Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH2:14][C:15](N1CCCC1)=[O:16].Cl.[O:23]1CCOCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[CH2:14][C:15]([OH:16])=[O:23]
Reactant: C1COCCO1
Reactant: O=C(Cc1ccc(CN2CCCC2)cc1Cl)N1CCCC1
Agent: Cl
Product: O=C(O)Cc1ccc(CN2CCCC2)cc1Cl
Yield: 25 %

Procedure:
A solution of 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine (crude, max. 44.70 mmol) in dioxane (100 ml) was stirred at r.t. A 6 M HCl solution was added. The mixture was stirred and refluxed for 3 days. The mixture was concentrated in vacuo. The residue was taken up in water and the mixture was brought to pH 10 with a 4 N NaOH solution. The solution was washed with diethyl ether (3×40 ml). The aqueous layer was acidified to pH 3 with a 6 N HCl solution. The mixture was concentrated in vacuo. The residue was purified by neutral high performance liquid chromatography (Column: Lana 300×50 mm, 10 μm; Mobile Phase: 0-20% CH3CN in water; Flow Rate: 80 ml/min; Finished Time: 25 min). The desired fraction was collected and evaporated in vacuo. Yield: 2.8 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (25% yield over last 3 steps).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[C@H:5]1[CH2:4][CH2:3]2.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>C(O)=O>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[CH2:13][CH2:12]3
Reactant: CN(C)CCCN
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O=CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCCN(C)C)CC[C@@H]12
Reaction time: 48 h

Procedure:
Formic acid (97-98%, 47.5 ml) is added dropwise to a cooled and stiffed mixture of estrone methyl ether (71.0 g) and 3-dimethylaminopropylamine (158 ml). The resulting mixture is heated in an oil bath (165°-175° C.) for 20 hours. The reaction is quenched in ice water (total volume 700 ml) and the resulting alkaline (pH--9) mixture is extracted twice with CH2Cl2. The combined extracts are washed with dilute aq. NAOH and with brine, dried (Na2SO4), filtered, and concentrated, Hexane (250 ml) is added to the residue and a white fluffy precipitate is filtered off, The solvent is removed, leaving a residual light brown oil which slowly crystallizes. A portion (20 g) of this material is chromatographed over silica gel (500 g) packed as a slurry in 7.5% of 10% NH4OH--CH3OH in CH2Cl2. The column is eluted (300 ml fractions) with the same solvent system. The desired material (about 14 g) is eluted in fractions 13-26 and pooled in CH2Cl2. As this solution stands at 20°-25°, crystals form. After two days, the crystals (4.803 g), mp 184°-192° C. with rapid heating, are collected by filtration. More crystals form in the filtrate and after 3 days these are collected. The compound can be recrystallized from methanol-acetone in the freezer, giving the second title compound as crystals, mp 184°-186° C. decomposition (dec) with bubbling.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17](SC)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>ClCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][N:18]=[C:17]([S:40]([CH3:43])(=[O:42])=[O:41])[N:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(C(=O)Nc2ccccc2)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To a stirred solution of 6 (0.35 g, 0.7 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dichloromethane (10 mL) at 0° C. was added mesyl chloride (0.12 g, 1.05 mmol) and then the reaction mixture stirred at room temperature for 1 h. It was quenched with water; the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to obtain 7 as colorless oil (0.4 g, crude).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:14]([CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:49][O:50][CH2:51][CH2:52]O.C(Cl)Cl.CCOC(/N=N/C(OCC)=O)=O>>[F:1][C:2]1[C:3]2[N:4]([C:14]([CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH2:52][CH2:51][O:50][CH3:49])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[CH:7]=1
Reactant: COCCO
Reactant: Cc1cc(-c2cc(F)c3nnc(COc4ccnc5cc(O)ccc45)n3c2)on1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)no5)cn34)ccnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol (0.110 g, 0.28 mmol), PPh3 (polymer supported: 2.3 mmol/g) (1.2 g, 2.8 mmol) and 2-methoxyethanol (0.11 ml, 1.3 mmol) were combined in DCM (11 ml, 0.28 mmol). The mixture was cooled to 0° C., and DEAD (0.089 ml, 0.56 mmol) was added dropwise. The reaction was removed from the ice bath, and stirred at RT for 1 h. The material was diluted with DCM, and the PS-PPh3 was filtered off and washed thoroughly with DCM. The filtrate was concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with 0-100% 90:10:1 DCM:MeOH:NH4OH in DCM) to yield 4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline (0.070 g, 55% yield) as a white solid. MS (ESI pos. ion) m/z: 450.0 (M+H). Calc'd Exact Mass for C23H20FN5O4: 449.44
Reaction SMILES: C(=O)([O-])[O-].Cl.[NH:6]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[NH2:7].C(O[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21])C>C(Cl)Cl.CO>[NH2:23][C:22]1[N:6]([C:8]2[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[CH:18][C:19]=1[C:20]#[N:21]
Reactant: Cc1ncccc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ncccc1-n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.4 %

Procedure:
MP-carbonate (2.64 mmol/g) (2.6 g, 6.80 mmol) was added to 3-hydrazinyl-2-methylpyridine hydrochloride (Intermediate V2) (362 mg, 2.27 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered and evaporated. 2-(Ethoxymethylene)malononitrile (277 mg, 2.27 mmol) was added to suspension of the above solid in MeOH (6 mL) under nitrogen cooled to −5° C. The reaction mixture was stirred at 0° C. for 30 mins and then allowed to warm to room temperature and heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (210 mg, 46.5%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.23 (3H, s), 6.65 (2H, s), 7.39-7.43 (1H, m), 7.74 (1H d), 7.79 (1H, s), 8.58-8.60 (1H, m), m/z (ESI+) (M+H)+=200; HPLC tR=1.21 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc(-c2ccccc2)c1
Product: Clc1ncccc1-c1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Dissolve 3-phenyl-pyridine 1-oxide (1.0 g, 5.84 mmol) in phosphorus oxychloride (14 mL, 153 mmol). Heat the reaction to 105° C. for 6 hours, cool to ambient temperature and pour reaction mixture slowly onto ice with stirring to quench the excess phosphorus oxychloride. Basify with concentrated ammonium hydroxide and extract with dichloromethane. Wash the organic extract with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: ethyl acetate-hexanes) to give 315 mg (28%) of 2-chloro-3-phenyl-pyridine as a yellow liquid. MS (m/z): 190 (M+1, 100), 192 (M+1, 60). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, 1H, J=4.6, 2.0 Hz), 7.87 (dd, 1H, J=7.5, 1.8 Hz), 7.54-7.41 (m, 6H). 1-(3-phenyl-pyridin-2-yl)-piperazine: Heat a mixture of 2-chloro-3-phenyl-pyridine (1.12 g, 5.9 mmol) and piperazine (5.08 g, 59.0 mmol) in a sealed tube at 165° C. for 23 hours. Cool to ambient temperature. Dissolve the reaction mixture in water and ethyl acetate. Extract the aqueous layer with ethyl acetate (3×). Wash the organic extracts with water (2×) and brine. Re-extract the water washes with ethyl acetate. Combine all ethyl acetate extracts, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: 2N ammonia in methanol-dichloromethane) to give 1.36 g (96%) of the title preparation as a yellow oil. HRMS-FAB (m/z): [M+H]+ calc'd for C15H18N3, 240.1500; found, 240.1492.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:64][CH2:65][O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.O>CN(C)C(=O)C>[CH2:67]([O:66][CH2:65][CH2:64][N:19]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[CH3:60])[C:17]([O:24][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:48])[CH3:47])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: BrCCOCc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCOCc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2 g) in N,N-dimethylacetoamide (36 mL) were added sodium hydride (55%, 0.26 g) and benzyl 2-bromoethyl ether (0.76 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.89 g).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][CH:4]([OH:11])[C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][CH:4]([O:11][S:24]([CH3:23])(=[O:26])=[O:25])[C:5]([CH3:9])([CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)C(C)(C)C(O)C=C(Cl)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)C(C)(C)C(C=C(Cl)C(F)(F)F)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
733 g (3 mol) of 6-chloro-3,3-dimethyl-4-hydroxy-7,7,7-trifluoro-hept-5-en-2-one, 360 g (3.6 mol) of triethylamine and 1.5 g of 4-(N,N-dimethylamino)pyridine in 1 l of toluene were admixed at 5° C. with 378 g (3.6 mol) of methanesulfonyl chloride. The mixture was subsequently stirred at 25° C. for 3 hours, the precipitate was filtered off, and the filtrate was extracted with dilute hydrochloric acid and with saturated sodium bicarbonate solution. Drying and concentrating the organic phase gave 948 g of product. Melting point: 50°-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13][O:14]C1C=C(C=CC=1OC)C(OC)=O>>[CH3:13][O:14][C:4]1[CH:5]=[C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Product: COc1ccc(C(C)(C)N)cc1OC
Yield: 61 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 3,4-dimethoxybenzoate, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 61%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].[OH-].[Na+].Cl>C(#N)C.N1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)=[CH:4][CH:3]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(-n2nnnc2S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc(-n2nnnc2S)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thirty grams of 1-(p-aminophenyl)-1,2,3,4-tetrazole-5-thiol was dissolved in 300 ml of acetonitrile and 20 ml of pyridine, and 16 ml of methacrylic acid chloride was added dropwise to the resulting solution with agitation. After the addition of the methacrylic acid chloride, the mixture was agitated for 1 hour at room temperature. Thereafter, a 10% aqueous solution of sodium hydroxide was added and the mixture was agitated for a white. The mixture was rendered weakly acidic with dilute hydrochloric acid and the end compound was obtained as a white crystal in an amount of 29.4 g (yield, 72%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CCOC(/N=N/C(OCC)=O)=O.[Br:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:23][C:22]=1[CH3:28]
Reactant: CN(C)CCCO
Reactant: Cc1cc(O)ccc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCN(C)C)ccc1Br
Reaction time: 2 h
Yield: 60.4 %

Procedure:
3-Dimethylamino-propan-1-ol (251 μL, 2.14 mmol) and DEAD (973 μL, 2.14 mmol) were added to a solution of 4-bromo-3-methyl-phenol (200 mg, 1.07 mmol) and PPh3 (561 mg, 2.14 mmol) in THF (10 mL) at 0° C. The mixture was stirred for two hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give [3-(4-bromo-3-methyl-phenoxy)-propyl]-dimethyl-amine (176 mg, 61%).
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3][NH:2]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([N:5]1[CH2:6][CH2:7][S:1](=[O:9])(=[O:8])[NH:2][CH2:3][CH2:4]1)(=[O:13])=[O:12]
Reactant: O=S1(=O)CCNCCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNS(=O)(=O)CC1

Procedure:
To a solution of 1,2,5-thiadiazepane 1,1-dioxide (0.10 g, 0.67 mmol) in methylene chloride (2 mL) at −10 C was added methane sulfonyl chloride (0.06 mL, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol). After 72 hr the reaction was quenched with NaHCO3 (sat. aq.) and extracted into methylene chloride. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[C:6]([NH2:14])(=[S:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C>CC#N>[C:7]1([C:6]2[S:13][S:4][C:2](=[O:3])[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(Cl)SCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=c1nc(-c2ccccc2)ss1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
All the glassware were dried in the preheated oven prior to the reaction for two hours at 200° C. A 500 ml three neck round bottom flask was equipped with magnetic bar, thermometer, pressure equalizing funnel and a positive inflow of argon. The assembly was placed on to the magnetic stirrer having ice bath. Chlorocarbonyl sulfenyl chloride (9.55 grams, 72.87 mmol) was transferred to the reaction flask. 100 ml of CH3CN was also added to the flask. The mixture was cooled down to 10° C. Thiobenzamide (10 grams, 72.87 mmol) was dissolved in a separate flask using 80 ml of CH3CN and diisopropylethylamine (18.84 gm, 145.76 mmol). This solution was transferred to the pressure equalizing funnel. The thiobenzamide solution was added slowly to the reaction flask. The temperature of the flask raised to 12-15° C. The mixture was stirred for 30 min. at 5-10° C. The disappearance of the starting material and formation of two isomeric nonpolar spots was observed on TLC. The reaction mixture was filtered through a sintered funnel. The filtrate was rotaevaporated to dryness and left on high vacuum for two hours. The solid was crystallized with a mixture of hexanes and ethyl acetate in a ratio of 95:5, respectively. The upper nonpolar spot on the TLC was left behind in the mother liquor and characterized as 3,5-diphenyl-1,2,4-thiadiazole. The crystals of 3-phenyl-1,2,4-dithiazoline-5-one were light yellow in color and the recovery was 9.25 gm (65%). The yield of the crude mix was 75%. The structure of 3-phenyl-1,2,4-dithiazoline-5-one was confirmed by 1H-NMR (FIG. 1), 13C-NMR (FIG. 2), mass spectrometry (FIG. 3) and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (500 mg, 2.18 mmol, Astatec Pharmaceutical Technology Co.) in DMF (10 mL) was added methyl iodide (163 μL, 2.62 mmol, Sigma-Aldrich) and K2CO3 (904 mg, 6.53 mmol). These ingredients were stirred at a temperature of about 25° C. for 1 h after which the reaction mixture was quenched with water (20 mL), extracted three times with EtOAc (20 mL for each extraction), washed twice with water (20 mL for each wash), washed with saturated aqueous NaCl (10 mL), dried (MgSO4), and concentrated under reduced pressure to provide tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate as an oil. To a mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (2.18 mmol) in dioxane (10 mL) at a temperature of about 25° C. was added 4N HCl in dioxane (10.8 mmol). Then the reaction mixture was stirred at 50° C. for 2 h. Thereafter, the mixture was concentrated under reduced pressure to provide 380 mg of the hydrochloride of methyl 2-(pyrrolidin-3-yl)acetate as a colorless oil (yield 96% for two steps), the identity of which was confirmed using 1H NMR and LC/MS.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][C:6]=1[O:15][CH3:16].[C:17](Cl)(=O)[C:18](Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[O:15][CH3:16])[CH2:11][C:12](=[O:14])[CH2:18][CH2:17]2
Reactant: COc1cc(CC(=O)O)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCC(=O)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DCM solution of (4-Bromo-3-methoxyphenyl)acetic acid (900 mg, 3.67 mmol) was added oxalyl chloride (0.64 ml, 7.3 mmol) and a drop of DMF. The solution was allowed to stir at RT for 3 hours, at which point bubbling stopped. The volatiles were removed under vacuum, and the residue was redissolved in DCM. The solution was cooled to 0° C. To this solution was added aluminum trichloride (1.2 g, 9.2 mmol). After stirring the mixture for 15 minutes, ethylene was bubbled into the reaction. The reaction was poured into ice, extracted with DCM, washed with brine, and purified by MPLC. LC-MS (IE, m/z): 255 [M+1]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CCN(C(C)C)C(C)C.C1C=CC(C([N:31]=[C:32]=[S:33])=O)=CC=1>ClCCl>[NH:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[CH2:4][NH:3][C:32]([NH2:31])=[S:33]
Reactant: NCc1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=S)NCc1nc2ccccc2[nH]1
Reaction time: 0.08 h
Yield: 61.4 %

Procedure:
To a suspension of 2-(Aminomethyl)benzimidazole dihydrochloride (0.66 g, 3.0 mmol) in dichloromethane (10 mL) was added DIPEA (1.05 mL, 6.0 mmol). The reaction mixture was stirred for 5 minutes and then benzoyl isothiocyante (0.44 mL, 3.3 mmol) was added dropwise. The resulting mixture was stirred for 1 h and then evaporated in vacuo. Ammonia (saturated, in MeOH, 15 mL) was added to the residue. After 4 h the reaction mixture was evaporated. Addition of CH2Cl2 to the residue afforded a solid, which was collected by filtration, washed with dichloromethane and dried to give the title compound (0.38 g, 62%). 1H NMR (DMSO-d6) δ ppm 12.32 (1H), 8.17 (1H), 7.52-7.19 (4H), 4.83 (2H); MS (ESI) m/z 205 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:23])=[O:22]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[C:16]([S:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:22])=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1Br
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Product: CCN(CC)S(=O)(=O)c1ccccc1-c1ccc(C(C)=O)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those described in Example 1 using (4-acetyl-3-fluorophenyl)boronic acid and 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. for C18H20FNO3S, 349.11; m/z found, 350.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J=7.9, 1.2, 1H), 7.92 (m, 1H), 7.61-7.56 (m, 1H), 7.55-7.49 (m, 1H), 7.29-7.27 (m, 2H), 7.25-7.24 (m, 1H), 2.95 (q, J=7.1, 4H), 2.69 (d, J=4.9, 3H), 1.01 (t, J=7.1, 6H).