Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:11][C:22](=[O:23])[O:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cccc(-c2ccccc2)c1
Yield: 58.5 %

Procedure:
11.18 g of 3-phenylbenzylamine in toluene (250 ml) was mixed with 7.24 g of pyridine at room temperature. The resulting solution was stirred under cooling with ice while 9.58 g of methyl chloroformate was added dropwise and then stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into aqueous citric acid and extracted with ethyl acetate, and the organic layer was washed with aqueous citric acid, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 8.61 g of methyl N-(3-phenylbenzyl)carbamate as pale yellow crystals. m.p. 49-52° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH3:29])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6].[O:32]1[C:34]([CH3:36])([CH3:35])[CH2:33]1.[OH-].[K+]>CN(C=O)C>[OH:32][C:34]([CH3:36])([CH3:35])[CH2:33][O:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH3:29])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6]
Reactant: CC1(C)CO1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCC(C)(C)O)ccc21
Yield: 4.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-2-methyl-propoxy)-ethyl]-amide (5 mg) was prepared by following General Procedure X starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (100 mg), 1,2-epoxy-2-methyl-propane (19 mg), and KOH (19 mg) in DMF. LC/MS: m/z 524.7.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=1[Cl:19].[CH3:21][S:22]([CH3:24])=[O:23].C1COCC1>C1COCC1>[Cl:19][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:20])[CH2:21][S:22]([CH3:24])=[O:23]
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Reactant: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)CS(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid methyl ester (3.3 g, 10.6 mmol) is dissolved in 30 ml of dry THF and added to a solution of dimsyl anion (JACS, 84, 866, 1982) (31.9 mmol) in 60 ml of 1:1 DMSO/THF at 0° C. under argon. When addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for five hours. The reaction is quenched with 400 ml of 1N hydrochloric acid, and extracted twice with 300 ml of chloroform. The combined chloroform extract is washed with 300 ml of water three times, and once with 300 ml of brine. This chloroform layer is dried over magnesium sulfate and evaporated. The residue solidifies after being dried at room temperature under vacuum for 12 hours. Recrystallization from methylene chloride in hexane gives 1.0 g of 1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone (26% yield); mp 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[I:17]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[I:17]
Reactant: II
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cncc(Cl)c1I
Reaction time: 1 h

Procedure:
To a stirred solution of 3,5-dichloropyridine (3.0 g, 20.4 mmol) in THF (15 mL) was added LDA (2.0 M solution in THF/heptane/ethylbenzene, 12.14 mL, 24.4 mmol) dropwise at 0° C. and the mixture was stirred at the same temperature for 1 h. A solution of iodine (2.7 g, 21.4 mmol) in THF (10 mL) added dropwise to above mixture. Upon completion of addition, the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound B15-1 (3.2 g, 57%) as a yellow gum.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([C:22]([OH:24])=O)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[C:2]=1[C:10]([OH:12])=[O:11].C(OC(=O)C)(=O)C>>[CH:5]1[CH:4]=[C:3]2[C:7]([O:11][C:10](=[O:12])[C:2]2=[C:1]([C:13]2[CH:18]=[CH:17][C:16]3[C:19]([O:21][C:22](=[O:24])[C:15]=3[CH:14]=2)=[O:20])[CH:6]=1)=[O:8]
Reactant: O=C(O)c1ccc(-c2cccc(C(=O)O)c2C(=O)O)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(-c3cccc4c3C(=O)OC4=O)ccc21
Temperature: 25 °C
Yield: 90.1 %

Procedure:
2,3,3′,4′-Biphenyltetracarboxylic acid (4) (33 gm, 100 mmol) was suspended in minimum amount of acetic anhydride and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature. The corresponding dianhydride precipitated out and was collected and washed with ether to remove trace of acetic acid before drying under vacuum to afford 26.5 g (90%) of a-BPDA. Mp=195-196° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:25][N:26]=[C:27]=[O:28]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:27](=[O:28])[NH:26][CH3:25])=[CH:9][CH:8]=1
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)OCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a sealed glass tube, a solution of 1.0 g of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [Example 25b)], 0.03 ml of triethylamine and 0.245 g of methyl isocyanate in 40 ml of dichloromethane was heated at 40° C. for 3 d. At that time a transformation rate of 50% was reached, determined by NMR. For the working-up, the reaction mixture was cooled and evaporated. The residue was dissolved in 2 ml of pyridine and 1 ml of acetic acid anhydride and the solution stirred at room temperature for 3 h. Thereafter, the mixture was evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 2:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 580 mg (47% of theory) of methyl-carbamic acid 4-(3-fluoro-benzyloxy)-benzyl ester as a white solid; MS: m/e=289 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[C:27]([Si:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>>[Si:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCCl
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCO[Si](C)(C)C(C)(C)C)cc3C)cc12

Procedure:
2-(4-(2-(2-(Tert-butyldimethylsilyloxy)ethoxy)ethoxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared following an analogous procedure to the preparation described for Example 145/Step 1, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with tert-butyl(2-(2-chloroethoxy)ethoxy)dimethylsilane.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:9]2[C:10]([CH3:20])=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:7][N:8]=1.C1C(=O)N([Cl:28])C(=O)C1>C(Cl)(Cl)Cl>[Cl:28][C:7]1[N:8]=[C:4]([CH2:3][O:2][CH3:1])[NH:5][C:6]=1[C:9]1[C:10]([CH3:20])=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COCc1ncc(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 5-(2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 230.5, 70 mg, 0.26 mmol) in chloroform (6 mL). NCS (35 mg, 0.26 mmol) was added to the reaction. The reaction mixture was stirred overnight at room temperature, then quenched with 1 mL of water. The aqueous phase was extracted with 2×5 mL of dichloromethane and the combined organic layers were concentrated under reduced pressure. The residue was applied onto a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to yield 30 mg (38%) of the title compound as a white crude solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)#[CH:10].O>C(N(CC)CC)C>[CH3:19][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: Nc1ncccc1Br
Reactant: C#Cc1ccc(C(C)C)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Yield: 46.6 %

Procedure:
A mixture of bis(triphenylphosphine)palladium(0)dichloride (0.811 g), 3-bromopyridin-2-amine (2 g), 1-ethynyl-4-isopropylbenzene (1.667 g) and copper iodide(I) (0.22 g) in triethylamine (38.6 mL) was heated under reflux. Water was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1273 mg) as a pale-yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31]O.C(Br)(Br)(Br)[Br:34]>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][Br:34]
Reactant: OCCc1c[nH]c2ccc(Br)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 11.5 g of triphenylphosphine in 60 ml of dichloromethane is added to a solution, cooled to 0° C., of 4 g of the compound obtained in Step 1 and 7.5 g of carbon tetrabromide in 100 ml of dichloromethane. After stirring for 48 hours at ambient temperature, the reaction mixture is concentrated in vacuo. The residue obtained is chromatographed on silica gel (dichloromethane/cyclohexane: 80/20), enabling the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: O=S(=O)(O)O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)NCC2
Temperature: -20 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of 6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone (3.4 g, 17.8 mmol) in H2SO4 (45 mL) at −20° C. was added HNO3 (1.58 mL, 21.3 mmol) dropwise. The mixture was allowed to stir for 3 h at −20° C. The mixture was poured into ice water and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure to give 6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (3.0 g, 71%). 1H NMR (CDCl3) δ 8.55 (1H), 6.88 (1H), 6.2 (1H), 4.0 (3H), 3.6 (2H), 3.05 (2H).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[OH:1])[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: Cl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid 10.0 g (55 mmol) in ethanol 100 mL was added dropwise 2 mL of conc. HCl, followed by stirring for 24 hrs under reflex. The mixture was cooled to room temperature, concentrated in a vacuum, and diluted with ethyl acetate. This dilution was washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated NaCl solution, dried over magnesium sulfate and concentrated in a vacuum. The concentrate was purified using column chromatography (developing solvent: ethylacetate/hexane=1/4) to afford the title compound 10.0 g (yield 86%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:8])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: ClCc1ccccc1
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(methylthio)-benzaldehyde and benzyl chloride by the same method as described in Step 1 of Example 4.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([F:37])[F:38])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(O)cc(F)c2)N1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(F)(F)F)[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 65.7 %

Procedure:
Add acetic anhydride (0.142 mL, 1.51 mmol) to an ice cold solution of (2S,3S,5R)-5-[(1S,2S)-2-Amino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-3-methyl-2-(2,2,2-trifluoro-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (823 mg, 1.43 mmol) in dichloromethane (9 mL). Stir for 50 minutes and add diisopropylethylamine (0.125 mL, 0.717 mmol) and stir for 2 hours. Quench with aqueous 1N hydrochloric acid, wash with saturated aqueous sodium bicarbonate, dry with magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound (493 mg). MS(ESI): m/z=525 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:29])[CH3:28]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:29][CH2:27][CH3:28])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCN
Solvent: CC#N
Product: CCNCC1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.7 g, 1.8 mmol), ethanamine (1 ml, 70% in water) and ACN (3 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on flash column chromatography and on SCX-3 column (TEA/MeOH). Yield: 0.4 g, 72%. The amine was converted to the hydrochloric acid salt and was crystallized from MeOH/Et2O. M.p. 261° C. MS m/z (rel. intensity, 70 eV) 271 (M+, 19), 226 (4), 207 (9), 79 (6), 58 (bp).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[SH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([S:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reactant: CCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
Propyl iodide (0.37 g) was added to a solution of ethyl 2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1N NaOH (4.0 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless prisms (0.4 g, 40%), m.p. 177-178° C. (decomp.).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.C(OC(C1C=NC2C(C=1[Cl:37])=NC(F)=CC=2)=O)C>>[Cl:37][C:4]1[C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:14]=[C:5]3[C:10]=2[CH:11]=[CH:2][N:3]=1
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3c(Cl)nccc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for synthesis for 5a using 15 instead of 4a. 1H-NMR (DMSO-d6) δ (ppm): 7.16 (1H, m), 7.44 (2H, dd, J=8.6, 7.6 Hz), 8.09 (1H, d, J=5.3 Hz), 8.14 (2H, dd, J=8.5, 1.1 Hz), 8.37 (1H, d, J=5.2 Hz), 8.51 (1H, s). m/z 297.7 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccnc(N)n1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2nccc(C)n2)c1=O
Temperature: 50 °C
Reaction time: 120 h
Yield: 11.3 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 2-amino-4-methylpyrimidine (46 mg, 0.417 mmol) was added. The resulting mixture was stirred at 50° C. during five days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (11 mg, 11.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:41])[C:12](=[CH:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:42]>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:42]
Reactant: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Yield: 91.2 %

Procedure:
To a solution of 2-chloro-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido-[1,2-a]indol-6(7H)-one (0.95 g) in acetic acid (47.5 ml) was added zinc powder (1.09 g) and the mixture was refluxed for 2.5 hours. The resulting precipitates were filtered off, and the filtrate was evaporated in vacuo. The residue was diluted in chloroform, washed with aqueous sodium bicarbonate, solution, water, and brine, dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform-methanol (0-5% V/V), to give 2-chloro-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.50 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:9][N:4]2[CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1.CCCCCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:7]=[C:5]3[N:4]([CH:9]=2)[CH:3]=[C:2]([C:22]([OH:24])=[O:23])[S:6]3)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cn2cc(-c3ccc(F)cc3)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a solution of 2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole (example 22, 100 mg, 0.336 mmol) in 5 ml THF were added 200 μl butyllithium (2.5 M) in hexane at −60° C. The mixture was stirred for 10 min, solid carbon dioxide was added and the mixture was allowed to warm at RT. The solution was quenched with methanol and water, acidified and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg (10%) of the desired product. MS: M+H+=263.03.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.CN(C)C=O>[CH2:25]([N:21]1[CH2:20][C:19](=[O:32])[N:18]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:23]([CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:22]1=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1C(C(c2ccccc2)c2ccccc2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran) (77 ml) was added portionwise to a stirred solution of 1,4-dibenzyl-2,5-piperazinedione (20.6 g) in a mixture of tetrahydrofuran (400 ml) and N,N-dimethylformamide (200 ml) at 0° C. The whole was stirred at 5° C. for 1 hour and thereto a solution of bromodiphenylmethane (19 g) in tetrahydrofuran (100 ml) was added at −78° C. and the mixture was stirred for 2 hours at the same temperature. After being stirred at 5° C. for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with a mixed solvent of ethyl acetate and isopropyl alcohol, and the resulting solid was collected by filtration to give 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione (10.55 g) as a colorless powder.