Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[CH3:2].Cl[C:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1>>[CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:26]3[C:35]4[C:30](=[CH:31][C:32]([C:36]([F:39])([F:37])[F:38])=[CH:33][CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CCc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1CC
Product: CCc1cccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1CC

Procedure:
In the manner given in Example 1C, 1-(2,3-diethylphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(2,3-diethylphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[Br:23][C:24]1[C:29]([F:30])=[CH:28][C:27](O)=[C:26]([F:32])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[Br:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[C:26]([F:32])[CH:25]=1
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCOc2cc(F)c(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (2.24 g, 7.38 mmol) in DCM (35 ml) was added 4-bromo-2,5-difluorophenol (1.62 g, 7.75 mmol), 3.93 g of triphenylphosphine (polymer-bound, 3.0 mmol/g) and di-tert-butyl diazene-1,2-dicarboxylate (2.21 g, 9.60 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The solid was filtered off through celite and the filtrate was concentrated. The residue was purified on Biotage column (50 g SNAP silica gel) using a gradient 0-20% then 20% EtOAc in hexanes to afford the title compound as colorless viscous oil. LC/MS (m/z): 496.2 (M+H)+.
Reaction SMILES: [C:1]([N:4](C)[C:5]1[CH:6]=[C:7]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(=O)C)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=O)C.Cl>[OH-].[Na+]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][CH3:1])[CH:6]=2)(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc(N(C)C(C)=O)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNc1cccc(NS(=O)(=O)c2ccc(N)cc2)c1
Yield: 85.7 %

Procedure:
2.5 g (0.0069 mol) of N-[4-[3-(acetyl-methyl-amino)-phenylsulfamoyl]-phenyl]-acetamide were dissolved in 150 ml of 1N NaOH and boiled in reflux for 4 hours. Subsequently, the pH value was adjusted to 4 with 1N HCl and the precipitate which separated was filtered off. After drying the material on the suction filter was chromatographed on silica gel with 3% methanol with dichloromethane. There were obtained 1.64 g (85%) of 4-amino-N-(3-methylamino-phenyl)-benzenesulfonamide as a yellowish solid; m.p.: 134-135° C.
Reaction SMILES: [C:1]1([CH:7]([NH2:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=2)[C:17](C)=[C:16]1C>>[Br:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([NH:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CCC(N)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccccc2Br)c2ccc(C(=O)O)cc12
Product: CCC(NC(=O)c1ccc2c(ccn2Cc2ccccc2Br)c1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 4, Example 38, using 1-phenylpropan-1-amine instead of the (S)-1-(4-nitrophenyl)ethanamine hydrochloride, and 1-(2-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-bromobenzyl)-1H-indole-5-carboxylic acid. ESI-MS (m/z): 447/449 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In one embodiment, the compounds can be prepared as shown in Scheme II. A dihydroxy benzoic acid methyl ester is reacted with benzyl chloride, to produce a Bis-benzyloxy benzoic acid methyl ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl to produce a phenyl-benzamide (3). The phenyl-benzamide (3) is then reacted with hydrazine to give a triazol (4). The hydroxy groups can then be unprotected in the presence of palladium on charcoal to give the final product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:11]=1
Reactant: C1CCNCC1
Reactant: CSc1nc(Cc2ccc(Cl)c(Cl)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCCC2)nc(Cc2ccc(Cl)c(Cl)c2)[nH]c1=O

Procedure:
100 mg (0.34 mmol) of 2-(3,4-dichlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are stirred with 261 mg (3.07 mmol) of piperidine at 85° C. for 16 h. After removal of the volatile constituents in vacuo, the residue is purified by preparative HPLC. 42 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([NH2:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([NH:40][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:31][CH:32]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 47 %

Procedure:
The title compound was prepared in a yield of 47% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and α-(4-methoxyphenyl)benzylamine.
Reaction SMILES: [CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CN(C)C1(Cc2ccccc2)CC=C(c2[nH]c3ccccc3c2CCCC(=O)O)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(Cc2ccccc2)CCC(c2[nH]c3ccccc3c2CCCC(=O)O)CC1

Procedure:
Palladium as the catalyst (Pd/C, 5%, 120 mg) was added to 4-[2-(4-benzyl-4-dimethylaminocyclohex-1-enyl)-1H-indol-3-yl]butanoic acid (300 mg, 0.7 mmol) in abs. methanol (30 ml) and hydrogenation was carried out at RT for 6 h (hydrogen pressure: 3 bar). The catalyst was removed with the aid of a frit provided with a layer of Celite 1 cm high. The residue was rinsed thoroughly with methanol (500 ml). The solvent was distilled off in vacuo. 4-(2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)butanoic acid was obtained in a yield of 260 mg (86%) as a yellow solid (one of the two possible diastereoisomers).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])/[CH:25]=[CH:26]/[O:27]C)[C:5]1=[O:31])[CH:2]=[CH2:3].Cl>C(#N)C>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[CH2:25][CH:26]=[O:27])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](/C=C/OC)CC)C1=O
Agent: Cl
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride was dried at 80° C. under vacuum for 3 h. To a solution of the dried (methoxymethyl)triphenylphosphonium chloride (1.96 g, 5.71 mmol) in THF (10 mL) was added 0.5 M KHMDS in toluene (10.2 mL, 5.08 mmol) at −78° C. The color of the solution turned blood red in color. After stirring at 0° C. for 30 min., a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C; 564 mg, 1.27 mmol) in THF (10.1 mL) was added at 0° C. dropwise. After being stirred at rt for overnight, the reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography on silica gel (SiO2, 40 g, 15% and 20% EtOAc/Hexanes) provided the vinyl ether (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-methoxypent-1-en-3-yl)-3-methylpiperidin-2-one. To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-methoxypent-1-en-3-yl)-3-methylpiperidin-2-one prepared above in acetonitrile (7.8 mL) was added 3 N hydrochloric acid (4.4 mL, 13 mmol) and the resulting solution was stirred at rt for 1.5 h. Then, the reaction was extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale yellow film.
Reaction SMILES: [ClH:1].C1C2C(=CC=CC=2)CCN1CCCC[N:16]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[C:23]=2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30].BrCCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O.BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[C:17]1(=[O:30])[C:18]2[C:23]3[C:22](=[CH:29][CH:28]=[CH:27][C:24]=3[C:25](=[O:26])[NH:16]1)[CH:21]=[CH:20][CH:19]=2
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCc2ccccc2C1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Product: O=C1NC(=O)c2cccc3cccc1c23

Procedure:
Following the procedure of part (b) of example 39 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-(3,4-dihydro)-2(1H)-isoquinolinyl)-pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21]C[N:19]([C:22]([O:24][C:25]([CH3:28])(C)C)=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].Cl[C:38]1[N:39]=[C:40](N2CCOC[C@@H]2C)[C:41]2CN(C(OCC)=O)CC=2N=1.N1C=CC(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][C@@H:30]1[N:29]([C:14]2[C:15]3[CH2:21][N:19]([C:22]([O:24][CH2:25][CH3:28])=[O:23])[CH2:18][C:16]=3[N:17]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:4]([NH:3][C:1]4[CH:41]=[CH:40][N:39]=[CH:38][CH:2]=4)=[O:36])=[CH:7][CH:8]=3)[N:13]=2)[CH2:34][CH2:33][O:32][CH2:31]1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)cc2)OC1(C)C
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 49 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 1-(pyridin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (low pH) yielding the title compound (38.2 mg, 0.08 mmol, 49%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C=O.O>[C:12]([C:11](=[C:15]([OH:17])[CH3:16])[C:10]([O:9][CH2:7][CH3:8])=[O:14])#[N:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C#N)=C(C)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcyanoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3×100 ml). Combined organic layer was washed with saturated sodium carbonate solution (3×100 ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3×100 ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].[CH3:20][C:21]1[N:22]=[C:23]([CH3:44])[N:24]2[C:29]=1[C:28](N1C=NC=N1)=[N:27][C:26]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)=[N:25]2>O1CCCC1>[CH3:20][C:21]1[N:22]=[C:23]([CH3:44])[N:24]2[C:29]=1[C:28]([O:19][C:11]1[CH:12]=[C:13]([O:17][CH3:18])[C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=1)=[N:27][C:26]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)=[N:25]2
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)nc(-n3cncn3)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Oc2nc(-c3cccc([N+](=O)[O-])c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
A solution of 175.17 mg (1.04 mmol) of potassium tert-butoxide and 287.53 mg (1.56 mmol) of 3,4,5-trimethoxyphenol in 20 ml of tetrahydrofuran is stirred for 30 min. 350 mg (1.04 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine from example 12A are added thereto and the mixture is heated for 2 h to 70° C. After cooling, the solvent is removed and the residue is taken up and extracted with dichloromethane and 1N sodium hydroxide solution. The organic phase is separated off, dried and the crude product is purified by flash chromatography. (Eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=1.[C:18]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=1)=[O:31])SC)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.C(N(CC)CC)C>[C:18]([O:22][C:23]([NH:25][C:26]([NH:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=1)=[O:31])=[N:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[CH:7][CH:8]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CSC(=NC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Reactant: CN(C)CCOc1ccc(CCCCN)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(CCCCN=C(NC(=O)OC(C)(C)C)NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
A suspension of compound 63 (0.22 g, 0.93 mmol) and 64 (0.33 g, 0.92 mmol) in THF/triethylamine (11 mL, 10/1) was stirred at room temperature for 48 h. After this time, a clear solution was formed. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 10:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) to provide the guanidine 65 (0.3 g, 60%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.19 (s, 6H), 2.58 (m, 4H), 3.99 (m, 2H), 6.83 (d, 2H), 7.12 (d, 2H), 7.40 (br s, 2H), 9.02 (m, 2H).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:14]([C:16]([CH3:18])=[O:17])[CH3:15]>CCOCC>[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:14]([CH3:15])[C:16](=[O:17])[CH3:18])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCC(C)=O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
300 g of 32% hydrochloric acid are added dropwise at 15°-20° C. over a period of 1 hour to a mixture of 300 g of p-tert.-butyl-benzaldehyde and 300 g of methyl ethyl ketone and the mixture is left to stir at room temperature for 22 hours. Subsequently, the mixture is taken up in 200 ml of ether, washed with water and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. By fractional distillation there is obtained pure 4-(p-tert.butyl-phenyl)-3-methyl-3-buten-2-one of boiling point 120° C./0.03 Torr.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C[N:13](C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:13])=[O:7]
Reactant: CSc1cccc(C(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CSc1cccc(C(N)=O)c1
Temperature: 120 °C

Procedure:
10 g of 3-methylsulfanylbenzoic acid and 0.05 ml of DMF were suspended in 50 ml of DCM. 9 ml of thionyl chloride were added and the mixture was heated under reflux for 4 h. The volatiles were removed in vacuo and the residue was taken up in 30 ml of toluene and transferred to a pressure bottle. 180 ml of a 0.5 M solution of ammonia in dioxane were added, the bottle was sealed and the mixture was heated to 120° C. for 5 h. The solvent was removed in vacuo and the residue taken in water and EA. The phases were separated and the aqueous layer was extracted with EA. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 8.6 g of the title compound were obtained as a brown solid.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)CC(N)c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)-propionic acid was substituted with 3-amino-3-(4-chlorophenyl)propionic acid. 1H NMR (CDCl3): δ 7.24-7.32 (m, 5H), 4.38 (t, 1H, J=5 Hz), 3.65 (s, 3H), 2.61 (d, 2H, J=5 Hz), 1.80 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:26][CH3:27])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(4-chlorophenyl)-3-(4-hydroxybenzoyl)benzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:10][O:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH:10]=[O:9])=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(I)cc2)CO1
Solvent: Cc1ccccc1
Product: CC(C=O)c1ccc(I)cc1
Yield: 83.3 %

Procedure:
To a solution of 15 g of 2-(4-iodophenyl)-2-methyloxirane in 75 ml of toluene was added 1.5 g of powdered Molecular Sieves 4A and the mixture was heated under reflux for 4 hours. After completion of the reaction, the Molecular Sieves was removed by filtration and the filtrate was concentrated and then distilled under reduced pressure to obtain 12.5 g (83% yield) of 2-(4-iodophenyl)propionaldehyde in oily form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:5]([NH:7][NH:8][C:9]([NH2:11])=[S:10])=O.N>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[S:10][C:9]([NH2:11])=[N:8][N:7]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: NC(=S)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(3-Fluoro-4-nitrobenzoyl)thiosemicarbazide (6.6 g, 26 mmol) was dissolved in 30 mL concentrated sulfuric acid and stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of 40 mL 33% aqueous ammonia and 200 mL ice with stirring. The resulting solution was adjusted to pH 8 with an additional amount of the ammonia solution. An orange solid formed during the process. The product was obtained as a yellow solid after filtering, washing with water, and drying in a vacuum for 24 hours at 50° C. LCMS (API-ES) m/z (%): 241.1 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (bs, 3H) 7.93 (d, J=12.32 Hz, 1H) 8.22 (t, J=8.12 Hz, 1H).