Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[N:16]([CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), (prepared as described for the starting material in Example 1), in DMF (70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and petroleum ether, the solid was collected by filtration and dried under vacuum to give 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=C1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:19]([OH:21])=O)=[C:14]([CH2:16][CH2:17][CH3:18])[N:15]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1NCC#N>O1CCCC1>[CH3:10][C:11]1[S:12][C:13]([C:19]([NH:3][CH:4]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[C:5]#[N:1])=[O:21])=[C:14]([CH2:16][CH2:17][CH3:18])[N:15]=1
Reactant: c1c[nH]cn1
Reactant: N#CCNc1cccs1
Reactant: CCCc1nc(C)sc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1nc(C)sc1C(=O)NC(C#N)c1cccs1
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2-methyl-4-n-propyl-5-thiazolecarboxylic acid (1.85 g; 10 mmol) was added thereto at once, and stirring was continued for 1 hour. To the mixture was added dropwise a solution of 2-(2-thienyl)aminoacetonitrile (1.65 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 volume) to give crude crystals. Recrystallization from n-hexane/ethyl acetate gave 1.61 g of 2-(2-methyl-4-n-propylthiazole-5-carboxamido)-2-(2-thienyl)acetonitrile as colorless crystals. m.p., 125°-126° C. Yield, 53%.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a cold solution of formic acid (40.2 mL, 1.04 mol) in dichloromethane (150 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (15.2 mL, 160 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cycloheptanecarboxylic acid from Preparation 37 (16.1 mmol theoretical) in dichloromethane (150 mL) was added. The reaction was stirred at 0° C. for 3 h and was concentrated in vacuo. Water (150 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purification by preparative, reverse-phase HPLC provided the title compound (2.56 g, 52%). MH+306.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:9]([O:11]C)=[O:10])=[CH:6][NH:7][CH:8]=1.I[CH2:14][CH3:15].[OH-].[Na+]>C(O)C.CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:4]([CH3:3])[C:5]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH3:15]
Reactant: COC(=O)c1c[nH]cc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCn1cc(C)c(C(=O)O)c1
Yield: 73.1 %

Procedure:
In the same manner as in Reference Example 37 and using 60% sodium hydride (340 mg, 8.62 mmol), N,N-dimethylformamide (25 mL), methyl 4-methyl-1H-pyrrole-3-carboxylate (1.00 g, 7.19 mmol), iodoethane (860 μL, 10.8 mmol), ethanol (6 mL) and 8N aqueous sodium hydroxide solution (1.8 mL) as starting materials, the title compound (805 mg, 73%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:48])([CH3:47])[Si:3]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:4][CH2:5][CH:6]([C:31]([F:34])([F:33])[F:32])[NH:7]/[C:8](=[N:20]/C(=O)OCC1C=CC=CC=1)/[NH:9]C(=O)OCC1C=CC=CC=1.[H][H]>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[Si:3]([O:4][CH2:5][CH:6]([NH:7][C:8]([NH2:20])=[NH:9])[C:31]([F:34])([F:33])[F:32])([C:2]([CH3:1])([CH3:47])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](OCC(N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(F)(F)F)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC(NC(=N)N)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
To a stirred solution of 346 (210 mg, 0.310 mmol) in 95% EtOH/THF (5 mL, 1:1) was added Pearlman's Catalyst (21.8 mg, 0.0310 mmol). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then maintained under 1 atmosphere of hydrogen pressure overnight. The mixture was then filtered through GF/F filter paper with 95% ethanol and the filtrate was concentrated to afford 127 mg (100%) of 1-(3-(tert-butyldiphenylsilyloxy)-1,1,1-trifluoropropan-2-yl)guanidine (348) as a white solid.
Reaction SMILES: [CH3:1][C@:2]12[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C@H:15]([OH:22])[C:13](=[O:14])[C@@H:12]1[C@:11]1([CH3:23])[C@H:5]([C:6]([O:8][C@@H:9]([C:24]3[CH:25]=[CH:26][O:27][CH:28]=3)[CH2:10]1)=[O:7])[CH2:4][CH2:3]2.[Na+].[I-].C(N(C(C)C)CC)(C)C.Cl[CH2:41][O:42][CH2:43][CH3:44]>CC(N(C)C)=O.CCOC(C)=O>[CH3:44][CH2:43][O:42][CH2:41][O:7][CH2:6][O:8][CH2:9][CH3:24].[CH3:1][C@:2]12[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C@H:15]([OH:22])[C:13](=[O:14])[C@@H:12]1[C@:11]1([CH3:23])[C@H:5]([C:6]([O:8][C@@H:9]([C:24]3[CH:25]=[CH:26][O:27][CH:28]=3)[CH2:10]1)=[O:7])[CH2:4][CH2:3]2
Reactant: CCOCCl
Agent: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@@H](c3ccoc3)C[C@]21C
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOCOCOCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
12-epi-Salvinorin B (15 mg, 0.038 mmol) was dissolved in DMA (500 μL) under argon. To this solution was added NaI (23 mg, 0.15 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and chloromethylethyl ether (16 μL, 0.19 mmol). This solution was warmed to 80° C., and stirred for 18 hours. The mixture was then cooled to rt and diluted with EtOAc, washed with water and brine, and dried over MgSO4. After evaporation of the solvent, flash chromatography (0% to 70% EtOAc in hexanes) gave ethoxymethyl ether 37 as an off-white solid. (11.2 mg, 65% yield); Rf 0.28 (98:2, CH2Cl2/MeOH); 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 1H), 7.40 (t, J=1.7 Hz, 1H), 6.41 (m, 1H), 5.29 (dd, J=6.0, 11.6, 1H), 4.76 (q, J=7.2, 2H), 4.16 (dd, J=7.4, 12.2, 1H), 3.72 (s, 3H), 3.69-3.51 (m, 2H), 2.72 (dd, J=3.3, 13.3, 1H), 2.46-2.27 (m, 4H), 2.20 (m, 1H), 2.05-1.68 (m, 4H), 1.57 (m, 1H), 1.38 (s, 3H), 1.18 (t, J=7.1, 2H), 1.06 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:31]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 130 °C
Yield: 80.1 %

Procedure:
To a solution of compound 5 (77 mg, 0.172 mmol) in dry toluene (2.5 mL) was added Lawesson's reagent (104 mg, 0.258 mmol) under nitrogen. The reaction mixture was heated in a CEM microwave reactor at 130° C. for 60 min. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (petroleum ether:EtOAc=3:1) to give compound 6 (67 mg, 84%) as a white solid.
Reaction SMILES: [CH:1]1([CH:4]2[N:9]=[C:8](Cl)[C:7]([C:11]3[N:12](C(=O)C)[CH2:13][CH2:14][N:15]=3)=[C:6](Cl)[N:5]2[NH2:20])[CH2:3][CH2:2]1.[CH3:21][O-:22].[Na+].[CH3:24][OH:25]>>[CH:1]1([CH:4]2[N:9]=[C:8]([O:22][CH3:21])[C:7]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)=[C:6]([O:25][CH3:24])[N:5]2[NH2:20])[CH2:2][CH2:3]1
Reactant: C[O-]
Reactant: CO
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C2CC2)N=C1Cl
Agent: [Na+]
Product: COC1=NC(C2CC2)N(N)C(OC)=C1C1=NCCN1

Procedure:
3.0 g 2-cyclopropyl-4,6-dichloro-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are mixed with a solution of 1.4 g sodium methylate in 15 ml methanol and heated for 6 hours under reflux. The solution then is concentrated, mixed with water, and extracted with chloroform. The chlorform phase is dried and concentrated. 1.8 g of 2-cyclopropyl-4,6-dimethoxy-5(2-imidazolin-2-yl)-aminopyrimidine (melting point 193°-195° C.) is obtained. The hydrochloride of this compound melts at 214°-216° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][NH2:1])[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCN=[N+]=[N-])ccc2c1-c1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc2cc(OCCN)ccc2c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
0.230 g (0.610 mmol) 6-(2-Azido-ethoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and 0.484 g (1.83 mmol) of triphenylphosphin were dissolved in 1.6 ml of tetrahydrofuran. After stirring of the reaction mixture for 15 minutes at room temperature, 0.1 ml of water were added and the reaction mixture heated to 60° C. for 16 hours. It was then evaporated under reduced pressure, poured into 50 ml of water and extracted 3 times with 10 ml of dichloromethane. The combined dichloromethane phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and methanol as the eluent giving 0.200 g (93.4%) 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylamine as colorless oil, MS: 352 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(-c4ccccc4)cc3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCc3[nH]c4ccc(-c5ccccc5)cc4c3CC2)cc1
Yield: 69.7 %

Procedure:
A solution of lithium aluminum hydride (0.17 g, 4.45 mmol) in tetrahydrofuran (3.0 mL) and a solution of 3-benzoyl-9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.17 g, 0.46 mmol) in tetrahydrofuran (5.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give an oil. Column chromatography (silica gel, 10-50% EtOAc/heptane) afforded 0.113 g (71%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.66-7.57, 7.49, 7.45-7.30, 7.13-7.04, 3.98, 3.18-2.97; MS (EI) m/z 366 (M+); HRMS (FAB) calcd for C25H24N2+H: 353.2018, found: 353.2021.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:8].[I-].[Na+].C(=O)=O.[CH3:24][C:25](C)=[O:26].[NH3:28]>O1CCCC1>[NH2:28][CH2:24][C:25]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:8])=[O:26]
Reactant: COC(=O)c1ccc(C(=O)c2ccsc2N)cc1
Reactant: N
Reactant: CC(C)=O
Agent: O=C=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)c2ccsc2NC(=O)CN)cc1
Temperature: -78 °C
Yield: 28 %

Procedure:
In a 100 mL round-bottomed flask was dissolved title compound 491 (1 g, 2.96 mmol) and sodium iodide (0.533 g, 3.55 mmol) in tetrahydrofuran (20 mL) to give a yellow suspension. The mixture was heated at reflux for 2 hours. The mixture was cooled to −78° C. A Dewar-type condenser was attached and filled with dry ice/acetone. Ammonia was introduced as a gas and about 30 mL was condensed into the flask. The reaction mixture was left to warm up to room temperature over the weekend. The solvent was removed in vacuo and the residue was purified via ISCO (50-100% EtOAc/Hexanes; 40 g silica gel column) to obtain product as a tan powder. The solid was purified by suspending it in 1:1 dichloromethane/ether and filtering to afford title compound 492 (265 mg, 28%) as a tan powder which was sufficiently pure for the next step. MS (m/z): 319.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-bromo-4-methoxybenzene (5 g, 27 mmol) in THF (100 mL) at −78° C. was added a solution of 1.6 M N-butyl lithium/hexanes (18.4 mL, 29.4 mmol), and the reaction mixture was stirred for 1 hr. Then a solution of 1-benzylpiperidin-4-one (4.81 g, 25.4 mmol) in 50 mL of THF was added. After the addition, the mixture was allowed to warm up to rt and was stirred for 1 h. The reaction was then quenched by the addition of 100 mL of 1.5 M aqueous HCl and the mixture was extracted with 200 mL of ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to yield 7.1 g (72% yield) of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol. LCMS (method F) RT 2.19 min, 81% AP, m/z298.4 (M+H+), 1H NMR (300 MHz, DMSO-d6) δ 7.23-7.39 (m 8.5H), 6.94 (m, 0.5H), 6.84-6.94 (m, 2H), 4.66 (s, 1H), 3.74 (s, 0.8H), 3.72 (s, 3H), 3.32 (s, 2H), 2.50-2.67 (m, 2H), 2.34-2.45 (m, 3H), 1.83-1.90 (m, 2H), 1.55 (d, J=11, 2H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:19]>>[ClH:19].[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:18])=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cl
Product: O=C(c1ccc(F)cc1)C1CCNCC1

Procedure:
A solution of 70.6 g of 1-acetyl-4-(4-fluorobenzoyl)piperidine in 200 ml of 6N HCl is refluxed for 2 hours. The cooled solution is extracted twice with ether, the aqueous solution basified with sodium hydroxide and then extracted with benzene. The benzene extracts are dried, filtered and the filtrate is concentrated under reduced pressure. The residual oil is dissolved in ether and HCl gas is bubbled into the solution with stirring. The salt is collected by filtration, washed with ether and dried. The salt is recrystallized from isopropanol to give the solid product of 4-(4-fluorobenzoyl)piperidine hydrochloride, mp 222°-224° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]#[N:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:14][OH:15])=[NH:12])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: N#CNc1ccc(C(=O)O)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(NO)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
In 150 ml of methanol was dissolved 6.56 g of 4-carboxyphenyl cyanamide produced in Reference Example 26. To the solution were added, while stirring at room temperature, 6.1 g of hydroxylamine hydrochloride and 8.88 g of triethylamine. The mixture was stirred for two hours. The resulting crystalline precipitate was collected by filtration to afford 4.45 g of the title compound as a colorless crystalline product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([NH:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:20][CH:21]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]1)(=[O:57])=[O:56]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
A solution of 0.25 g of tert-butyl 3-{2-[2-(2-aminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at room temperature with a solution of 0.12 ml of triethylamine in 1 ml of dichloromethane. Subsequently, a solution of 0.034 ml of methanesulphonyl chloride in 1 ml of dichloromethane is added dropwise. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane, washed with 1M aqueous potassium bisulphate solution (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.07 (1:2 EtOAc-heptane); Rt=5.78.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.O>C1COCC1>[Cl:18][CH2:19][CH2:20][CH2:21][N:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:8](=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccc(NCCCCl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Oc1ccccc1)N(CCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S:33]([OH:36])(=[O:35])=[O:34])[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][N+:21]4[CH:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[CH:25][CH:26]=4)[CH2:18][S:19][C@H:12]23)=[O:9])=[CH:5][CH:6]=1.C([O-])(=O)C.[Na+:41]>CN(C=O)C.O>[CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S:33]([O-:36])(=[O:34])=[O:35])[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]3[C:16]([C:30]([O-:32])=[O:31])=[C:17]([CH2:20][N+:21]4[CH:26]=[CH:25][C:24]([C:27]([NH2:29])=[O:28])=[CH:23][CH:22]=4)[CH2:18][S:19][C@H:12]23)=[O:9])=[CH:5][CH:6]=1.[Na+:41]
Reactant: NC(=O)c1cc[n+](CC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(c4ccccc4)S(=O)(=O)O)[C@H]3SC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(c4ccccc4)S(=O)(=O)[O-])[C@H]3SC2)cc1

Procedure:
Cefsulodin (5.0762 g) was dissolved in 10 mL of DMF and cooled in an ice bath. To this cold, yellow, syrupy solution was added 1.1 eq. of sodium acetate in 15 mL of water with stirring. The mixture was stirred at ice temperature for 10 more minutes. The mixture was then placed in a refrigerator overnight. The crystallized cefsulodin sodium was filtered, dried using heat under reduced pressure to a water content of about 3.18% by weight. 2.82 g of cefsulodin sodium were obtained (63%). Microscopic analysis of the resulting crystals showed that the cefsulodin sodium was spherical-type crystals.