Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]/[C:2](/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[C:3](/[F:8])\[Si](C)(C)C.[F-].[K+].O>C(#N)C>[F:1]/[C:2](/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[CH:3]/[F:8]
Reactant: CCCc1ccc(/C(F)=C(\F)[Si](C)(C)C)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCc1ccc(/C(F)=C\F)cc1
Yield: 82.7 %

Procedure:
Then, 19.1 g (0.075 mol) of the obtained (Z)-1,2-difluoro-1-(4-n-propylphenyl)-2-trimethylsilylethylene was dissolved in 50 ml of acetonitrile, and then 8.70 g (0.15 mol) of potassium fluoride and 4.05 g (0.225 mol) of water were added thereto. The mixture was reacted for one hour at 70° C. The reaction mixture was cooled, and then 200 ml of water was added thereto. The mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over CaCl2. After filtration, the solvent and low boiling substances were distilled off, and the residue was further distilled under reduced pressure to obtain 11.3 g (yield: 83%) of (E)-1,2-difluoro-1-(4-propylphenyl)ethylene.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].CN(C)C=O>C(OCC)C>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:46][CH:45]=[CH2:44])[C@@:16]2([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 424 mg, 0.8 mmol), potassium carbonate (770 mg), allyl bromide (0.5 ml) and N,N-dimethylforamide (3 ml) was stirred at room temperature for 3 days. The reaction mixture was treated with 1:1 mixture diethyl ether:iso-hexane, washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (362 mg, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][N:9]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:10]([CH3:11])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)NCCC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 0.935 g (0.005 mole) of 3-isopropylamino-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.6 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (IV-43).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]([OH:25])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]([Cl:28])=[O:25])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(C(=O)O)CCC2c2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C(C(=O)Cl)CCC2c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4.05 g, 11.1 mmol) in toluene (60 ml) was added thionyl chloride (1.21 ml, 16.7 mmol) and the mixture was stirred at 80° C. for 1.5 h. Evaporation of the solvent yielded (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic chloride as a light brown solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[CH:32]=O>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:32][C:31]1[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:29]([O:28][CH3:27])[CH:30]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(=O)c4ccccc4oc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)-4-acetylxanthen-9-one (2.4 g, 0.0075 mol) and 3, 4, 5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.2 g of product m.p. 153-55° C., 1H NMR (CDCl3) δ:1.69 (s, 3H); 1.72 (s, 3H); 3.85-3.91 (m, 9H); 4.73 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 6.78 (s, 2H); 7.03 (d, 1H, J=16 Hz); 7.09 (d, 1H, J=8.8 Hz); 7.23-7.42 (m, 2H); 7.27 (d, 1H J=16 Hz); 7.80-7.87; (m, 1H); 8.32 (d, 1H, J=8.8 Hz); 8.44 (d, 1H, J=8.9 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[C:11]1([CH:21]2[CH2:23][O:22]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C>[OH:9][CH2:8][CH2:7][O:10][CH2:23][CH:21]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[OH:22]
Reactant: c1ccc2c(C3CO3)cccc2c1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCCOCC(O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 4.5 g of potassium tert-butoxide and 45 ml of ethylene glycol was heated to 80° C. Thereto was dropwise added 13.7 g of 2-(1-naphthyl)oxirane in 1 hour. The resulting mixture was stirred for 1 hour at the same temperature. The reaction mixture was cooled and added to a mixture of 50 ml of ethyl acetate and 50 ml of ice water. The organic layer was separated. The aqueous layer was extracted twice each with 20 ml of ethyl acetate. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=1/3) to obtain 8.3 g of 2(2-hydroxyethoxy)-1-(1-naphthyl)ethanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:9]O)[NH:8][C:4]=2[N:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:9][C:7]1[NH:8][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: OCc1cc2scnc2[nH]1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2scnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of (4H-pyrrolo[2,3-d]thiazol-5-yl)methanol (3.5 g, 22.7 mmol) in anhydrous dichloromethane (50 mL) was added triethylsilane (5.23 g, 45.4 mmol) dropwise below 0° C., trifluoroacetic acid (5.18 g, 45.4 mmol) was added dropwise followed below 0° C. The resulting reaction system was warm to the ambient temperature and allowed to stir for 2 hours at room temperature. The reaction mixture was poured into saturated sodium bicarbonate, extracted with dichloromethane (50 mL×3), the combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 15:1→8:1) to give the title compound (2.5 g, 80%) as a yellow solid. LCMS (M+H+) m/z: calc'd. 138.03. found 138.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([CH:8]2OCC[O:9]2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:13]([OH:16])([CH3:14])[CH3:15])[CH:3]=1)[CH:8]=[O:9]
Reactant: CC(C)(O)c1cc(Cl)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)c1cc(Cl)cc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
To a solution of 2-(3-chloro-5-(1,3-dioxolan-2-yl)phenyl)propan-2-ol (5.45 g, 22.46 mmol) in acetone (50 mL) was added p-toluenesulfonic acid hydrate (0.85 g, 4.47 mmol) and the reaction mixture was stirred at room temperature for 1 h to give an orange-red solution. The solvent was evaporated in vacuo to give an orange-brown residue. The residue was partitioned between aqueous saturated NaHCO3 solution (25 mL) and ethyl acetate (50 mL), the organic layer was removed, washed with brine (1×25 mL), dried over anhydrous sodium sulfate, filtered and evaporated in-vacuo to give an orange-red viscous liquid (4.75 g). Purification of the crude product by Silica-gel flash chromatography on silica gel column and elution with 5-40% ethyl acetate in n-hexane afforded the desired product as a cream crystalline solid (2.35 g). 1H NMR (400 MHz, CDCl3): δ 1.59 (s, 6H, (CH3)2C—OH), 1.76 (brs, 1H, (CH3)2C—OH), 7.71 (dd, J=1.80 Hz, 1H), 7.75 (appt, J=1.80 Hz, 1H), 7.85 (appt/dd, J=1.40 Hz, 1H), 9.96 (s, 1H, —CHO). 1H NMR spectrum of the solid was consistent with the suggested structure of the product.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O[CH:13]([CH3:16])[CH:14]=O)(=O)C>[Fe].CO>[CH3:8][O:7][C:1]([C:2]1[CH:14]=[C:13]([CH3:16])[O:4][C:3]=1[CH3:5])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)OC(C)C=O
Agent: [Fe]
Solvent: CO
Product: COC(=O)c1cc(C)oc1C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
27 parts by weight of anhydrous iron-III chloride are added to a solution of 116 parts by weight of methyl acetoacetate in 120 parts by weight of methanol and thereafter 149 parts by weight of 85.5 percent strength α-acetoxypropionaldehyde are added dropwise, sufficiently slowly that the temperature does not rise above 37° C. The mixture is stirred overnight at room temperature (20° C.), is then boiled for 2 hours, and, when it has cooled, is worked up as described in Example 1. Distillation gives 116.6 parts by weight of 2,5-dimethylfuran-3-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH3:29])[C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:26][CH:25]=1
Reactant: CNc1ccc(OC)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Product: COc1ccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)cc1
Reaction time: 120 h
Yield: 37 %

Procedure:
Using the general procedure described above, the reaction of 6 (180 mg, 0.59 mmol) and 4-methoxy-N-methylaniline (612 mg, 4.46 mmol) was run for 120 hours, to provide 88 mg of 11 as a brown solid in 37% yield. TLC Rf 0.57 (chloroform-methanol 15:1); mp 288.5-289.4° C.; 1H NMR (DMSO-d6) 81.26 (s, 9H, C(CH3)3,) 3.60 (s, 3H, OCH3), 3.69 (s, 3H, NCH3), 5.87-7.33 (m, 8H, Ar—H), 9.58 (s, 1H, 2-NH, exch), 11.88 (s, 1H, 9-NH, exch).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][O:15][CH3:14])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
In 30 ml of 95% ethanol were dissolved 1.5 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.85 g of 4-(2-methoxyethoxy)benzyl bromide, and then 0.48 g of anhydrous sodium carbonate was added thereto. The resulting mixture was stirred overnight at room temperature, poured into water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure and the resulting solid was recrystallized from n-hexane-benzene to obtain 1.64 g of the aimed compound, m.p. 105.6°~107.3° C.
Reaction SMILES: [CH2:1]([N:6](C)[C:7](=[O:11])[O:8][CH2:9]Cl)[CH2:2][CH2:3][CH2:4][CH3:5].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:9][O:8][C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:11])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCCCCN(C)C(=O)OCCl
Agent: [Na+]
Product: CCCCCNC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 32.1 %

Procedure:
In the same manner as in step b) in Example 125, 125 mg of the title compound was prepared from 160 mg of chloromethyl N-pentan-1-yl-N-methylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.[CH3:30][S:31]C.[Na].C(COC)OC>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[S:31][CH3:30])=[CH:13][CH:14]=1
Reactant: CSC
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Agent: [Na]
Solvent: COCCOC
Product: CCCCCn1c2nc(SC)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 78.1 %

Procedure:
A mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (271 mg, 0.6 mmol) and sodium methyl sulfide (45.5 mg, 0.65 mmol) in dimethoxyethane (13.4 ml, 129 mmol) was refluxed for 2 h. The reaction was quenched with water. The solid formed was filtered and dried to yield the desired product (200 mg, 79.5%). LCMS calculated for C21H27N6O2S (M+H): 427.2; found 427.2.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and DIEA (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 10% hexane in ethyl acetate, affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′-Carbonyldiimidazole (CDI) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0.570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and DIEA (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 10% hexane in ethyl acetate, affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar 7 min).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>CN(C)C=O>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 140 °C
Yield: 91.75 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in N,N-dimethylformamide (70 mL) respectively and heated to 140° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.68 g, yield: 91.75%).
Reaction SMILES: [Li].[CH3:2][C:3]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([CH3:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.O>O1CCCC1>[CH3:9][C:3]([NH:10][S:11]([CH2:14][CH:21]([OH:22])[C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)(=[O:12])=[O:13])([CH3:2])[CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)CC(C)(C)NS(C)(=O)=O
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)CC(O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
nButyl lithium (1.6M in hexanes) (31.3 mL, 50 mmol) was added dropwise to N-(1,1,3,3-tetramethyl-butyl)-methanesulfonamide (5.23 g, 25 mmol) in tetrahydrofuran (30 mL) at −78° C. under an atmosphere of nitrogen. The mixture was warmed to 0° C. for 30 minutes then cooled to −78° C. 3-Pyridine carboxaldehyde (2.4 mL, 25 mmol) in tetrahydrofuran (20 mL) was added dropwise to the mixture over 20 minutes and the mixture was warmed to room temperature and stirred for a further 1 hour. Water (100 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate (2×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a pale yellow solid. The solid was washed with dichloromethane (10 mL) in heptane (100 mL) to afford 2-hydroxy-2-pyridin-3-yl-ethanesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide as a pale yellow solid (5.67 g, 72%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].[CH3:17]I.O>C1COCC1>[CH3:17][O:4][CH2:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:1])[CH3:5]
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol (prepared by the method described in WO02/66470) (200 mg, 1 mmol) in THF (15 mL) was added NaH (43 mg, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 20 min, MeI (0.22 mL, 1.5 mmol) was added and the mixture was stirred for 2 h at 0° C. then overnight at RT. H2O was added and the mixture was extracted with EtOAc. The organic phase was dried, filtered and evaporated to give 1-(2-methoxy-1,1-dimethyl-ethyl)-4-nitro-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1C
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
A solution of ethyl 3-(5-chloro-2-methylphenyl)-3-oxopropanoate (28.4 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75.3 mmol, 2.6 equiv) was heated at 90° C. After 3 hours, the reaction mixture was concentrated in vacuo, and the resultant residue was purified by flash column chromatography on silica gel (0 to 80% ethyl acetate in dichloromethane) to yield 2.87 g (34%) of ethyl 2-(5-chloro-2-methylbenzoyl)-3-(dimethylamino)acrylate. LCMS (ESI) m+H=296.3.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:39]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:39].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: CSc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]azetidine (117) (8.7 mmol) using the procedure described for compound (9) (2.29 g, 68%).