Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:2]([CH3:4])=[O:3].[CH:21]([NH2:24])([CH3:23])[CH3:22].[ClH:25].C([BH3-])#N.[Na+]>CO>[OH2:3].[ClH:25].[CH:21]([NH:24][CH:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:23])[CH3:22].[CH:21]([NH:24][CH:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:23])[CH3:22].[ClH:25]
Reactant: CC(C)N
Reactant: COc1ccc(C2=C(CC(C)=O)C(=O)NCCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Product: O

Procedure:
The solution of 13.6 g of 3-acetonyl-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 25.5 ml of isopropylamine, 10 ml of 5.8 N methanolic hydrogen chloride and 3.4 g of sodium cyanoborohydride in 260 ml of methanol is refluxed for three days. The mixture is cooled to 0°, acidified to pH=1 with concentrated hydrochloric acid and evaporated. The residue is taken up in water, the mixture washed with diethyl ether, rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and 13.5 g of the residual free base is dissolved in 80 ml of acetone. The solution is treated with 10.5 ml of 4.4 N ethanolic hydrochloric acid, the mixture evaporated, the residue crystallized from diethyl ether and recrystallized from isopropanol-ethyl acetate, to yield the 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone hydrochloride hemihydrate melting at 165°-167°.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]([O:5][C@H:6]1[C@@H:11]2[C:12]([CH2:15]OC(=O)C(C)(C)C)=[CH:13][CH2:14][C@@H:10]2[C:9]([C:23]([O:25][CH3:26])=[O:24])=[CH:8][O:7]1)=[O:4].C([O-])=O.[NH4+]>O1CCCC1.[C].[Pd]>[CH3:15][C:12]1[C@H:11]2[C@H:6]([O:5][C:3](=[O:4])[C:2]([CH3:28])([CH3:27])[CH3:1])[O:7][CH:8]=[C:9]([C:23]([O:25][CH3:26])=[O:24])[C@H:10]2[CH2:14][CH:13]=1
Reactant: COC(=O)C1=CO[C@@H](OC(=O)C(C)(C)C)[C@@H]2C(COC(=O)C(C)(C)C)=CC[C@H]12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1=CO[C@@H](OC(=O)C(C)(C)C)[C@@H]2C(C)=CC[C@H]12
Temperature: 80 °C
Yield: 76.3 %

Procedure:
Methyl (1S, 4aS, 7aS)-1,4a,5,7a-tetrahydro-1-trimethylacetoxy-7-(trimethylacetoxymethyl)cyclopenta[c]-pyran-4-carboxylate (200 mg, 0.00051 mol) obtained in Example 14 was dissolved in 15 ml of tetrahydrofuran, and 10% palladium carbon (10 mg) was suspended. After ammonium formate (320 mg, 0.0046 mol) was added, the reaction mixture was refluxed at 80° C. Twelve hours later, celite filtration was carried out, and 50 ml of ethyl acetate was added to the filtrate. After this organic layer was washed with saturated sodium chloride solution (30 ml), it was dried by adding magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=8:2 eluent was concentrated. A colorless oily substance was thus obtained, i.e., methyl (1S, 4aS, 7aS)-1,4a,5,7a-tetrahydro-7-methyl-1-trimethylacetoxycyclopenta[c]-pyran4-carboxylate (114.5 mg, yield=72.8%). This methyl (1S, 4aS, 7aS)-1,4a,5,7a-tetrahydro-7-methyl-1-trimethylacetoxycyclopenta[c]pyran-4-carboxylate had the following physicochemical properties:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[NH:4][C:3]1=O.[CH2:15]([C:17]1[O:21][N:20]=[C:19]([CH2:22][N+:23]#[C-:24])[N:18]=1)[CH3:16]>>[CH2:15]([C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:4]3[C:5]4[C:10](=[CH:9][C:8]([Cl:13])=[CH:7][CH:6]=4)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=23)[N:18]=1)[CH3:16]
Reactant: Cn1c(=O)[nH]c2ccc(Cl)cc2c1=O
Reactant: [C-]#[N+]Cc1noc(CC)n1
Product: CCc1nc(-c2ncn3c4ccc(Cl)cc4c(=O)n(C)c23)no1

Procedure:
M.p. 196°-198° C. by reaction between 3-methyl-6-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline and 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[C:10]([C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][C@H:12]2[N+:25]([O-])=O)=[C:9]([Si](C)(C)C)[S:8][CH:7]=1)=[O:5])[CH3:2].Cl>C(O)C.C(Cl)Cl.[Zn]>[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[C:10]([C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][C@H:12]2[NH2:25])=[CH:9][S:8][CH:7]=1)=[O:5])[CH3:33]
Reactant: CCN(CC)C(=O)c1csc([Si](C)(C)C)c1[C@@H]1c2cc(OC)c(OC)cc2CC[C@H]1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CCO
Product: CCN(CC)C(=O)c1cscc1[C@@H]1c2cc(OC)c(OC)cc2CC[C@H]1N
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of 554 mg of trans-4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-nitronaphthalene-1-yl) -5-trimethylsilyl-3-thiophenecarboxylic acid, N,N-diethylamide, from step 2c above, in 8 mL of ethanol and 3 mL of 6 N HCl was added 700 mg of Zn dust, and the mixture was stirred for 15 min. The mixture was diluted with 20 mL of methylene chloride, then filtered. The organic layer of the flitrate was separated. The aqueous layer was adjusted to pH 10 and extracted with methylene chloride. The extract was dried over Na2SO4, filtered and concentrated. The residue was dissolved in 7 mL of methanol, 3 mL of 6N HCl was added, and the solution was stirred for 4 hours. The methanol was evaporated off, and the residue was dissolved in 6 mL of water, which was then extracted with ether. The aqueous layer was adjusted to pH 10 and extracted with ethyl acetate. Removal of the solvent gave 256 mg of the title product. MS 389 (M+H)+. NMR (CDCl3) δ:7.24 (d, 1 H, J=6 Hz), 6.93 (d, 1 H, J=6 Hz), 6.58 (s, 1H), 6.43 (s, 1H), 4.23 (d, 1H, J=10 Hz), 3.85 (s, 3H), 3.67 (s, 3H), 3.64 (m, 1H), 3.50-3.30 (m, 4H), 3.0-2.76 (m, 2H), 2.32-2.22 (m, 1H), 1.90-1.80 (m, 1H), 1.26-1.12 (m, 6H).
Reaction SMILES: C(O[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C]=[O:12].CN1CCC[C:15]1=[O:19]>>[C:5]1([CH2:4][C:15]([OH:19])=[O:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN1CCCC1=O
Reactant: [C]=O
Reactant: O=COCc1ccccc1
Product: O=C(O)Cc1ccccc1
Reaction time: 2 h

Procedure:
The same autoclave as used in Example 17 is charged with 20 grams of benzyl formate, and 20 grams of N-methyl-2-pyrrolidone and 1.4 grams of mercurous iodide are added thereto. Carbon monoxide is introduced into the autoclave under pressure and the reaction is conducted at a pressure of 300 kg./cm.2 gauge and a temperature of 210° C. for 2 hours. As a result there is obtained phenyl acetic acid in a yield of 12.6 grams, which corresponds to a conversion of 63% based on the starting benzyl formate.
Reaction SMILES: [Br-].[CH2:2]([NH:6][S:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][PH3+])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]([CH3:5])[CH3:4].[H-].[Na+].[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)(=[O:23])=[O:22]>CN(C=O)C.CCOC(C)=O>[CH2:2]([NH:6][S:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:27]2[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Reactant: CC(C)CNS(=O)(=O)c1ccc(C[PH3+])cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CNS(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of 4-isobutylsulfamoyl-benzyl-phosphonium bromide (1.87 g, 3.29 mmol) in DMF (10 mL) was treated with NaH (60% dispersion in mineral oil, 329 mg, 8.22 mmol) and stirred at room temperature for 1 hour. 1-(Methylsulfonyl)piperidin-4-one (758 mg, 4.28 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) gave N-isobutyl-4-(1-methanesulfonyl-piperidin-4-ylidenemethyl)-benzenesulfonamide (392 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 6.43 (s, 1H), 4.40 (t, J=6.5 Hz, 1H), 3.37 (t, J=5.7 Hz, 2H), 3.25 (t, J=5.8 Hz, 2H), 2.82-2.76 (m, 5H), 2.60 (t, J=5.7 Hz, 2H), 2.53 (t, J=5.7 Hz, 2H), 1.80-1.66 (m, 1H), 0.88 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 523.1 [M+Na]+.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][CH3:21])=[C:10]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH:11]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][CH3:21])=[C:10]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH:11]=1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CC#N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 1.63 g potassium cyanide and 8 g of the compound from Example 1 in 50 ml of DMSO was stirred at room temperature overnight. The solution became darker in color with time, going from orange to purple to black. After being stirred overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The residual red oil was eluted through a dry silica column with 20% ethyl acetate--80% dichloromethane. The product band was isolated to give 3.0 g solid m.p. 146°-147° C.;
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])Cl.[C:10]([Li])#[C:11]C.[CH2:14](OCC)C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:14])[C:8]#[C:10][CH3:11]
Reactant: [Li]C#CC
Reactant: CCOCC
Reactant: C[Si](C)(Cl)CCCCBr
Product: CC#C[Si](C)(C)CCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
This novel monomer was synthesized by adding 6.7 g (0.029 mole) of 4-bromobutyldimethylchlorosilane dropwise at 0° C. to a stirred solution of propynyllithium (1.34 g, 0.029 mole) in 50 ml of dry diethyl ether. The reaction mixture was stirred overnight at 25° C. and then poured into 400 ml of ice water. The ether layer was washed with distilled water, separated, and dried over MgSO4. The ether layer was then filtered and the product separated by removing the ether using a rotovapor. The resulting oil was purified by vacuum distillation and had a b.p. of 70°-75° C. at 15 mm Hg pressure. Yield was 75% of theoretical. 'H NMR confirmed the structure.
Reaction SMILES: Cl.[CH3:2][OH:3].[N:4]([CH2:7][C:8]([C:10]1[N:11]=[CH:12][N:13]2[CH:17]=[CH:16][S:15][C:14]=12)=[O:9])=[N+]=[N-].[H][H]>CO.C1COCC1.[Pd]>[CH:2]([NH:4][CH2:7][C:8]([C:10]1[N:11]=[CH:12][N:13]2[CH:17]=[CH:16][S:15][C:14]=12)=[O:9])=[O:3]
Reactant: [N-]=[N+]=NCC(=O)c1ncn2ccsc12
Reactant: CO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: O=CNCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 110% hydrochloric acid/methanol solution (1 ml) and 120 mg of 10%Pd—C were added to a solution of 0.44 g of 7-azidoacetylimidazo[5,1-b]thiazole in 50 ml of methanol and 50 ml of THF. The atmosphere in the reactor was replaced with hydrogen. The system was stirred at room temperature for 2 hr. The reaction mixture was filtered. The solvent was removed by distillation. To the residue were added 10 ml of DMF, 0.39 g of 4-nitrophenyl formate, and 0.66 ml of triethylamine. The mixture was stirred at room temperature for 30 min. Dichloromethane was added to the reaction solution. The mixture was washed with water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 0.24 g of 7-formylaminoacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:15]([CH2:25][O:26]S(C)(=O)=O)([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C@H:11]([O:12][CH3:13])[C@@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C@H:10]2[O:26][CH2:25][C@:15]1([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:14][C@H:11]2[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 201 (3.32 g, 7.34 mmol) in anhydrous DMF (25 mL) was stirred at 0° C. and a 60% oil dispersion of sodium hydride (700 mg, 16.9 mmol) was added. The mixture was stirred at room temperature for 90 min, quenched with water (300 mL) and extracted with diethyl ether (2×300 mL). The combined extract was washed with water (200 mL) and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane as eluent to give the two products 202 and 203 as clear oils (1.571 g, 60% and 0.777 g, 30% respectively). (1S,3R,4R,7S)-7-Benzyloxy-1-benzyloxymethyl-3-methoxy-2,5-dioxabicyclo[2.2.1]heptane (202). 1H NMR (CDCl3): δ 7.36-7.26 (10H, m, Bn), 4.81 (1H, s, H-1), 4.65 (1H, d, J 11.9 Hz, Bn), 4.61 (2H, s, Bn), 4.56 (1H, d, J 11.9 Hz, Bn), 4.11 (1H, s, H-2), 4.09 (1H, s, H-3), 4.01 (1H, d, J 7.5 Hz, H-5′), 3.80-3.77 (3H, m, H-5′, H-5), 3.39 (3H, s, OCH3); 13C NMR (CDCl3): δ 138.05, 137.36, 128.47, 128.44, 127.88, 127.73, 127.63 (Bn), 104.97 (C-1), 85.13 (C-4), 79.16 (C-3), 77.18 (C-2), 73.64 (Bn), 72.26, 72.10 (Bn, C-5′), 66.50 (C-5), 55.34 (OCH3); MS FAB: 379 (M+Na, 28%). Found. C, 70.55; H, 6.97; C21H24O5 requires C, 70.77; H, 6.79%. (1S,3R,4R,7S)-7-Benzyloxy-1-benzyloxymethyl-3-methoxy-2,5-dioxabicyclo[2.2.1]heptane (203). 1H NMR (CDCl3): δ 7.36-7.26 (10H, m, Bn), 5.00 (1H, s, H-1), 4.67-4.54 (4H, m, Bn), 4.18 (1H, s, H-2), 3.99 (1H, s, H-3), 3.99-3.90 (2H, m, H-5′), 3.75-3.68 (2H, m, H-5), 3.49 (3H, s, OCH3); 13C NMR (CDCl3): δ 137.83, 137.53, 128.51, 128.48, 127.96, 127.82, 127.71, 127.62 (Bn), 104.05 (C-1), 88.44 (C-4), 79.54 (C-3), 77.16 (C-2), 73.68 (Bn), 72.61 (C-5′), 72.24 (Bn), 65.73 (C-5), 56.20 (OCH3); MS FAB: 379 (M+Na, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)CCSc1ccc(OC)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
4-Methoxythiophenol (4.80 g) was added to a stirred solution of methyl acrylate (3.08 ml) in dichloromethane (60 ml) at 0° C. Potassium carbonate (4.72 g) was added and the mixture was allowed to warm to room temperature overnight. The mixture was filtered over a plug of Celite® and the solvent was removed in vacuo to give the title compound as a yellow liquid (7.70 g, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=1.C([CH2:18][O:19][C:20]1[C:21]([F:30])=[C:22]([C:27]([NH2:29])=[O:28])[C:23]([F:26])=[CH:24][CH:25]=1)#N>>[F:30][C:21]1[C:20]([O:19][CH2:18][C:9]2[S:10][C:6]3[CH:5]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:13]=[CH:12][C:7]=3[N:8]=2)=[CH:25][CH:24]=[C:23]([F:26])[C:22]=1[C:27]([NH2:29])=[O:28]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(OC(F)(F)F)cc3s2)c1F
Yield: 34 %

Procedure:
Synthesised from 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide, according to Method K, scheme 26. Yield 34% (second step), mp 174-175° C., HPLC-MS (method 1): m/z 405 [M+H]+, Rt=4.14 min.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:10]1[CH2:14][S:13][CH2:12][CH:11]1[C:15](OC)=[O:16].[Na].C(O)(=O)C>CO.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:15](=[O:16])[C:11]2[CH2:12][S:13][CH2:14][C:10]=2[NH:2]1
Reactant: COC(=O)C1CSCC1=O
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=c1c2c([nH]n1-c1ccccn1)CSC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of 7 g (64.1 mmol) of 2-hydrazinopyridine and 10.3 g (64.1 mmol) of methyl 4-oxotetrahydrothiophene-3-carboxylate in 130 mL of MeOH is heated for 12 hours at 80° C. The medium is then concentrated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel, eluting with a DCM/MeOH gradient of from 0 to 10% MeOH. After concentrating under reduced pressure, 8.7 g (34.5 mmol) of hydrazone intermediate, in the form of a yellow powder, are isolated and are then added portionwise, at room temperature, to a solution of 0.8 g (34.5 mmol) of sodium in 46 mL of anhydrous MeOH. The reaction medium is stirred for 2 hours at room temperature, and the precipitate formed is then filtered off and washed successively with 10 mL of MeOH and 20 mL of pentane. The residue obtained is dissolved in 20 mL of water and 10 mL of acetic acid are added. The precipitate obtained is filtered off, washed with 10 mL of water, dried under vacuum and recrystallized from EtOH. 4.2 g of 2-pyridin-2-yl-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one are obtained in the form of a whitish powder.
Reaction SMILES: CO.O.[CH3:4][C:5](O)=O.C[C:9]1[C:14]([F:15])=[N:13][C:12]([CH3:16])=[CH:11][N:10]=1.[F:17][B-:18]([F:21])([F:20])[F:19].C[O+](C)C>C(Cl)Cl>[F:17][B-:18]([F:21])([F:20])[F:19].[F:15][C:14]1[C:5]([CH3:4])=[N+:10]([CH3:9])[CH:11]=[C:12]([CH3:16])[N:13]=1
Reactant: CC(=O)O
Reactant: Cc1cnc(C)c(F)n1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1c[n+](C)c(C)c(F)n1

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A:- 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H). 12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v. 13. n.m.r. in solvent B: 3.46 (d,1H), 3.72 (d,1H); 3.97 (s,3H); 4.25 (s,3H); 4.11 (d,1H); 4.63 (d,1H); 5.13 (d,1H); 5.73 (d,1H); 6.97 (s,1H); 7.57 (d,1H); 7.98 (dd,1H); 8.93 (d,1H). 14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v. 15. n.m.r. in solvent B: 3.43 (d,1H); 3.69 (d,1H); 3.97 (s,3H); 4.19 (s,3H); 4.23 (d,1H); 4.66 (d,1H); 5.12 (d,1H); 5.69 (d,1H); 7.0 (s,1H); 7.98 (d,1H); 8.2 (s,1H); 8.6 (d,1H). 16. The starting material was prepared by reaction of 3,6-difluoropyridazine and trimethyloxonium tetrafluoroborate in CH2C 12 for 15 hours at ambient temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate. This compound in acetonitrile was treated with a solution of ammonia in chloroform in the presence of 1 equivalent of NaHCO3 for 0.5 hours at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium tetrafluoroborate. 17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v. 18. n.m.r. in solvent B: 1.53 (s,6H); 3.5 (m,2H); 3.7 (s,3H); 3.95 (d,1H); 4.5 (d,1H); 5.15 (d,1H); 5.8 (d,1H); 7.0 (s,1H); 7.3 (s,2H). 19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluoropyrazine and trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium tetrafluoroborate. 20. n.m.r. in solvent B: 1.53 (s,6H); 2.38 (s,3H); 2.53 (s,3H); 3.5 (m,2H); 4.1 (s,3H); 4.2 (d,1H); 4.85 (d,1H); 5.1 (d,1H); 5.85 (d,1H); 7.05 (s,1H); 7.9 (s,1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C

Procedure:
A solution of 2,4-dihydroxybenzaldehyde (20 g, 0.144 mol), potassium flouride (16.7 g, 2 equivalents) and benzyl chloride (29 mL, 1.75 equivalents) in acetonitrile (150 mL) is heated at reflux temperature for 16 hr, cooled to room temperature, concentrated, diluted with water and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated in vacuo to give an oil residue. The residue is chromatographed (silica gel/10% EtOAc in hexanes to 50% EtOAc in hexanes as gradient eluents) to give the title product as a white solid, 25.9 g, identified by NMR and mass spectral analyses.
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6]2([C:12]#[N:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C(Cl)Cl>[CH:2]1([CH2:5][C:6]2([C:12]#[N:13])[CH2:7][CH2:8][N:9]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:11]2)[CH2:4][CH2:3]1
Reactant: N#CC1(CC2CC2)CCNCC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CC2)CC1
Reaction time: 2 h

Procedure:
A suspension of 4-(cyclopropylmethyl)piperidine-4-carbonitrile hydrochloride (I-3, 2.5 g, 12.5 mmol) in CH2Cl2 (130 mL) at 0° C. was treated with i-Pr2NEt (8.7 mL, 50 mmol) and EtSO2Cl (1.8 mL, 18.7 mmol) dropwise. After 2 h, the reaction was quenched with the addition of 1 M aqueous NaOH (40 mL) and stirred 18 h before being extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidine-4-carbonitrile (I-4, M+H+=256.1) as an off-white amorphous solid. This material was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O=[C:28]([CH3:42])[CH2:29][CH2:30][N:31]1C(=O)C2C(=CC=CC=2)C1=O>>[F:1][C:2]1[C:10]2[O:9][C:8]([CH:21]3[CH2:22][CH2:23][N:24]([CH:28]([CH3:42])[CH2:29][CH2:30][NH2:31])[CH2:25][CH2:26]3)([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Fc1cccc2c1OC(c1ccc(C(F)(F)F)cc1)(C1CCNCC1)O2
Product: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Oc3cccc(F)c3O2)CC1

Procedure:
Using general procedure B with the above amine (18 mg, 0.049 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (21 mg, 0.098 mmol) and then using general procedure D afforded 3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (11 mg, 52% over 2 steps).