Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][S:5]([N:8]([CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6].[OH-].[Na+].Cl>CO.O>[CH3:24][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[S:5]([CH2:4][C:3]([OH:25])=[O:2])(=[O:6])=[O:7]
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of methyl-2-({methyl[(4'-cyanobiphen-4-yl)methyl]amino}-sulfonyl)acetate (200 mg, 0.56 nunol) in methanol (2 ml) and tetrahydroflran (5 ml) was added 1 M aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with water (10 ml), acidified to pH 2 with 2 M aqueous hydrochloric acid and extracted with dichloromethane (2×30 ml). The combined organic layers were dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (130 mg).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14](C=O)=[CH:13][C:12]=2[N+:19]([O-:21])=[O:20])[CH2:4][CH2:3]1.[CH:22]([O:27][CH3:28])([O:25][CH3:26])OC.Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[CH3:28][O:27][CH:22]([O:25][CH3:26])[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=Cc1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Reactant: COC(OC)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 4-(2-morpholinoethoxy)-3-nitrobenzaldehyde hydrochloride obtained in Step 1 (2.97 g, 9.38 mmol) in dichloromethane (10.0 mL) was added with trimethyl orthoformate (15.0 mL, 13.7 mmol) and a 10% solution of hydrogen chloride in methanol (5.00 mL), followed by stirring at room temperature for 4 hours. The reaction mixture was added with potassium carbonate (10.0 g, 72.4 mmol), then stirred at room temperature for 5 hours, and the solvent was evaporated under reduced pressure. The residue was added with water (50 mL) and was extracted with ethyl acetate (50 mL×3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 4-dimethoxymethyl-1-(2-morpholinoethoxy)-2-nitrobenzene (2.98 g, 97%).
Reaction SMILES: [C@H:1]1([O:12][C@@H:13]2[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:16]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C@H:15]([OH:29])[C@H:14]2[OH:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O>[C@H:1]1([O:12][C@@H:13]2[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:16]([S:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:31](=[O:33])[CH3:32])=[CH:22][CH:23]=3)[C@H:15]([OH:29])[C@H:14]2[OH:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reaction time: 0.17 h

Procedure:
A 1.0 g portion of 4-aminophenyl 4-O-(α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside was dissolved in 5 ml of water and 0.340 ml of acetic anhydride was added with vigorous stirring. After stirring 10 minutes the reaction was concentrated, reconcentrated from toluene, dissolved in ethanol and precipitated with ether, giving 836 mg of the desired intermediate.
Reaction SMILES: Cl.[CH3:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([O:31]C)=O)[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]>>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([NH:3][CH3:2])=[O:31])[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CN
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2O1
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine gave (±)-N4-(3,4-dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.52 (s, 1H), 9.09 (s, 1H), 8.08 (m, 3H), 7.76 (bd, 1H, J=9.3 Hz), 7.50 (d, 1H, J=9.0 Hz), 7.43 (bs, 1H), 7.24 (bd, 1H, J=8.7 Hz), 6.73 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H, J=6.3 and 6.6 Hz), 3.39 (dd, 1H, J=10.5 Hz), 3.15 (dd, 1H, J=6.3 Hz), 2.60 (d, 3H, J=4.8 Hz); LCMS: purity: 99%; MS (m/e): 450 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl>[CH3:35][CH:34]([CH3:36])[CH2:33][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)=[O:37]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a stirred solution of 0.16 g of 6,11-di-hydro-5-(4-aminobenzoyl)-5H-dibenz [b,e]azepine in 2 ml of methylene chloride is added 0.10 g of triethylamine followed by 0.09 g of iso-valeryl chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na2SO4), filtered through hydrous magnesium silicate and evaporated in vacuo to a residue which is stirred with ether-hexanes to give 0.21 g of light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:14])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[N+:1]([C:4]1[CH:13]=[C:12]2[CH2:11][CH2:10][CH2:9][C:8]3=[N:15][NH:14][C:6]([CH:5]=1)=[C:7]23)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: Nc1cc([N+](=O)[O-])cc2c1CCCC2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc2c3c(n[nH]c3c1)CCC2
Reaction time: 20 h
Yield: 60.3 %

Procedure:
To a solution of 3-nitro-5,6,7,8-tetrahydro-naphthalen-1-ylamine (5.9 g, 31.0 mmol) prepared in Step A in glacial acetic acid (100 mL) was added a solution of sodium nitrite (2.13 g, 31.0 mmol) in water (5.0 mL) at 0° C., and the resultant dark solution was stirred at this temperature for 20 h. The volatiles were evaporated and the residue was basified with a saturated solution of sodium bicarbonate (100 mL). The aqueous was extracted with ethyl acetate (4×200 mL) and the combined extracts were washed with brine, dried (MgSO4) and evaporated to a residue that was purified by column chromatography (silica, 20% to 30% gradient of ethyl acetate in hexane) to give an oil (3.8 g, 60%): MS (ES) m/z 204 (M+); 1H NMR (CDCl3) δ 8.22 (1H,s), 7.77 (1H, s), 3.06 (4H, m), 2.26 (2H, m).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.O>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-n3ccnc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of -1-cyclopentyl-3-ethyl-6-methylsulfonylpyrazolo[3,4-d]pyrimidin-4-one (3.1 g, 0.01 mol) and imidazole (2.1 g, 0.03 mol) was heated at 165°-175° C. for 3.5 hours. The mixture was cooled to room temperature and water (25 ml), followed by acetic acid (3 ml) were added. A precipitate was obtained which was collected by filtration and washed with water. The product was recrystallized from ethanol/ether to afford 2.4 g (81%) of 1-cyclopentyl-3-ethyl-6-(1-imidazolyl)pyrazolo[3,4-d]-pyrimidin-4-one as white crystals, m.p. 228°-230° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:26]([OH:27])[CH2:25][C@@:24]3([CH3:28])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:23])[CH2:17]OS(C)(=O)=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1.[Cl-:31].[Li+].O>CN(C)C=O>[Cl:31][CH2:17][C:16](=[O:23])[C:15]1[C@:24]2([CH3:28])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:26]([OH:27])[CH2:25]2)[C@:3]2([CH3:30])[C:8](=[CH:7][C:6](=[O:29])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][CH:14]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)COS(C)(=O)=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
To a solution of 17.5g of 9-fluoro-11β-hydroxy-21-methanesulfonyloxypregna-1,4,16-triene-3,20-dione in dry dimethylformamide (250 ml) is added lithium chloride (30g). The mixture is heated, with stirring, from 30° to 100° C. over a 30-minute period. It is cooled and poured into cold water (1.51) and the precipitated solid is isolated and crystallized from methanol to afford 12g of the title compound, melting point 258°-260° C.(dec.).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:11][S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1>CN(C=O)C>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([CH2:27][CH2:26][N:11]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:29]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=S(=O)(NCCc1ccccc1)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)N(CCc1ccccc1)CCc1c[nH]c2ccccc12
Reaction time: 2.5 h
Yield: 83.6 %

Procedure:
Under inert atmosphere, to a stirred solution of NaH (0.016 g, 0.36 mmol) in 0.20 ml anhydrous DMF at 0° C., was added a solution of compound of Example 2 (0.108 g, 0.35 mmol) in 0.60 ml anhydrous DMF. The temperature was maintained during 1.5 h. After this time, a solution of 3-(2-Bromoethyl)indole (0.088 g, 0.39 mmol) in 0.6 anhydrous DMF was added dropwise to the reaction mixture of step at 0° C., and was stirred during 2.5 h. Once the solvent was evaporated, the crude mixture was chromatographically purified over SiO2 using Hexane/AcOEt (70:30) as the eluant, furnishing 133 mg of the desired product in 84% yield (purity ≧80%, expressed in % HPLC area).
Reaction SMILES: O[C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6].C(N(S(F)(F)[F:39])CC)C>C(Cl)Cl.O>[F:39][C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)O)CC3)nc(-c3ccccc3O)nc2c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 40.3 %

Procedure:
To 4-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (330 mg, 0.76 mmol) at −78° C. in 3 mL of CH2Cl2 was added (diethylamino)sulfur trifluoride (185 mg, 1.15 mmol). The reaction mixture was stirred −78° C. for 2.5 h. The reaction mixture was diluted with 10 mL of water and 10 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 11-100% EtOAc-hexanes to give 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (133 mg, 40% yield). LC/MS: m/z 435.4.3 (M+H)+ at 2.92 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.I[CH2:24][CH2:25][F:26]>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:24][CH2:25][F:26])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FCCI
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(CCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
16.5 g (74.91 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 495 ml of abs. THF, and 35.96 ml (89.89 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for 15 min. Subsequently, the reaction solution was warmed up to 0° C. 13.03 g (74.91 mmol) of 1-iodo-2-fluoroethane were added dropwise to the reaction solution, which was stirred at 0° C. for a further 15 min. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed with saturated aqueous sodium chloride solution. The aqueous phase was reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:dichloromethane/cyclohexane=1/1 to 2/1). 18.7 g of the target compound were obtained (80% of theory, 85% purity).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25]Br>>[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CN(CCc1ccccc1)C(=O)CBr
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Product: COC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(=O)N(C)CCc1ccccc1

Procedure:
Following the procedure of Example 10, 5-benzyloxy-2-carbomethoxyindole is alkylated with N-methyl-N-phenethyl-2-bromoacetamide to give N-methyl-N-phenethyl-2-(5-benzyloxy-2-carbomethoxyindol-1-yl)acetamide. (m.p. 155°-156° C.)
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=1[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(#N)C>[Cl:13][C:14]1[C:15]2[CH2:21][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:6](=[O:7])[NH:20][C:16]=2[N:17]=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CNCc2c(Cl)ccnc2N)cc1
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (583 mg, 3.56 mmol) was added to a solution of 4-chloro-3-((4-methoxybenzylamino)methyl) pyridin-2-amine (100 mg, 1.19 mmol) in acetonitrile (5 mL), and stirred for 1 h at room temperature. The resulting precipitate was filtered, and washed with H2O and MeOH, to provide 1 as a solid. LC-MS (M+H=303, obsd.=303. 1H NMR: (DMSO-D6) δ 3.74 (s, 3H); 4.34 (s, 2H); 4.52(s, 2H); 6.92 (d, 2H); 7.03 (d, 1H); 7.26 (d, 2H); 8.03 (d, 1H); 10.08 (s, 1H).
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(O)C>[CH2:4]([CH:3]([CH2:6][CH3:7])[CH2:2][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH3:5]
Reactant: CCC(CC)CBr
Reactant: NCCCCO
Solvent: CCO
Product: CCC(CC)CNCCCCO
Temperature: 75 °C
Yield: 80.8 %

Procedure:
A mixture of 3-bromomethyl-pentane (3.0 g, 20 mmol) and 4-amino-1-butanol (5.06 mL, 55 mmol) in ethanol (20 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (50 mL) and the aqueous layer extracted with dichloromethane (20 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as an oil (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=S)[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1cccc(N=C=S)c1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-methoxy phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 50 min. Upon cooling to room temp, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O. Suspend the solid in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Again suspend the solid in 1 N NaOH and stir for 1 hr. Collect the solid and wash with water and Et2O. Dry to afford the title compound: 1H NMR (400 MHz, DMSO-d6) ppm 3.78 (s, 3 H) 6.61 (dd, J=8.15, 1.83 Hz, 1 H) 7.14-7.19 (m, 1 H) 7.28 (t, J=8.15 Hz, 1 H) 7.34 (t, J=2.15 Hz, 1 H) 7.64 (dd, J=9.35, 6.69 Hz, 1 H) 7.70 (s, 1 H) 7.84 (br. s., 2 H) 7.72 (d, J=1.89 Hz, 1 H) 8.11 (br. s., 1 H) 10.67 (br. s., 1 H) 13.29 (br. s., 1 H); MS m/z=452.1 (M+1).
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([OH:16])=O)=[C:7]2[N:6]=[N:5]1.C(N=C=NCCCN(C)C)C.[C:28]([NH:36][NH2:37])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[C:28]([NH:36][NH:37][C:14]([C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:3][S:2][CH3:1])[N:5]=[N:6][C:7]=12)=[O:16])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CSCn1nnc2c(C(=O)O)ncn2c1=O
Reactant: NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CSCn1nnc2c(C(=O)NNC(=O)c3ccccc3)ncn2c1=O
Reaction time: 0.02 h
Yield: 65 %

Procedure:
3-(Methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.73 mmol, 175 mg, 1 eq.), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (0.76 mmol, 146 mg, 1.05 eq.) and benzohydrazide (0.76 mmol, 104 mg, 1.05 eq.) were placed in a round bottom flask and dissolved in acetonitrile (3 mL). A suspension developed 1 minute after starting room temperature stirring and it was stirred for further 90 minutes. The reaction mixture was filtered and the obtained solid washed with water, acetonitrile and ether, and dried under vacuum. The filtrate was poured into ice/water and the filtration, washing and drying steps were repeated. Yield 65%. δH (DMSO-d6) 10.35 (1H, bs), 10.28 (1H, bs), 8.75 (1H, bs), 7.74 (2H, m), 7.37 (3H, m), 5.25 (2H, bs), 2.07 (3H, bs).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[NH:5][CH:6]=1.[C:17](O)(=[O:20])[C:18]#[CH:19].N1(C(N2C=CN=C2)=O)C=CN=C1>>[Br:1][C:2]1[NH:3][C:4]2[N:5]([CH:6]=1)[C:17](=[O:20])[CH:18]=[CH:19][C:7]=2[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C(Cc1nc(Br)c[nH]1)c1ccc(F)cc1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccc(F)cc1)c1ccc(=O)n2cc(Br)[nH]c12

Procedure:
The compound is prepared as described in example 6 with 446.0 mg (1.58 mmol) of 2-(4-bromo-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone (example XXXII), 172.43 mg (2.36 mmol) of propiolic acid and 459.82 mg (2.84 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH:14]=2)[NH2:11])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1.Cl>C(O)C>[N:1]1([C:6]([C:8]2[CH:9]=[C:10]([NH:11][C:23]3[C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)[CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1cc(C(=O)N2CCCC2)cc(C(=O)N2CCCC2)c1
Agent: Cl
Solvent: CCO
Product: O=C(c1cc(Nc2ccnc3cc(Cl)ccc23)cc(C(=O)N2CCCC2)c1)N1CCCC1
Yield: 646.1 %

Procedure:
3,5-Bis[(pyrrolidin-1-yl)carbonyl]aniline (287 mg, 1.0 mmol) and 4,7-dichloroquinoline (198 mg, 1 eq) were refluxed in 20 mL of ethanol and 2 mL of HCl 1M for 12 h. The reaction mixture was then evaporated. The residue was purified by flash chromatography (DCM/MeOH//9/1) to yield expected compound as a yellow powder (2.90 g, 78% yield). m/z (ESI) 449.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[N:12]([C:5]=2[CH2:4][CH2:3][NH:2]1)[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[N:9]=3.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(Br)C1C=CC=CC=1>C(OCC)(=O)C>[C:17]1([CH2:23][N:2]2[CH2:3][CH2:4][C:5]3[N:12]4[C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[N:9]=[C:8]4[S:7][C:6]=3[CH2:1]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Agent: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCc3c(sc4nc5ccccc5n34)C2)cc1

Procedure:
1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (1.9 g., 0.008 mole) is dissolved in 100 ml. of boiling toluene. Triethylamine (5 ml.) is added at 80°. Benzyl bromide (1.7 g., 0.01 mole) is dissolved in 5 ml. of toluene and added dropwise to the reaction mixture. After the addition, the reaction mixture is refluxed for two hours. It is filtered and concentrated in vacuo to yield 3.6 g. of oil. Ethyl acetate is added and the product, 1,2,3,4-tetrahydro-2-(phenylmethyl)pyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole crystallizes. This is filtered and recrystallized from ethyl acetate:ethanol (10:1) to yield 1.4 g. of analytical product, m.p. 124°-129°.