Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH3:54][O:55][CH2:56][CH2:57][S:58]([NH2:61])(=[O:60])=[O:59]>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:61][S:58]([CH2:57][CH2:56][O:55][CH3:54])(=[O:60])=[O:59])=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:27][CH:28]3[CH2:29][CH:30]([CH2:31][CH:32]([CH2:34]3)[CH2:33]1)[CH2:35]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with 2-methoxyethane-1-sulfonamide, the title compound was obtained as a colorless solid (0.05 g, 9%): 1H NMR (300 MHz, CDCl3) δ 8.68-8.54 (m, 1H), 8.13-8.03 (m, 1H), 6.74-6.62 (m, 1H), 3.91-3.74 (m, 4H), 3.59 (s, 2H), 3.31 (s, 3H), 2.05 (s, 3H), 1.85-1.64 (m, 12H); MS (ES−) m/z 458.3 (M−1), 460.3 (M−1).
Reaction SMILES: Cl.[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:5].[C:34]1([C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N+]=[N-])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+].Cl[C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56]>CO.O>[CH2:58]([O:57][C:55]([NH:26][C@H:25]([C:24]([NH:23][C@@H:20]([CH2:21][OH:22])[C@@H:19]([OH:32])[C@@H:18]([OH:33])[C@H:3]([OH:2])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([O:11][CH:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:10])=[O:5])=[O:31])[CH2:27][CH:28]([CH3:29])[CH3:30])=[O:56])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid hydrochloride (4.35 g) in methanol (100 ml) was added a solution of diphenyldiazomethane (3.40 g) in methanol (100 ml) under ice-cooling and the mixture was stirred at room temperature for 15 hours. Removal of the organic solvent gave a residue, which was suspended in water (200 ml). To the suspension were added sodium hydrogencarbonate (2.20 g) and benzyl chloroformate (18 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (5.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[C:6]([C:8]2[NH:9][C:10]([CH3:21])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([OH:19])=O)[NH:13][C:12]3=[O:20])[CH:7]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[C:6]([C:8]2[NH:9][C:10]([CH3:21])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([NH2:32])=[O:19])[NH:13][C:12]3=[O:20])[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c(=O)c12
Yield: 0 %

Procedure:
A mixture of Example 32a (0.07 g, 0.162 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.074 g, 0.195 mmol), N-ethyl-N-isopropylpropan-2-amine (0.142 mL, 0.812 mmol) and 0.5 M ammonia (1.625 mL, 0.812 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for two hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Purification by reverse phase chromatography (C18, CH3CN/10 mM ammonium acetate in water, 10-100% gradient) afforded the title compound (0.022 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.95 (s, 1H), 8.07 (s, 1H), 7.56 (d, J=2.44 Hz, 1H), 7.40-7.52 (m, 2H), 7.26-7.39 (m, 3H), 7.06-7.15 (m, 1H), 6.87 (d, J=8.85 Hz, 1H), 2.63 (s, 3H). MS (APCI+) m/z 430 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:22][CH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2oc(C)nc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc2oc(CBr)nc12
Yield: 20 %

Procedure:
453 mg (2.37 mmol) of methyl 2-methylbenzoxazole-4-carboxylate (prepared by the method in J. Heterocyclic Chem. 27, 335 (1990)) are dissolved in 40 ml of chlorobenzene, 421 mg (2.37 mmol) of NBS and 20 mg of benzoyl peroxide are added, and the resulting mixture is refluxed for 2 hours. It is concentrated, and the residue is taken up in ethyl acetate, extracted by shaking with saturated NaHCO3, 10% strength Na2SO3 and saturated NaCl solution and dried over Na2SO4. Concentration and chromatography on SiO2 with n-heptane-ethyl acetate (2:1) yields 128 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:9]=2[N:10]=1>[Fe].C(O)(=O)C>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN(C)CCN(C)c1nc2cc(N)ccc2o1
Reaction time: 3 h

Procedure:
The title compound was prepared according to the procedure described in General Method B using N,N,N′-Trimethyl-N′-(5-nitro-benzooxazol-2-yl)-ethane-1,2-diamine (4.131 g, 15.63 mmol), acetic acid (50 mL), and Fe (8.72 g, 78.15 mmol), stirring for 3 h: (3.57 g, 98%): mass spectrum (m/e): 265.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].CO>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 6 h

Procedure:
To a mixed suspension of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) and hexamethyldisilazane (16.42 g) in toluene (60 ml) was added sulfuric acid (0.80 g) dropwise and the silylation reaction was carried out at an internal temperature of 110˜120° C. for 6 hours. After completion of silylation, the toluene was distilled off to recover a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (13.72 g) and ethyl bromoacetate (3.40 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 6 hours. After completion of reaction, the reaction mixture was cooled to an internal temperature of ≦70° C. and ethyl acetate (80 ml) was added. Then, methanol (60 ml) was added dropwise over 30 minuets. After completion of dropwise addition, the mixture was cooled to ≦20° C. and stirred for 1 hour. The resulting crystal crop was harvested by filtration, washed serially with methanol (40 ml) and water (100 ml) and dried to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (28.16 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@H:13]([O:14][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1
Reactant: Oc1ccc(F)cc1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2F)C1
Product: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2F)C1

Procedure:
The procedure of Example 53 is repeated with cis-3-(2-fluorophenyl)-1-methyl-4-piperidinol and 4-fluorophenol to yield trans-3-(2-fluorophenyl)-4-(4-fluorophenoxy)-1-methylpiperidine. This compound is treated with a solution of fumaric acid in ether containing ethanol to yield trans-4-(4-fluorophenoxy)-3-(2-fluorophenyl)-1-methylpiperidine fumarate, m.p. 205.5°-206.5° C. The crude salt is recrystallized from isopropanol to afford colorless crystals, m.p. 205.5-106.5.
Reaction SMILES: [C:1]([Cl:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:11]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[S:16][CH:15]1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:40]CO)[CH:37]([CH3:39])[CH3:38])(=[O:13])[CH3:12].N1C=CC=CC=1.[C:49](=O)([O-:51])[OH:50].[Na+]>C(Cl)Cl>[ClH:9].[C:11]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[S:16][CH:15]1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[O:32][CH2:33][CH2:34][CH2:35][N:36]([CH:37]([CH3:39])[CH3:38])[CH2:40][CH:1]([C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: O=C([O-])O
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OCCCN(CC(C(=O)O)c2ccccc2)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reaction time: 2 h
Yield: 62 %

Procedure:
Benzoyl chloride (0.20 ml, 1.20 mmol) was added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (300 mg, 0.58 mmol) and pyridine (0.39 ml, 4.70 mmol) in methylene chloride (0.5 ml) under ice-cooling. The mixture was stirred at the temperature for two hours, then a saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with a 10% aqueous citric acid solution (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/methanol=10/1). The obtained oily matter was dissolved in ethyl acetate (1 ml), and a 4 N solution (0.5 ml) of hydrogen chloride in ethyl acetate was added thereto under ice-cooling. The mixture was concentrated under reduced pressure to give 211 mg (62%) of the target compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[S:24]([O-:28])([O-:27])(=[O:26])=[O:25].CS[C:31]([NH2:33])=[NH2+:32].CSC(N)=[NH2+]>O>[OH2:25].[S:24]([OH:28])([OH:27])(=[O:26])=[O:25].[NH:6]1[CH:7]=[CH:8][N:9]=[C:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH2:33])=[NH:32]
Reactant: CSC(N)=[NH2+]
Reactant: O=S(=O)([O-])[O-]
Reactant: NCCCc1ncc[nH]1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Product: N=C(N)NCCCc1ncc[nH]1
Product: O=S(=O)(O)O

Procedure:
A solution of 2-(3-aminopropyl)imidazole, prepared from its dihydrochloride (0.9 g) by means of an ion-exchange resin (OH-), and S-methylthiouronium sulphate (1.26 g) in water (20 ml) is heated under reflux for 18 hours. The product, isolated in a manner similar to that described in Example 1, is recrystallized from aqueous ethanol yielding 3-(2-imidazolyl)propylguanidine sulphate monohydrate, m.p. 260°-262°C (dec.).
Reaction SMILES: [NH3:1].[S:2](=[O:6])(=[O:5])([OH:4])[OH:3]>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[NH4+:1].[NH4+:1].[S:2](=[O:4])(=[O:3])([OH:6])[OH:5]
Reactant: N
Agent: O=S(=O)(O)O
Product: O=S(=O)([O-])[O-]
Product: [NH4+]

Procedure:
The ammonia reacts with the sulfuric acid according to the reaction 2NH3+H2SO4→(NH4)2SO4 and a precipitate of aqueous ammonium sulfate and unreacted sulfuric acid is formed and collects in the effluent basin 44. The demister 28 removes additional droplets from the gas stream 22, which exits the conduits 18 to the atmosphere 24, the gas stream now stripped of over 70% of its ammonia content. The precipitate of aqueous ammonium sulfate and unreacted sulfuric acid is returned to the reservoir 34 via piping 46.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Br:10])[C:4]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br-].[Na+]>C(O)C>[CH2:12]([O:11][C:4]1[C:3]([Br:2])=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[Br:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(Br)cc(F)cc1Br
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Fc1cc(Br)c(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.21 g (96 mmol) of sodium is dissolved in 66 ml of ethanol with exclusion of moisture. 21.6 g (80 mmol) of 2,6-dibromo-4-fluorophenol is added to this solution. A suspension results. 20.5 g (120 mmol) of benzyl bromide is added to the suspension. It is stirred for 30 minutes at room temperature and then is refluxed for 1 hour. A sample of the suspension then reacts neutrally to moist reaction paper. The precipitate of the sodium bromide is suctioned off, the filtrate is evaporated to dryness and the residue is crystallized from ethanol. 23.7 g (66 mmol)=82.5% of the theoretical yield is obtained as a crystallizate. Melting point 83° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[S:4].Cl[CH2:23]CCl.S(=O)(=O)(O)O>CO>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:5][CH3:23])=[S:4]
Reactant: ClCCCl
Reactant: CCCCCCCCCCCCCCCCC(C)C(O)=S
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCCCCCCCCCCCCCC(C)C(=S)OC
Yield: 97 %

Procedure:
A 250 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was charged with 50 g (0.15 mole) of alpha-methylthiostearic acid, 60 ml of 1,2-dichloroethane, and 25 ml of methanol. The resulting mixture was stirred and warmed with a heating mantle while 0.6 ml of concentrated sulfuric acid was added. It was then heated to reflux overnight. The reaction mixture was cooled, placed in a separatory funnel and washed three times with 10% aqueous sodium chloride solutions. The organic solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The product was further dried under high vacuum and consisted of 50.5 g (97% yield) of methyl alpha-methylthiostearate.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:34])[CH:24]([NH:25][C:26](=[O:33])[CH2:27][C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH:35]=[N:36][O:37][CH3:38])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:38][O:37][N:36]=[CH:35][C:18]1[CH2:19][S:20][C@@H:21]2[CH:24]([NH:25][C:26](=[O:33])[CH2:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:34])[N:22]2[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.42 h
Yield: 78.7 %

Procedure:
To a solution of diphenylmethyl-3-methoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (394 mg) in methylene chloride (11 ml) are added anisole (1.1 ml) and trifluoroacetic acid (1.1 ml) at 0° C. under argon atmosphere, and the mixture is kept at the same temperature for 25 minutes, and at room temperature for 25 minutes. The reaction mixture is evaporated, and trituration of the residue in ether gives 3-methoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (216 mg). m.p. 186°-189° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:34].CCN(CC)CC.O>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:36]([O:35][C:33](=[O:5])[O-:34])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCOC(=O)Cl
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOC(=O)[O-]
Temperature: 25 °C

Procedure:
To the solution of budesonide (431 mg, 1.0 mmol) in DCM (4.5 mL) was added decyl chloroformate (460 μL, 2.0 mmol) and Et3N (512 μL, 3.7 mmol) at room temperature. After the reaction mixture was stirred at room temperature over night, it was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide decylcarbonate. The product was purified by chromatography, eluted with Hexane: AcOEt=9:1 to 3:1 to provide 348 mg of 1:1 mixture of epimers (originated from budesonide) (99.22 area % purity on HPLC). 1H NMR (CDCl3) δ 0.85-2.24 (m, 42H), 2.36 (dd, 1H, 13.4 and 2.9 Hz), 2.59 (dt, 1H, 13.5 and 4.5 Hz), 4.18 (t, 1H, 6.7 Hz), 4.51 (s, 1H), 4.6-5.2 (m, 5H), 6.03 (s, 1H), 6.30 (d, 1H, 10.1 Hz), 7.49 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 14.14, 14.17, 14.31, 17.06, 17.24, 17.36, 17.68, 21.19, 22.83, 25.78, 28.76, 29.37, 29.40, 29.66, 30.52, 31.16, 32.04, 33.05, 33.56, 34.22, 35.16, 37.25, 40.58, 40.89, 44.38, 46.06, 47.49, 49.98, 53.05, 55.38, 55.48, 68.90, 68.94, 69.65, 69.75, 69.92, 70.01, 82.05, 83.34, 97.69, 98.56, 104.65, 108.47, 122.51, 127.84, 155.04, 156.96, 170.61, 170.71, 186.84, 186.89, 202.08 and 203.37. Mass spectrum (m/e) 615 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NC1CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with cyclopentylamine (1.90 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-cyclopentylamino-cyclopentanecarboxylic acid ethyl ester (1.48 g, 6.57 mmol, 34.2%), as a light yellow oil. LC-MS (ESI) calcd for C13H23NO2 225.17, found 226.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[C@@H:22]([CH3:25])[CH2:23][CH3:24])[C:9]([C@@H:11]2[CH2:13][C@H:12]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:40]1([CH2:44]Br)[CH2:43][CH2:42][CH2:41]1.C(Cl)(=O)C>CO.CN(C=O)C>[NH2:26][C@@H:21]([C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:20][N:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:44][CH:40]2[CH2:43][CH2:42][CH2:41]2)=[CH:7][CH:6]=1)[C:9]([C@@H:11]1[CH2:13][C@H:12]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:10]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(OCC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of tert-butyl (2S,3S)-1-((1R,2R)—N-(4-hydroxyphenyl)-2-(pyridin-2-yl)cyclopropanecarboxamido)-3-methylpentan-2-ylcarbamate (69 mg, 0.15 mmol), potassium carbonate (63 mg, 0.46 mmol) and DMF (3 mL) was treated with cyclobutylmethyl bromide (21 μL, 0.18 mmol). The resulting reaction mixture was maintained at 70° C. with vigorous stirring overnight. The mixture was allowed to cool to room temperature, then partitioned between H2O (30 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×20 mL). Combined organics were washed with H2O (30 mL) and brine (30 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue that was purified by column chromatography on silica gel (eluting with 30% ethyl acetate in hexanes) to afford an oil that was dissolved in methanol (2 mL) and cooled to 0° C. The cold solution was then treated dropwise with acetyl chloride (290 μL, 4.0 mmol), and then maintained at room temperature overnight. The reaction was concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4-cyclobutylmethoxy-phenyl)-amide (56 mg, 88% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.61 (d, J=5.3 Hz, 1H), 8.34 (t, J=8.3 Hz, 1H), 7.79 (t, J=6.7 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 4.28 (dd, J=14.9, 8.8 Hz, 1H), 3.94 (d, J=6.6 Hz, 2H), 3.69 (dd, J=14.9, 2.8 Hz, 1H), 3.34-3.39 (m, 1H), 2.86-2.96 (m, 1H), 2.77 (dt, J=14.6, 7.2 Hz, 1H), 2.08-2.21 (m, 3H), 1.85-2.02 (m, 5H), 1.73-1.84 (m, 1H), 1.67 (dt, J=8.8, 5.5 Hz, 1H), 1.33-1.46 (m, 1H), 1.17-1.30 (m, 1H), 0.98 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 422.3 [(M+H)+, calcd for C26H36N3O2 422.3].