromatography (silica gel eluting sequentially with 95/5 dichloromethane/methanol and 9/1 dichloromethane/methanol) to provide 1.75 g of 2-methyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as a white foam.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[NH:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]([OH:45])=O)=[CH:42][C:36]=3[N:35]=2)=[N:26]1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CS(C)=O>[CH2:46]([NH:53][C:43]([C:41]1[CH:40]=[CH:39][C:37]2[NH:38][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][N:26]=3)=[N:35][C:36]=2[CH:42]=1)=[O:45])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CS(C)=O
Product: O=C(NCc1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 27.3 mg of HBTU in 0.2 ml of dimethylformamide is added, at a temperature in the region of 20° C., to a solution of 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid in 0.42 ml of anhydrous dimethylformamide. After stirring at a temperature in the region of 20° C. for one hour, 15.7 ml of benzylamine are added, followed by addition of 12.4 ml of N,N-diisopropylethylamine dissolved in 0.32 ml of dimethylformamide. After 20 hours, at a temperature in the region of 20° C., the reaction medium is concentrated under reduced pressure, at a temperature in the region of 40° C. The crude residue obtained is dissolved in DMSO and purified by preparative LC-MS. The fractions containing the desired product are combined and concentrated under reduced pressure at a temperature in the region of 40° C. 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-Carboxylic acid benzylamide are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows: