Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CC#N>[CH2:23]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a mixture of ethyl 1H-pyrazole-4-carboxylate (35.0 g, 250 mmol) and K2CO3 (69.0 g, 500 mmol) in CH3CN (250 mL) was added BnBr (42.7 g, 250 mmol). The mixture was stirred at RT for 18 h and concentrated. The residue was suspended in EA (500 mL), washed with water (200 mL×2), dried over Na2SO4 and concentrated to give the desired compound as a white solid (53.0 g, 91.2%). 1H NMR (DMSO-d6) δ 8.46 (s, 1H), 7.88 (s, 1H), 7.41-7.19 (m, 5H), 5.37 (s, 2H), 4.21 (q, 2H, J=5.4 Hz), 1.25 (t, 3H, J=5.4 Hz). MS (ESI) m/e [M+1]+ 231.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].Cl.[C:19]([C:22]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]1)(O)=[O:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH:17][C:19]([C:22]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]1)=[O:20]
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: NC(=O)C1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1(C(=O)Nc2ccc(OCc3ccc(F)cc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A mixture of 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (272 mg, 1 mmol), 1-carboxycyclopropanecarboxamide (129 mg, 1 mmol), N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (EDCI, 211 mg, 1.1 mmol) and triethylamine (111 mg, 1.1 mmol) in DCM (7 mL) was stirred at rt for 2 h. Then the mixture was poured into water and the mixture extracted with DCM. The combined organic extracts were then dried and evaporated to afford the title compound (130 mg, 38%) as a light brown solid after purification by chromatography on silica gel eluting with ethyl acetate: heptane (1:1 to 3:1). MS: m/e=347.0 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 46.3 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloro-2-cyanopyridine (80 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (2 mL) yielded 60 mg (46%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.7 %

Procedure:
A solution of 5-hydroxy-1H-indole (0.13 g, 1.0 mmol) in acetonitrile (10 mL) was successively added with N-(2-chloroethyl)morpholine hydrochloride (0.19 g, 1.0 mmol), and potassium carbonate (0.28 g, 2.0 mmol), and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure, then the residue was added with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (50:50→20:80)) to obtain 4-[2-(1H-indol-5-yloxy)ethyl]morpholine (0.12 g, 50%).
Reaction SMILES: Br.C(OC(=O)[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]2[CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=4)[N:20]=[CH:19][C:18]=3[O:17][CH2:16]2)[CH2:11][CH2:10]1)(C)(C)C>C(O)(=O)C>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH:15]2[CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=4)[N:20]=[CH:19][C:18]=3[O:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Agent: Br
Solvent: CC(=O)O
Product: N[C@H]1CC[C@H](C2COc3cnc4ccc(O)cc4c3C2)CC1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
47% Hydrobromic acid (36 mL, 0.33 mol, 75.0 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester (1.8 g, 4.36 mmol, 1.0 eq) in acetic acid (25 mL). After 18 hours stirring at 130° C., the reaction mixture is cooled down to 0° C. and the resulting precipitate is collected by filtration, washed with acetonitrile and dried under high vacuum to afford 3-(trans-4-amino-cyclohexyl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-6-ol as a light yellow solid (1.13 g, 87% yield).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:14][S:15]([O:13][CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC1CCC(CO)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
8.0 g of 4-n-pentylcyclohexylmethanol was dissolved in a mixture solvent of 8 ml of pyridine and 8 ml of toluene. To the solution, 6.0 g of methanesulfonyl chloride was added dropwise below 10° C., followed by stirring overnight at room temperature. After the reaction, the reaction mixture was poured into cold water and subjected to extraction with toluene, followed by washing successively with 5%-hydrochloric acid aqueous solution and water and drying with anhydrous magnesium sulfate. The resultant organic layer was subjected to filtration, followed by distilling-off of the solvent to obtain 11.3 g of 4-n-pentylcyclohexylmethyl methanesulfonate.
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][C:9]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].[CH3:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O.Cl>O1CCCC1.CC(C)=O.O>[CH3:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1/[CH:30]=[C:12]1/[C:11](=[O:14])[CH:10]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:9](=[O:8])[CH2:13]/1
Reactant: Cc1ccsc1C=O
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)C/C(=C\c3sccc3C)C2=O)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Potassium tertiary butoxide (0.53 g, 4.72 mmol) is added to a cold solution of mixture of 3-Methoxy-2-(2,4,6-trimethylphenyl)cyclopent-2-enone (0.5 g, 2.16 mmol) in tetrahydrofuran (5 ml). The reaction mixture is stirred for 30 minutes at 0° C. and to this mixture is added a solution of 3-methyl-2-thiophene carboxaldehyde (0.23 g, 1.82 mmol) in tetrahydrofuran (1 ml). The reaction mixture is stirred at 0° C. for 2 hours, acidified to pH 1 with 2N aqueous hydrochloric acid and the aqueous phase is extracted with ethyl acetate (3×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulphate. The mixture is filtered, and the filtrate is evaporated under reduced pressure to give a crude residue. The crude residue is dissolved in acetone (6 ml), added concentrated hydrochloric acid (3 ml) and the resulting solution is heated to 60° C. for 8 hrs. The reaction mixture is diluted with water and extracted with ethyl acetate (3×25 ml). The combined organics are washed with brine, dried over sodium sulphate, filtered and concentrated in vacuum to give a residue. This residue is then purified using silica gel column chromatography to give 4-[1-(3-methylthiophen-2-yl)-meth-(E)-ylidene]-2-(2,4,6-trimethylphenyl)cyclopentane-1,3-dione (100 mg).
Reaction SMILES: NCCCCCCN.[CH2:9]([P:11]([CH2:18][CH2:19][C:20]#[N:21])(=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10].[H][H]>[Ni].[OH-].[K+].O>[CH2:9]([P:11]([CH2:18][CH2:19][CH2:20][NH2:21])(=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10]
Reactant: [H][H]
Reactant: CCCCOP(=O)(CC)CCC#N
Agent: [Ni]
Agent: NCCCCCCN
Agent: [K+]
Solvent: O
Product: CCCCOP(=O)(CC)CCCN
Reaction time: 8 h
Yield: 80.9 %

Procedure:
In a glass autoclave, 240 g of hexamethylenediamine, 52 g of water, 6.4 g of Raney® nickel (doped with 1.5% by weight of chromium), 0.18 g (4 mmol) of potassium hydroxide, 75.1 g (0.37 mol) of butyl ethyl(2-cyanoethyl)phosphinate (produced as in Example 8) are reacted at 50° C. with hydrogen at 25 bar. After 8 hours, the autoclave is let down. For purification, the reaction solution is filtered, passed through a column charged with Deloxan® THP II and concentrated in vacuo. The product is purified by chromatography to obtain 62.0 g (81% of theory) of butyl ethyl(3-aminopropyl)phosphinate as colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:13][N+:14]1[N:15]([CH3:26])[C:16](Cl)=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:26][N+:15]1[N:14]([CH3:13])[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:16]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cn1c(Cl)cc(-c2ccccc2)[n+]1C
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cn1c(-c2ccccc2)cc(N2CCCCC2)[n+]1C

Procedure:
Piperdine (2.56 g, 0.03 mole) is added to 1,2-dimethyl-3-chloro-5-phenylpyrazolium methyl sulfate (4.77 g, 0.015 mole) in absolute ethanol (30 ml) and the mixture stirred with a bar magnet and heated under reflux for 4 hours. After cooling, the reaction mixture is evaporated under reduced pressure to a brown oil, and the dissolved in 50 ml of aqueous saturated sodium bicarbonate solution. The aqueous layer is extracted with ether and this organic layer discarded, then with chloroform. Evaporation of the chloroform layer affords 1,2-dimethyl-3-phenyl-5-piperidinopyrazolium methyl sulfate as a viscous oil. The oil is redissolved in water and saturated aqueous potassium iodide solution is added. An immediate copious white precipitate of 1,2-dimethyl-3-phenyl-5-piperidinopyrazolium iodide is formed, then filtered and washed with ice cold water to give 3.37 g, (56%) of product having a melting point ranging from 179° to 180° C. The melting point is unchanged by dissolving in chloroform, filtering and reprecipitating with diethyl ether and filtering off the solid. The analysis of resultant product is set forth below in Table I, compound 1, following Example 12, hereinbelow.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].[CH3:21]O>>[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[CH:12][C:8]=1[C:9]([O:11][CH3:21])=[O:10]
Reactant: CO
Reactant: COc1cc(C(=O)O)c(Br)cc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(OC)c(C)cc1Br
Temperature: 70 °C

Procedure:
H2SO4 (0.5 mL, 9.3 mmol) was added to a suspension of 2-bromo-5-methoxy-4-methylbenzoic acid (4.07 g, 16.6 mmol) in MeOH (40 mL) and the resulting rxn mixture was heated to 70° C. overnight. The rxn mixture was cooled to 0° C. and basified with 1M aq. NaOH (10 mL) to pH 11. The rxn mixture was extracted with DCM and the combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield methyl 2-bromo-5-methoxy-4-methylbenzoate as a yellow solid that was used as such in the next step without purification. LC-MS A: tR=0.90 min, [M+H]+=258.91.
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[CH3:18][O-:19].[Na+].Cl>O>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2)=[C:3]([N+:15]([O-:17])=[O:16])[C:2]=1[O:19][CH3:18]
Reactant: C[O-]
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1c(F)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Reaction time: 0 h
Yield: 77.5 %

Procedure:
To a solution of 21 mg (0.086 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione in 0.5 mL of DMSO-d6 was added 16 mg (0.29 mmol) of sodium methoxide. The solution was shaken in a vortex for 10 s and kept at room temperature for 3 h. It was then added to 3 mL of water and acidified with 2 N HCl to pH=4. The precipitate was filtered, washed with water, and dried to leave a yellow solid (17 mg, 77%); mp 290-292° C.; 1H NMR (DMSO-d6), 3.899 (s, 3), 7.163 (1, d, J=11.6), 11.97 (mb, 1), 12.137 (s, 1). 19F NMR, -134.48 (mb). MS, 255 (M+, 100), 243 (15), 179 (16), 151 (40). HRMS, Calcd for C9H6FN3O5 255.0287, found 255.0308.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:15]=[N:14][C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([NH:7][CH3:6])[CH2:9]5)=[CH:18][CH:17]=4)[CH2:24][CH2:23][C:22]=3[CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Dissolve ((R)-1-{5-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.367 g, 0.70 mmol) in DMF (10 mL). Treat the mixture with 60% NaH (33.7 mg, 0.84 mmol). Stir the resulting suspension at room temperature for 1 h. Add iodomethane (66 μL, 1.05 mmol) and stir at room temperature for 3 h. Quench the mixture with water (35 mL) and extract with EtOAc (3×40 mL). Wash the combined organic layers with water (3×30 mL), dry with Na2SO4, filter, and concentrate. Dissolve the resulting crude material in CH2Cl2 (5 mL), treat with TFA (3 mL) and stir at room temperature for 1 h. Remove the excess reagent in vacuo. Dilute the residue with CHCl3 (40 mL) and wash with 2.0 M NaOH (30 mL). Treat the cloudy organic layer with CH3OH (1.0 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 10% CH3OH (with 2M NH3)/CHCl3 to give 0.222 g (72%) of 2-(4-chloro-phenyl)-6-[6-((R)-3-methylamino-pyrrolidin-1-yl)-pyridin-3-yl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:15])([C@H:12](O)[CH3:13])[CH2:10]O.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:15])([C@H:12]([S:17]([CH3:16])(=[O:19])=[O:18])[CH3:13])[CH2:10][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@](O)(CO)c1cc(F)ccc1F
Product: C[C@H]([C@](O)(CS(C)(=O)=O)c1cc(F)ccc1F)S(C)(=O)=O
Yield: 218.6 %

Procedure:
In the same manner as that described in Example 7(iii) above, 4.80 g (10.1 mmol) of (2R,3 R)-2-(2,5-difluorophenyl)-1,2,3-butanetriol [prepared as described in Step 8(ii) above] were reacted with 7.75 g (67.8 mmol) of methanesulfonyl chloride and the resulting product was purified by chromatography on a silica gel (110 g) column using a 1:2 to 1:1 mixture of ethyl acetate and hexane as the eluant to afford 7.56 g (yield 92%) of the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].O>C(#N)C>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)CCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.775 mmol) in acetonitrile (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and N,N-dimethylethylenediamine (82 mg, 0.93 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (240 mg, 95% yield) as orange crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:11]2)#[N:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a suspension of 1F (103.9 mg, 0.6 mmol) in CH3CN (3 mL) at RT under argon was added DIPEA (0.11 mL, 0.66 mmol), followed by dropwise addition of benzene sulfonylchloride (0.08 mL, 0.63 mmol). The reaction mixture was stirred at RT for 1.5 h, then concentrated under reduced pressure. The residue was taken into EtOAc, washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (30-50%) in hexane to give the title compound (170 mg, 90%). HPLC: 99% at 5.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 314 [M+H]+.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]([C:11]2[N:12]3[CH2:18][CH2:17][N:16]=[C:13]3[S:14][CH:15]=2)=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.[CH3:23][S:24]SC.[Cl-].[NH4+]>O1CCCC1>[S:6]1[C:10]([C:11]2[N:12]3[CH2:18][CH2:17][N:16]=[C:13]3[S:14][C:15]=2[S:24][CH3:23])=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2
Reactant: CSSC
Reactant: C1=C(c2cc3ccccc3s2)N2CCN=C2S1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Temperature: -70 °C
Reaction time: 0.42 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes; 4.0 ml) was added dropwise under nitrogen at −70° C. to a stirred solution of 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole (2.58 g; prepared in a manner similar to that described in Example 15) in tetrahydrofuran (40 ml), then the mixture was stirred at −70° C. for 25 minutes. Dimethyl disulphide (0.9 ml) was added, the mixture was stirred at ambient temperature for 2 hours, then it was poured into saturated aqueous ammonium chloride solution (200 ml). The product was extracted into ethyl acetate (300 ml), then the extract was washed with water (200 ml) and saturated aqueous sodium chloride solution (2×100 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 3-(benzo[b]thiophen-2-yl)-2-(methylthio)-5,6-dihydroimidazo[2,1-b]thiazole (0.79 g) as a yellow solid, m.p. 95-97° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-:15].[K+]>C(O)CCC>[CH2:2]([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [K+]
Solvent: CCCCO
Product: CCCCOCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 14.9 %

Procedure:
11-bromoundecanoic acid (2 g, 17.5 mmol) was added to a solution of potassium hydroxide (1.7 g, 30.2 mmol) in 1-butanol (20 mL) and the solution was stirred at 40° C. for 5 hrs. After cooling, the reaction mixture was extracted with ethyl acetate and water at pH=2. The organic phase was then washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified over silica column chromatography in 2-10% ethyl acetate/hexane/0.2% formic acid to yield 11-(1-butoxy)undecanoic acid (336 mg, 17%). mp 29°-30.5° C.; 1H NMR (300 MHz, CDCl3) δ 0.84-0.96 (t, 3H, J=7.3, CH3), 1.18-1.46 (bm, 14H, methylene envelope), 1.47-1.68 (bm, 6H, CH2CH2OCH2CH2, CH2CH2COOH), 2.31 (t, 2H, CH2COOH), 3.32-3.46 (bm, 4H, CH2OCH2), 11.02 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3 δ 14.02, 19.43, 24.74, 26.21, 29.11, 29.28, 29.35, 29.56, 29.64, 29.76, 31.85, 34.14, 70.63, 70.94, 179.82; m/z 259 (M+H).
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:15][C:18]1[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 95.9 %

Procedure:
A solution of n-tridecanoic acid (Sigma Chemical Co, 12.5 g), 2,4,5-trichlorophenol (11.5 g), and N,N'-dicyclohexylcarbodiimide (12.0 g) in methylene chloride (650 ml) is stirred at room temperature for 16 hours. The reaction mixture is then filtered and dried in vacuo to give 2,4,5-trichlorophenyl tridecanoate (22 g). The material is purified by column chromatography over silica gel (Woelm) using toluene as the eluent. Fractions are monitored by TLC using a shortwave UV light for detection. Fractions containing the purified product are pooled and concentrated in vacuo to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[NH:12][C:11](=[S:21])[C@H:10]([CH2:22][C:23]([O:25]C)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[NH:12][C:11](=[S:21])[CH:10]([CH2:22][C:23]([OH:25])=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=NC(CC(=O)O)C(=S)N2
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of racemic Intermediate 6 (2.6 g, 6.7 mmol) in 1,4-dioxane (70 mL) at RT was added slowly 1N NaOH (13.5 mL) and the reaction mixture was stirred overnight before adding another 1N NaOH (13.5 mL). The mixture was then further stirred for 2 h before 1,4-dioxane was removed in vacuo. The aqueous layer was acidified with 1N HCl to ca pH 6 and extracted with DCM. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.9 g, 76% yield) as a yellow solid. LC/MS: m/z 375 [M(35Cl)+H]+, Rt=1.6 min.