Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:17][C:18]([O:21][C:22]([N:24]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:25]([C:33]1[C:38]([F:39])=[C:37](Cl)[N:36]=[C:35]([Cl:41])[N:34]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:20][C:18]([O:21][C:22]([N:24]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:25]([C:33]1[C:38]([F:39])=[C:37]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:36]=[C:35]([Cl:41])[N:34]=1)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[O:23])([CH3:17])[CH3:19]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCOCC2)c1F
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of commercially available tetrahydro-2H-pyran-4-amine (0.122 g, 1.21 mmol) in DMF (6 mL) was cooled to 0° C. Then diisopropylethylamine (0.24 mL, 1.33 mmol) and tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.600 g, 1.21 mmol) were added. The resulting solution was left to reach room temperature and stir overnight. The mixture was extracted with ether and washed with water, and the resulting aqueous layer was extracted once with ether. The combined ether layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was purified by silica gel chromatography with (5-60% ethyl acetate in hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate as a white solid (0.602 g, 89%). LCMS: (M+H−2Boc)+=362.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][NH:21][CH3:22]>O1CCOCC1.O1CCCC1>[CH3:20][N:21]([CH3:22])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 2-nitro-benzenesulfonyl chloride (15 g, 0.068 mol) in 1,4-dioxane (100 mL) was added sodium carbonate (10.76 g, 0.1015 mol) and 2.000 M of dimethylamine in tetrahydrofuran (40.61 mL) at room temperature and the reaction mixture was stirred for 4 hours. The reaction mixture was partitioned between water and dichloromethane, and the aqueous layer was extracted once with dichloromethane. The combined organic extracts were dried (MgSO4), concentrated, and the solid residue was recrystallized from MeOH to afford N,N-dimethyl-2-nitro-benzenesulfonamide (14.7 g, 94%) as a white solid. LC/MS (ESI+): 230.92 (M+H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2)(=[O:13])=[O:12].[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36]([CH:41]=O)=[CH:35]3)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:41][C:36]1[NH:37][C:38]2[C:34]([CH:35]=1)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:40][CH:39]=2)(=[O:13])=[O:12]
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc4C3)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc4C3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
5-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 90.8 %

Procedure:
A mixture of 30.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 17.2 g of 2-(dimethylamino)ethyl chloride hydrochloride, 31.8 g of potassium carbonate and 240 ml of acetone is refluxed for 30 minutes after stirring. Then, 10 ml of water are added to the mixture, and the aqueous mixture is further refluxed for 3 hours under stirring. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetone. The residue is dissolved in toluene, and the solution is washed twice with water. The toluene layer is collected and then evaporated under reduced pressure to remove toluene. The residue is dissolved in ethanol. After cooling the solution, said solution is acidified with 10% HCl/ethanol and then stirred at a temperature below 5° C. for 5 hours. The crystalline precipitates are collected by filtration, washed with ethanol and then dried. 37.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride are thereby obtained. Yield: 90.7%
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:45])[CH:7]([NH:29][CH:30]([C:35]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]CC3C=CC=CC=3)[CH:16]=2)[C:11]1=[O:28])([CH3:4])[CH3:3].[H][H]>[Pd].C(O)C>[CH3:1][C:2]([O:5][C:6](=[O:45])[C@H:7]([NH:29][C@H:30]([C:35]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[C:11]1=[O:28])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(OCc3ccccc3)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(O)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reaction time: 15 h
Yield: 77.4 %

Procedure:
100 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 76 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 10 mg of 10% Palladium on carbon in 2.5 mL absolute ethanol under 1 atmosphere of hydrogen. The mixture was stirred for 15 h and filtered through celite. The solvent was removed by evaporation and the residue was w ashed with hexane. The solvent was removed by evaporation yielding 66 mg of a white solid
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccccc1-c1ccccc1
Product: c1ccc(-c2ccccc2Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-amino-biphenyl by Procedure A. The crude product was purified by preparative LCMS to give the title compound as the free base (white solid, mp 152-154° C.). MS(ES+) m/z 286 ([M+1]+, 100).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51](Br)(Br)([Br:53])[Br:52]>O>[Br:52][C:51]([Br:53])=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCC(CC=C(Br)Br)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0° C., triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added. The reaction was stirred at 0° C. for 10 min, water was added and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, NH4OH) to give 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%). 1H NMR (400 MHz, CDCl3): δ 8.9 (s, 2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS (M+H)+: m/z=556
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:6]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]>O>[CH3:1][O:2][C:3]([C@H:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C@@H:6]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Solvent: O
Product: COC(=O)[C@H](c1ccccc1)[C@H]1CCCCN1
Temperature: 47.5 °C
Reaction time: 2 h

Procedure:
The chiral resolution generally proceeds by initially charging the racemic threo-methylphenidate, chiral acid and lower alkanol to a suitable reactor under agitation and ambient conditions. The base is then charged at a temperature ranging from about 20 to 30° C., and the resulting slurry is heated to an effective temperature, such as about 40 to 55° C. Process water is then charged and the mixture may be aged, such as aging at 40 to 45° C. for an effective amount of time, such as from about 15 minute to 1 hour. The heated resolution mixture is then cooled to a temperature and for a time effective to precipitate the d-threo-methylphenidate chiral acid salt. For example, the reaction can be cooled to about 0 to 25° C. over the course of approximately 1 to 3 hours and then aged at about 0 to 25° C. for about 1 to 3 hours. The precipitated d-threo methylphenidate/chiral acid salt is then isolated, such as by filtration.
Reaction SMILES: [CH2:1]([C:8]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[S:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([OH:17])=O)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH2:48]([O:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:8]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:20])=[O:21])[S:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:56][O:55][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)O)C2=O)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)NOCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To a solution of 2-[5-Benzyl-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-3-yl]-acetic acid (Example 27) (0.400 g, 0.92 mmol) in 13 mL of dichloromethane was added 1-hydroxybenzotriazole (0.126 g, 0.93 mmol), 4-methylmorpholine (0.506 g, 5.00 mmol), O-benzylhydroxylamine hydrochloride (0.440 g, 2.76 mmol), and 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.232 g, 1.21 mmol) and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The mixture was diluted with 50 mL of dichloromethane and washed with 2×100 mL of water. The combined aqueous washings were back extracted with 100 mL of dichloromethane and the combined organic phases were washed with 100 mL of brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Column chromatography provided 0.280 g of 2-[5-Benzyl-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-3-yl]-N-benzyloxyacetamide as a colorless foam. This material was dissolved in 25 mL of dioxane and stirred at room temperature under a hydrogen atmosphere with an excess of 10% Pd on carbon for 2 days. The mixture was filtered through a celite pad washing with dioxane, followed by ethyl acetate, then methanol. The combined filtrates were concentrated in vacuo and column chromatography provided 0.050 g of the title compound as a white powder. m.p. 81-85° C.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([NH:4][C:15]1[C:14]([F:19])=[CH:13][C:12]([Cl:11])=[CH:17][N:16]=1)(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: Fc1cc(Cl)cnc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ncc(Cl)cc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
Under a nitrogen atmosphere, a suspension of acetamide (620 mg, 10.5 mmol) and potassium t-butoxide (1.01 g, 10.5 mmol) in DMF (4.5 mL) was heated to 50° C. and stirred for 1.5 hours. It was cooled to 0° C., 5-chloro-2,3-difluoropyridine (450 mg, 3.0 mmol) was added dropwise, DMF (0.45 mL) was further added, and the mixture was stirred at that temperature for 2.5 hours. A saturated ammonium chloride aqueous solution (4.5 mL) and water (4.5 mL) were added to the reaction mixture in that order, and extraction was performed with ethyl acetate (9.0 mL). The aqueous layer was extracted twice with ethyl acetate (9.0 mL), and the combined organic layers were washed with a sodium chloride aqueous solution (4.5 mL) and dried over anhydrous sodium sulfate. A portion (22.1%) of the organic layer was sampled for 1H-NMR quantification, and the solvent was distilled off from the remaining organic layer under reduced pressure. A mixed solvent (7.0 mL) of heptane and t-butyl methyl ether (15:1) was added to the residue to form a suspension, and the suspension was stirred. The precipitated solid was collected by filtration, washed with a mixed solvent (3.5 mL) of heptane and t-butyl methyl ether (15:1), and dried under reduced pressure to obtain the title compound (321 mg, 1.7 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N[CH2:33][CH2:34][SH:35].C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]4[S:35][CH2:34][CH2:33][N:28]=4)[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Reactant: NCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C2=NCCS2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile (100 mg, 0.24 mmol) in methanol (20 mL) was added 2-aminoethanethiol hydrochloride (41 mg, 0.36 mmol) and triethylamine (0.1 mL, excess). The reaction mixture was heated to reflux for 14 h and cooled to room temperature. After concentration, the residue was purified by prep. HPLC to yield the title compound (76 mg, 66%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.10 (1H, s), 7.71 (1H, s), 7.66 (1H, s), 7.25–7.53 (4H, m), 6.33 (1H, d, J=7.6 Hz), 5.01 (1H, dd, J=4.2, 7.0 Hz), 4.58 (2H, t, J=8.6 Hz), 3.91 (2H, t, J=8.6 Hz), 3.73 (1H, dd, J=4.2, 13.7 Hz), 3.63 (1H, dd, J=7.0, 13.7 Hz), 2.64 (3H, s). LCMS (M+H)+ m/z 480 (t=1.70 min.).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH2:21][C:22](=O)[CH3:23])=O)=[CH:16][C:15]=3[S:27]([CH3:30])(=[O:29])=[O:28])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>O1CCOCC1>[F:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]4[S:34][C:22]([CH3:23])=[CH:21][N:20]=4)=[CH:16][C:15]=3[S:27]([CH3:30])(=[O:29])=[O:28])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)CNC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(F)cc3c2C)c(S(C)(=O)=O)c1
Solvent: C1COCCO1
Product: Cc1cnc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)s1
Reaction time: 4.5 h
Yield: 77 %

Procedure:
Into 5 mL of 1,4-dioxane solution of 150 mg of 4-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)sulfonamido-3-methanesulfonyl-N-(2-oxopropyl)benzamide was added 135 mg of diphosphorus pentasulfide, followed by 4.5 hours of heating under refluxing. The reaction was terminated by adding water to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, successively and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 2/1 to 1/1) to obtain 115 mg of the title compound as amorphous.
Reaction SMILES: C(=O)([O-])[O-].[Mn+2:5].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH-].[Na+]>>[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8].[Mn+2:5].[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8]
Reactant: CCC(=O)O
Agent: [Mn+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(=O)[O-]
Reaction time: 10 h
Yield: 80 %

Procedure:
In a reaction vessel, 145.83 grams of manganese carbonate, 328.92 grams of propionic acid and 25.38 grams of sodium hydroxide, a relative molar ratio of 2:7:1 respectively, was combined and heated to reflux. Water was removed from the vessel during the reaction by means of a fractional distillation column. The reaction went to completion after 10 hours, producing a dark burgundy solution from which about 80 percent of the remaining acid was removed. The product solidified at 130° C. The final product contained 80.7 percent manganese propionate and 19.3 percent sodium propionate.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[N:9][N:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:11]=1[CH3:12])=[O:6]>C1COCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[N:10]2[C:11]([CH3:12])=[C:7]([C:5]([OH:6])=[O:4])[N:8]=[N:9]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1nnn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3 N NaOH (0.1 mL) was added to 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (synthesized according to general procedure GG, 22 mg, 0.047 mmol) in THF and the resultant reaction mixture stirred at 60° C. overnight. The following day, the reaction mixture was concentrated to dryness and purified by preparative TLC to generate the title compound: MS (ES) M+H expected 449.1, found 449.3.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[OH:9]O>C(O)(=O)C>[CH3:8][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:7])[CH:1]=1
Reactant: OO
Reactant: Cc1cccc(O)c1
Solvent: CC(=O)O
Product: CC1=CC(=O)C=CC1=O
Temperature: 55 °C

Procedure:
A mixture of m-cresol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and 2-methyl-1,4-benzoquinone formed (99%) was separated by chromatographic purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(=O)c1ccccc1OC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Br)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-acetylphenol: ESMS m/e: 576.6 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[Br:8][C:9]1[CH:10]=[C:11]([C:16](Cl)=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])[C:12]([Cl:15])=[N:13][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[Cl:25])[CH:3]=[CH:4][N:5]=2)[C:12]([Cl:15])=[N:13][CH:14]=1
Reactant: COC(CN)OC
Reactant: ClC(=Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Clc1cccc(-n2ccnc2-c2cc(Br)cnc2Cl)c1Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 2,2-dimethoxyethanamine (0.053 g, 0.505 mmol) in anhydrous tetrahydrofuran (5 mL) at 0-5° C. was added the N-((5-bromo-2-chloropyridin-3-yl)chloromethylene)-2,3-dichlorobenzenamine (0.1 g, 0.2526 mmol) as a solution in anhydrous tetrahydrofuran (5 mL). After stirring overnight, p-toluene sulfonic acid (0.05 g, 0.51 mmol) was added and the reaction mixture was stirred an additional 2 hours. After concentration to dryness the resulting solid purified by flash chromatography (0 to 30% ethyl acetate/methylene chloride) to provide 0.092 g of 5-bromo-2-chloro-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridine. Using the same procedure, 5-bromo-2-chloro-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridine and 5-bromo-2-chloro-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridine can be produced from 5-bromo-2-chloro-N-(2,3-difluorophenyl)pyridine-3-carboxamide and 5-bromo-2-chloro-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:19](=[O:20])[CH2:18][CH2:17][O:16][CH3:15])=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Reactant: COCCC(=O)Cl
Solvent: CCOCC
Product: COCCC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 2.62 g. of 1-(2',4'-difluoro-4-biphenylyl)-3-hydroxypropan-1-one, obtained by acylating 2,4-difluorobiphenyl with 3-methoxypropionyl chloride to give 1-(2',4'-difluoro-4-biphenylyl)-3-methoxypropan-1-one and subsequently effecting ether scission, in 20 ml. of THF is added dropwise, at 20° to stirred Grignard solution prepared from 3 g. of methyl iodide and 0.5 g. of magnesium in 100 ml. of ether. The mixture is stirred for 4 hours more and the resulting alcoholate is decomposed with water and dilute sulfuric acid. The reaction mixture is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.