Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:24][CH:25]=O)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:24][CH2:25][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COc1c(CC=O)cc(F)cc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(CCc2cc(F)cc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]acetaldehyde (D80) (95 mg), acetic acid (0.044 mL) and sodium acetate (113 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (106 mg) in one charge. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (195 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylate (D82) (100 mg). The crude product was used for next step without further purification. MS (ES): C26H28ClFN2O4S requires 518. found 519.2 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:6][CH2:5]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCNCC1
Reactant: ClC(c1ccccc1)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Temperature: 50 °C
Yield: 23.4 %

Procedure:
A mixture of 5.2 parts of 1,3-dihydro-1-[3-(1-piperzinyl)propyl]-2H-benzimidazol-2-one, 5.28 parts of 2-(chlorophenylmethyl)pyridine hydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated overnight at 50° C. The reaction mixture is cooled and poured onto ice-water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2 parts (23.4%) of 1,3-dihydro-1-[3-{4-[phenyl(2-pyridinyl)methyl]-1-piperazinyl}propyl]-2H-benzimidazol-2-one; mp. 141.7° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]>C(O)C>[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Yield: 89.7 %

Procedure:
23.2 g of cyclopropylamine are added dropwise, with stirring and cooling in ice, to a solution of 123.9 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate in 250 ml of ethanol. When the exothermic reaction has subsided, the mixture is stirred for a further 1 hour at room temperature, the solvent is removed in vacuo, and the residue is recrystallized from cyclohexane/petroleum ether. 115 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate of melting point 63°-65° C. are obtained.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=2)[S:4][C:3]=1[CH:17]1[O:21]CCO1.C[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1>>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[S:4][C:3]([CH:17]=[O:21])=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][C:26]=3[CH3:33])[C:6]=2[CH3:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1F
Product: Cc1cc(O)ccc1-c1c(C=O)sc(-c2ccc(O)c(F)c2)c1C
Yield: 37.7 %

Procedure:
Starting from 2-[3-bromo-5-(3-fluoro-4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (0.90 g, 2.4 mmol, made in Example 8, Step 1) and substituting 4-methoxy-2-methylphenylboronic acid (0.44 g, 2.7 mmol) in place of 4-methoxyphenylboronic acid (Step 2), the title compound (0.31 g, 76%, m.p. 227-30° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[C:8]([C:10]2[S:14][C:13](CCCCCC)=[CH:12][CH:11]=2)[C:7]([S:21](C)=O)=[CH:6][C:5]=1[C:24]1SC(CCCCCC)=[CH:26][CH:25]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.F[C:50](F)(F)[S:51](O)(=O)=O>>[S:14]1[C:10]2[C:8]3[CH:9]=[C:4]4[S:2][C:25]5[CH:26]=[CH:50][S:51][C:24]=5[C:5]4=[CH:6][C:7]=3[S:21][C:11]=2[CH:12]=[CH:13]1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCCCCC)s3)cc2S(C)=O)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: c1cc2sc3cc4c(cc3c2s1)sc1ccsc14
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 10 ml round bottomed flask was filled with 5,5′-(2,5-bis(methylsulfinyl)-1,4-phenylene)bis(2-hexylthiophene) (2b) (200 mg, 0.53 mmol), phosphorus pentoxide (28 mg, 0.2 mmol) and trifluoromethanesulfonic acid (6 ml). The mixture was stirred for 72 h at room temperature to give a dark brown solution, which was then poured into ice-water (100 ml). The yellow precipitate was collected by suction filtration and dried under vacuum. The structure of this compound, which was insoluble in apolar organic solvents, was assumed to be the sulfonium salt. Demethylation of the solid was achieved by refluxing it in pyridine (40 ml) for 12 h. When the suspension was cooled to room temperature, a large volume of CH2Cl2 was added to extract the product. Dithieno[2,3-d:2′,3′-d′]benzo[1,2-b:4,5-b′]dithiophene (1b) was thus obtained as off-white powder by Hexane as an eluent (120 mg, 70%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=1[NH2:13]>C1(C)C(C)=CC=CC=1>[NH2:13][C:12]1[C:11]([Cl:10])=[CH:17][C:16]([CH2:3][C:4]2[N:5]=[CH:6][NH:7][C:8]=2[CH3:9])=[CH:15][C:14]=1[Cl:18]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1[nH]cnc1Cc1cc(Cl)c(N)c(Cl)c1
Reaction time: 3 h

Procedure:
A mixture of 6.0 g of 4-chloromethyl-5-methylimidazole hydrochloride, 9.0 g of 2,6-dichloroaniline and 40 ml of xylene is refluxed with stirring for 3 hours. The mixture is then filtered and the precipitate is washed with xylene. The precipitate is dissolved in 50 ml of water and the pH is adjusted to 8. The solution is extracted with toluene (3×30 ml). The combined toluene extracts are washed with 10 ml of water and evaporated to dryness. The residue, which is crude 4-(4'-amino-3',5'-dichlorobenzyl)-5-methylimidazole, is converted to the hydrochloride in isopropanol with HCl-ethyl acetate. The free base is liberated from the hydrochloride in water with sodium hydroxide. The melting point of the base is 172°-175° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1Br>CC(O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[Br:19])[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccncc1Br
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2Br)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 0.20 g, 0.81 mmol), 3,4-dibromo-pyridine (Chem. Abstracts, 58:5627) (0.19 g, 0.81 mmol) in IPA (0.5 mL) was heated at 100° C. in a sealed reaction tube for 7 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM IPA hexane)) to give 4-[(3-Bromo-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):405.27
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=3[C@H:5]1[CH2:4][CH2:3]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:20][C:18]1[CH:17]=[CH:16][C:15]2[C@@H:5]3[C@H:6]([C@H:7]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:10]([O:11][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:8]4)[CH2:12][CH2:13][C:14]=2[CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Reaction time: 0.17 h
Yield: 190 %

Procedure:
Dimethylformamide (11 ml) was added to β-estradiol (1.08 g, 4.0 mmol) under nitrogen atmosphere, followed by cooling on ice. Sodium hydride (480 mg of 60% suspension) was added to the reaction mixture followed by stirring for 10 minutes on ice and then stirred for 1 hour at room temperature. After cooling again on ice, Benzyl bromide (2.05 g, 12 mmol) was added to the reaction mixture followed by stirring for 10 minutes on ice and then stirred for 20 hours at room temperature. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator and the resulting residue was triturated with methanol to precipitate solids. The solids were collected by filtration and vacuum dried to give 3,17β-bis(benzyloxy)estra-1,3,5(10)-triene (1.72 g, Yield 95%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45].[NH2:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:8]2[C:7](=[O:37])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@H]3CCCC[C@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 65 °C
Yield: 92 %

Procedure:
A mixture of tert-butyl (1R,2S)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (41.5 mg, 0.070 mmol) and TFA (2 mL) was heated at 65° C. for 3 h. Following reaction, the solvent was removed in vacuo. The residue was diluted with DMSO and MeOH (1/1), passed through a microfiltration frit, and purified via preparative HPLC. The fractions were collected and dried in vacuo to give a TFA salt of the title compound as a white solid (22 mg, 92%). 1H NMR (500 MHz, CD3OD) δ ppm 1.56-2.01 (m, 8H), 3.85 (br s, 1H), 3.94 (br s, 3H), 4.45 (br s, 2H), 4.67 (br s, 1H), 8.31 (br s, 1H), 8.81 (br s, 1H). [M+H] calc'd for C17H21FN6O, 345; found, 345.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[NH:12][CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[F:36][C:2]([F:35])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1C(c2ccc(Cl)cc2)=C(c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n2N1Cc1ccccc1
Temperature: 80 °C
Yield: 11.5 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (15 mg, 0.028 mmol) prepared as described in Example 469 in DMF (0.5 mL) at RT was added K2CO3 (11.6 mg, 0.084 mmol), followed by benzyl bromide (9.6 mg, 0.056 mmol). The reaction was heated at 80° C. for overnight. The reaction was filtered. The collected solution was concentrated under educed pressure. The crude product was purified using reverse phase HPLC to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-5-benzyl-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (2 mg, 11%) as a white solid. HPLC retention time: 4.44 min; MS [M+H]+: found 621. 1H NMR (CDCl3, 400 MHz) δ 7.60 (d, 2H), 7.45 (d, 2H), 7.33-7.29 (m, 5H), 7.23-7.13 (m, 4H), 7.05-7.00 (m, 2H), 6.87-6.81 (m, 2H), 5.04 (s, 2H), 4.26-4.15 (m, 2H), 3.98-3.93 (q, 1H), 1.30 (d, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CCO>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH2:20][CH3:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 90 °C
Yield: 52 %

Procedure:
A reaction mixture of 32 and N-Boc-1,3-diaminopropane (800 μl) in EtOH (10 ml) was heated at 90° C. for 14 h, then cooled to room temperature and purified by preparative HPLC to give 33 (350 mg) at the yield of 52% for two steps. 33 had an analytical HPLC retention time=3.03 min. (Column: YMC S5 Combiscreen 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4) 1H-NMR (400 MHz, CDCl3): δ 7.25–7.41 (m, 5H), 5.80 (d, J=16.41 Hz, 1H), 5.16 (d, J=16.41 Hz, 1H), 5.04 (brs, 1H), 4.66 (t, J=5.82 Hz, 1H), 3.11 (m, 2H), 2.89 (s, 3H), 2.72 (m, 1H), 2.57 (m, 1H), 2.02 (m, 2H), 2.74 (m, 2H), 1.43 (s, 9H), 0.84 (t, J=7.36 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([CH3:32])[CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21](C(C)=C)[C:20]4=[O:31])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(O)C.Cl>CC(O)C>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([CH3:32])[CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:31])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CC(C)CN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CC(CN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)Cn1c(=O)[nH]c2ccccc21
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
A solution of 7 parts of 5-chloro-1-[1-{3-[1,3-dihydro-3-(1-methylethenyl)-2-oxo-2H-benzimidazol-1-yl]-2-methylpropyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one in 120 parts of ethanol is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. The whole is boiled for 5 minutes. The reaction mixture is evaporated and the residue is taken up in water. The mixture is alkalized with a concentrated ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and ethanol. The product is filtered off and dried, yielding 1.3 parts (19.7%) of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methylpropyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 244° C.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](F)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[OH-:14].[Na+].Cl>S1(=O)(=O)CCCC1>[F:11][C:6]1[N:5]([CH3:12])[N:4]=[C:3]([CH:2]([F:13])[F:1])[C:7]=1[C:8]([OH:14])=[O:9]
Reactant: Cn1nc(C(F)F)c(C(=O)F)c1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
67.5 g of a solution (10% molar) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl fluoride in tetrahydrothiophene-1,1-dioxide were added dropwise to 400 mL of an aqueous 1N NaOH solution. During the addition, the temperature was kept below 20° C. After 2 h of stirring at room temperature, the mixture was carefully acidified to pH 2 using concentrated hydrochloric acid. The white precipitate formed was filtered off, washed with water and dried. This gave 6 g of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[NH:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:17][C:13](=[CH:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[C:14](=[O:19])[NH:15]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3NC(=O)NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4NC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-imidazolidine-2,4-dione (which was obtained in Example 42) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>201° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.95 (m, 2 H), 2.50–2.90 (m, 5 H), 2.92 (s, 3 H), 3.70–3.85 (m, 2 H), 4.48 (dd, J=8.0, 4.2 Hz, 1 H), 6.33 (s, 1 H), 6.81 (d, J=8.1 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.02 (dd, J=8.1, 1.8 Hz, 1 H), 7.18 (d, J=61.8 Hz, 1 H), 7.47 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 516.1 (MH+); HRMS Calcd. for C24H30N5O6S (MH+): 516.1917. Found: 516.1922.
Reaction SMILES: [CH:1]12[C:11]3([Cl:15])[C:12]([Cl:14])([Cl:13])[C:8]([Cl:18])([C:9]([Cl:17])=[C:10]3[Cl:16])[CH:2]1[C:3]([O:5][C:6]2=[O:7])=O.C1(C)C=CC=CC=1.[SH:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29]>O>[SH:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[N:29]1[C:6](=[O:7])[CH:1]2[CH:2]([C:8]3([Cl:18])[C:12]([Cl:13])([Cl:14])[C:11]2([Cl:15])[C:10]([Cl:16])=[C:9]3[Cl:17])[C:3]1=[O:5]
Reactant: Nc1ccccc1S
Reactant: O=C1OC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2C(C(=O)N1c1ccccc1S)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
A 3000 ml 3-neck round bottom flask, equipped with a Dean-Stark water trap and a mechanical stirrer, was charged with 203.5 g (10% molar excess) of chlorendic anhydride and 1600 ml of toluene. Sixty-two grams of 2-mercaptoaniline was added to the resultant solution, whereupon a pale yellow suspension was formed. The reaction mixture was heated gradually until the solvent began to reflux and the evolution of water commenced and it was collected in the Dean-Stark water trap. The heating and refluxing were continued until the calculated amount of water, 9 ml. was collected, this requiring a total of 6 hours. At this point, there was no solid left in the reaction mixture. Solvent was then distilled to reduce the volume to about one-half. The residue, a clear solution, was then poured into 1000 ml of Skellysolve B (a mixture of hexanes, b. pt. = 146°-156° F., from Skelly Oil Co.) and the resultant solid was separated by filtration on a Buchner funnel and dried in air overnight. One crystallization from toluene gave white crystals of the dicarboximide with a melting point of 195°-8° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[Cl-].[Na+]>O.C([O-])(=O)C.[Na+]>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(S)[C@H](N)C(=O)O

Procedure:
Cupric acetate is dissolved in water to prepare a solution having a concentration of 10 mg Cu++ /ml. D-penicillamine is dissolved in 0.05 molar sodium acetate buffer, pH 5.6, containing 2% sodium chloride to give a concentration of 10 mg penicillamine/ml. The copper solution is added to the penicillamine solution in a ratio of 16 ml of copper solution to 50 ml of penicillamine solution. The ratio of penicillamine to copper in moles is 1.3. The solution immediately takes on a red-violet color indicating the formation of the complex. The solution is dried to yield a powder and formed into tablets each containing 10 mg of the combination.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: Clc1ccccc1CCBr
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(-c2cn(CCc3ccccc3Cl)cn2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (400 mg, 2.13 mmol, PREPARATION 7), 1-(2-bromo-ethyl)-2-chloro-benzene (557 mg, 2.55 mmol) and K2CO3 (587 mg, 4.26 mmol) in DMF (10 mL) was stirred overnight at 80° C. LC/MS showed the reaction was completed. It was then purified by flash column chromatography to give the title compound (228 mg, 33%) as a yellow solid. [M+H] Calc'd for C17H15ClN4O, 327. Found, 327.