Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[CH:18][C:17]=2[N+:32]([O-])=O)=[C:9]([CH3:35])[CH:8]=1)=[O:4].P(OC)(OC)OC>>[CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:32][C:17]3[C:16]([CH:15]=2)=[CH:31][CH:30]=[C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:18]=3)=[C:9]([CH3:35])[CH:8]=1)=[O:4]
Reactant: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Agent: COP(OC)OC
Product: COC(=O)/C=C/c1cc(C)c(-c2cc3ccc(C(=O)OCc4ccccc4)cc3[nH]2)c(C)c1
Temperature: 110 °C

Procedure:
A mixture of benzyl 4-{(E)-2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-vinyl}-3-nitrobenzoate (1.87 g, 3.97 mmol) and trimethyl phosphite (5.0 mL, 5.26 g, 42 mmol) was heated at 110° C. for 3 h. The solvent was removed under reduced pressure and the residue chromatographed using a 10-50% gradient of heptane/ethyl acetate to give the title compound.
Reaction SMILES: [CH2:1]([S:5]([CH:8]1[C:12]([S:13]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:15])=[O:14])=[CH:11][S:10][CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:5]([C:8]1[C:12]([S:13]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:15])=[CH:11][S:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)C1=CSCC1S(=O)(=O)CCCC
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)c1cscc1S(=O)(=O)CCCC

Procedure:
Under a nitrogen atmosphere, 3,4-bis(butane-1-sulfonyl)dihydrothiophene and chloroform were placed in a reaction vessel to dissolve 3,4-bis(butane-1-sulfonyl)-dihydrothiophene in chloroform. To the solution, thionyl chloride (3.0 equivalents) was added, followed by heating under reflux for 36 hours. A disodium hydrogenphosphate/sodium dihydrogenphosphate buffer which had been adjusted to pH 7 was added to the reaction mixture to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off. The resultant crude product was purified through a silica gel column (hexane:ethyl acetate=2:1) to obtain the reaction product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][S:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]#[N:24].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][S:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][C:10]([O:12][CH2:22][C:23]#[N:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
2-((tert-Butoxycarbonyl)(2-(tert-butyldisulfanyl)ethyl)amino)acetic acid (Compound 6f-A, 268.1 mg, 0.83 mmol) and 2-bromoacetonitrile (199 mg, 1.66 mmol) were dissolved in DMF (1.0 ml), DIPEA (0.43 ml, 2.49 mmol) was added and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=3:1) to afford the title compound (287.7 mg, 96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>[Pd].COCCOC>[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(Cl)n2)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(-c3ccccc3O)n2)C1
Yield: 49.1 %

Procedure:
A mixture of (S)-tert-butyl 3-(2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.120 g, 0.400 mmol), 2-hydroxyphenyl boronic acid (0.166 g, 1.20 mmol), palladium catalyst (0.013 g, 0.020 mmol), and 1 M aqueous Na2CO3 (0.80 mL, 0.80 mmol) in DME (4 mL) was refluxed for 24 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (66% ethyl acetate/hexanes) to give the title compound as an oil (0.070 g, 49%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH3:7][C:8]1[NH:9][C:10]([CH3:21])=[C:11]2[C:15]([CH3:18])([C:16]#[N:17])[CH2:14][C:13]([CH3:20])([CH3:19])[C:12]=12.Cl.Cl[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28]>O>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][CH2:24][N:9]1[C:10]([CH3:21])=[C:11]2[C:15]([CH3:18])([C:16]#[N:17])[CH2:14][C:13]([CH3:20])([CH3:19])[C:12]2=[C:8]1[CH3:7]
Reactant: CN(C)CCCCl
Reactant: Cc1[nH]c(C)c2c1C(C)(C)CC2(C)C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c2c(c(C)n1CCCN(C)C)C(C)(C#N)CC2(C)C
Temperature: 15 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
To a solution prepared by heating 23.2 g. (0.55 mole) of a 67% mineral oil dispersion of sodium hydride in 200 ml. of anhydrous dimethylsulfoxide was added 50.5 g. (0.25 mole) of the 2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile described above in Example 3. The mixture was stirred under nitrogen for about two hours, cooled to 15° C., and treated with 39.5 g. (0.25 mole) of 3-chloro-N,N-dimethylpropylamine hydrochloride. When the foaming had subsided, the mixture was stirred at room temperature overnight, poured into water, and the gummy solid which separated was taken into diethyl ether and the solution washed first with water, then with saturated brine, dried and taken to dryness to give 69 g. of a solid which was recrystallized once from hexane and once from isopropanol to give 29 g of 2-[3-(di-methylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile, m.p. 90.5°-91.0° C.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C)C.[BH4-].[Na+]>C1COCC1.CO>[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](CO)CC1)OCc1ccccc1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trans-4-benzyloxycarbonylaminocyclohexanecarboxylic acid (417 mg, 1.50 mmol) in THF (15 mL) was added BH3.Me2S complex (2.0 M in THF, 1.5 mL, 3.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h30. More BH3.Me2S complex (2.0 M in THF, 1.0 mL, 2.00 mmol) was added at 0° C. followed by NaBH4 (12 mg, 0.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. MeOH was carefully added to quench the reaction, the volatiles were removed under reduced pressure and the residue co-evaporated with MeOH (2×). Purification by FC (hept-EA, 1:0->3:2) gave pure trans-4-benzyloxycarbonylaminocyclohexane-methanol as a white solid. TLC:rf (1:2 hept-EA)=0.35. LC-MS-conditions 01: tR=0.82 min; [M+H]+=264.05.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[N:15]=1)=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=3)=O.Cl.[NH2:19][OH:20].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N:19](=[CH:1][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[N:15]=1)=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=3)[OH:20]
Reactant: NO
Reactant: O=Cc1ccc2c(n1)-c1ccc(Br)cc1C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1c2cc(Br)ccc2-c2nc(C=NO)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 286 mg (1 mmole) of 3-formyl-7-bromo-4-aza-9-fluorenone (prepared as described in Example 42), 85 mg (1.2 mmole) of hydroxylamine hydrochloride in ~2 mL of pyridine is stirred overnight at R.T. Ethyl acetate and excess sodium bicarbonate solution are then added and the precipitated solid precipitate is filtered and dried to give 3-oximinomethyl-7-bromo-4-aza-9-fluorenone.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.C([O-])(=O)C.[Cs+]>CS(C)=O.[OH-].[Na+].[Cu]>[C:11]([O:10][C:9](=[O:15])[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:3][CH2:4]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
Tert-butyl trans-4-aminocyclohexylcarbamate (1.9965 g, 9.32 mmol), 2-bromo -5-methylpyridine (1.923 g, 11.18 mmol), copper (0.047 g, 0.745 mmol), and cesium acetate (11.09 g, 57.8 mmol) were suspended in dry DMSO (11.65 ml) and stirred at 100° C. for 22 hours. The reaction was allowed to cool to room temperature. The reaction mixture was diluted with 1N sodium hydroxide and extracted with ethyl acetate. The organic extract was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide tert-butyl(trans-4-((5-methylpyridin-2-yl)amino)cyclohexyl)carbamate (0.9695 g, 3.17 mmol, 34.1% yield).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:26]1([C:32]2[O:33][C:34]3[C:42](OS(C(F)(F)F)(=O)=O)=[CH:41][CH:40]=[CH:39][C:35]=3[C:36](=[O:38])[CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:26]1([C:32]2[O:33][C:34]3[C:42]([C:7]4[C:8]5[O:9][C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[C:12]=5[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[CH:41][CH:40]=[CH:39][C:35]=3[C:36](=[O:38])[CH:37]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c3c2oc2ccccc23)OC1(C)C
Reactant: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(N2CCOCC2)oc2c(-c3ccc([N+](=O)[O-])c4c3oc3ccccc34)cccc12
Temperature: 140 °C
Yield: 122.4 %

Procedure:
To a solution of 1-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-dibenzofuran (12, 0.30 mmol, 0.10 g) in anhydrous dioxane (2 ml) was added trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-1-benzopyran-8-yl ester (0.24 mmol, 0.091 g, see WO 03/024949), potassium carbonate (0.6 mmol, 0.083 g) and tetrakis (triphenylphosphine) palladium (0.015 mmol, 0.018 g). The reaction vessel was sealed and heated under the influence of microwave radiation (140° C., 10 minutes, low absorption setting). Upon completion the reaction mixture was filtered through a thin pad of silica and the cake washed with CH2Cl2. The solvents were then removed in vacuo to give a light brown solid residue (0.13 g, 100%) which was used without further purification. m/z 443.4 [M+H]+ (Rt=4.76 min).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[C:17]([CH3:27])([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:17]([CH3:27])([CH3:26])[C:16]([OH:28])=[O:15])=[CH:24][CH:23]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Product: CC(C)Sc1ncccc1COc1ccc(CC(C)(C)C(=O)O)cc1
Yield: 81.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.02 g, 0.099 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.022 g, 0.099 mmol) obtained in Step D of Preparation Example 39 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.029 g, 81%).
Reaction SMILES: C(OCC1C[CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[O:19][C:20](=O)[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2C1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.[NH3:36]>CN(C)C=O>[OH:19][CH2:18][CH:17]1[CH2:21][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[NH:36][C:20](=[O:19])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:16]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: N
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CO)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 2.90 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 30 ml of dimethylformamide and 23 ml of 33% aqueous ammonia was heated to 140° C. for 7 hours. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from ethyl acetate gave 1.87 g of 3-[6,7,8,9-tetrahydro-8-(hydroxymethyl)pyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of a red solid of melting point 262°-263° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[H-].[Na+].Cl[CH:15]1[CH2:19][CH2:18][CH:17]=[CH:16]1>CN(C)C=O>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:18][CH2:17][CH:16]=[CH:15]1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClC1C=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1C=CCC1
Reaction time: 8 h

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (14.20 g) in dry dimethylformamide (300 mL) is treated portionwise with sodium hydride (60% dispersion in oil; 3.70 g) at room temperature under nitrogen. 3-Chlorocyclo-pentene (9.6 mL) is added and the resulting mixture is stirred overnight. The solvent is then removed under reduced pressure and the residue is partitioned between water (500 mL) and dichloromethane (500 mL) and the aqueous layer is further extracted with dichloromethane (500 mL). The combined organic extracts are dried and evaporated under reduced pressure and the residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:1 v/v), to give 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde, in the form of a pale brown oil (11.2 g).
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16](=[NH:20])OCC)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]2[C:31](N)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:24][CH:23]=1>CO>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][N:29]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[N:20]=[C:16]2[CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(CNc2ccccc2N)cc1
Reactant: CCOC(=N)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: Cc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)cc1
Reaction time: 4 h
Yield: 63 %

Procedure:
A mixture of 116.5 parts of O-ethyl 1-(phenylmethyl)-4-piperidineethanimidate hydrochloride, 61.5 parts of N1 -[(4-methylphenyl)methyl]-1,2-benzenediamine and 400 parts of methanol was stirred and refluxed overnight. Another portion of 40 parts of O-ethyl 1-(phenylmethyl)-4-piperidineethanimidate hydrochloride was added and stirring was continued for 4 hours at reflux. The reaction mixture was evaporated. Water was added to the residue. The solution was treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 74.5 parts (63%) of 1-[(4-methylphenyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 124.2° C. (6).
Reaction SMILES: [IH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:16]2([CH2:20][CH2:19][C:18](SC)=[N:17]2)[CH:14]2[CH2:15][CH:11]1[CH2:12][CH2:13]2.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[IH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:16]2([CH2:20][CH2:19][C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:17]2)[CH:14]2[CH2:15][CH:11]1[CH2:12][CH2:13]2
Reactant: C1CCNC1
Reactant: COc1ccccc1C1C2CCC(C2)C12CCC(SC)=N2
Agent: I
Solvent: CCO
Product: COc1ccccc1C1C2CCC(C2)C12CCC(N1CCCC1)=N2

Procedure:
12 mmoles of 3-(2-methoxyphenyl)-5'-methylthio-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline]hydriodide and 2 g of pyrrolidine in 50 ml of ethanol are refluxed. The solvent is stripped off and the residue obtained is recrystallized from isopropanol. Colorless crystals of melting point 228° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][N:27]([CH3:41])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:41])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCN(C)C
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCN(C)C

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.15) according to general procedure II.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][CH2:11][CH:12]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[O:13]C2CCCCO2)[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].[ClH:44]>CC(C)=O.C(OCC)C.C(Cl)(Cl)Cl.O>[ClH:44].[ClH:44].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][CH2:11][CH:12]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[OH:13])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCOCC(OC2CCCCO2)c2cccc3ccccc23)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCOCC(O)c2cccc3ccccc23)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In 30 ml of acetone was dissolved 3.3 g of 2-[2-(4-methylpiperazin-1-yl)ethoxy]-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)ethane. To the solution were added 3.46 g of p-toluenesulfonic acid monohydrate and 7 ml of water at room temperature. The resulting mixture was stirred at the same temperature for 30 minutes and further at 40° C. for 1 hour. The reaction mixture was added to a mixture of 60 ml of chloroform and 60 ml of ice water. The mixture was adjusted to pH 11 with a 10% aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted with 20 ml of chloroform. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 40 ml of acetone. Hydrogen chloride gas was blown into the solution with ice cooling. The resulting solution was stirred at room temperature for 30 minutes. Thereto was added 40 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 30 minutes. The resulting crystals were collected by filtration, washed with acetone, and dried to obtain 2.35 g of 2-[2-(4-methylpiperazin-1-yl)ethoxy]-1-(1-naphthyl)ethanol dihydrochloride (compound No. 259).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([I:19])C(=O)C1>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([I:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (500 mg, 2.90 mmol) in acetic acid (20 ml) was added NIS (650 mg, 2.89 mmol). The resulting solution was stirred overnight at room temperature and then diluted with water (40 ml). The solids were collected by filtration to afford 5-chloro-4-iodo-2-nitroaniline as a brown solid (800 mg, crude). To a solution of 5-chloro-4-iodo-2-nitroaniline (800 mg, crude) in water (4 ml) and ethanol (20 ml) was added Fe powder (600 mg, 10.74 mmol) and ammonium chloride (430 mg, 8.04 mmol). The resulting solution was stirred overnight at reflux and then cooled to room temperature. The solid was filtered out and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (200 ml) and washed with brine (100 ml), dried over Na2SO4 and concentrated under vacuum to afford 4-chloro-5-iodobenzene-1,2-diamine as a brown solid (600 mg, crude).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:12][CH:11]=1.[I:22]I>C1COCC1>[I:22][C:20]1[S:19][CH:18]=[C:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: II
Reactant: Fc1ccc(Cc2ccsc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2csc(I)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 87.6 %

Procedure:
To a solution of LDA (3.67 mmol) in THF at -78° C. was added a solution of 3-(4-fluorophenylmethyl)thiophene (640 mg, 3.33 mmol), prepared as in Example 35, step 1, and the reaction mixture was stirred for 25 min. A solution of I2 (1.01 g, 4.00 mmol) in THF was added and the cold bath was removed. The reaction mixture was warmed to ambient temperature, quenched with saturated aqueous NH4Cl, and extracted with ether. The organic phase was washed with 1N aqueous H3PO4, saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 928 mg of 2-iodo-4-(4-fluorophenylmethyl)thiophene which was used without further purification.