Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:32])C.C1COCC1.CO.[OH-].[Na+]>CCOC(C)=O.Cl>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[C:8]([CH3:32])[CH:9]=3)=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A 1 L round-bottomed flask was charged with compound 7.4 (40.9 g, 85.8 mmol), THF (100 mL) and MeOH (100 mL). Next, 2 N NaOH (86 mL, 172 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 h. The solution was neutralized with 2 N HCl (86 mL) and the organic solvent was evaporated to give an aqueous solution and an insoluble oil. The residue was diluted with AcOEt (300 mL) and 1N HCl (300 mL), and partitioned. The organic phase was successively washed with water (400 mL) and brine (400 mL), dried over MgSO4, and concentrated to give white crystals. Recrystallization from 520 mL of AcOEt/hexane (3/10) gave compound 7 (33.4 g) as white crystals. MS APSI m/e: 447 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 13.0 (1H, brs); 7.64 (2H, d, J=8.8 Hz); 7.38 (2H, d, J=8.3 Hz); 7.30-7.20 (2H, m); 7.16 (4H, d, J=8.3 Hz); 6.89 (1H, d, J=8.5 Hz); 5.14 (2H, s); 4.74 (2H, s); 2.19 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23]([N:27]=[C:28]=[S:29])([CH3:26])([CH3:25])[CH3:24].[N-]=C=S>C(O)C.CCOCC>[CH2:16]([O:15][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:2]([NH:1][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[S:29])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)N=C=S
Agent: [N-]=C=S
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Temperature: 80 °C

Procedure:
The process is performed as in Example 2, starting with 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)carbonyl]-amino}hexanoate with 5 cm3 of tert-butyl isothiocyanate in 200 cm3 of anhydrous ethanol at a temperature in the region of 20° C. for 20 hours. The reaction is completed by addition of a further 1 cm3 of isothiocyanate and heating for 2 hours at a temperature in the region of 80° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in ether and concentrated again under the above conditions. 13 g of ethyl (2R)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]amino}hexanoate are obtained in the form of a colorless oil. (αD20=−12.5±0.5 at a concentration of 0.5% in methanol).
Reaction SMILES: [C:1]([O:5][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][CH2:21][CH2:22][CH3:23])(=[O:4])[CH:2]=[CH2:3].[CH2:24]([O:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:25][CH2:26][CH3:27].[C:33]([O:37]CCO)(=[O:36])[CH:34]=[CH2:35].CC(N=NC(C#N)(C)C)(C#N)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][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][CH2:21][CH2:22][CH3:23])(=[O:4])[CH:2]=[CH2:3].[C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:32])[CH:30]=[CH2:31].[OH:4][C:34](=[CH2:35])[C:33]([O-:37])=[O:36]
Reactant: C=CC(=O)OCCO
Agent: C=CC(=O)OCCCC
Agent: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(O)C(=O)[O-]

Procedure:
To a 1 L flask equipped with a stirrer, a nitrogen introducing tube, a thermometer and a condenser, 50 g of stearyl acrylate, 49 g of n-butylacrylate, 1 g of hydroxyethyl acrylate, 0.89 g of AIBN, 100 mL of toluene and 100 mL of ethyl acetate were added and subjected to polymerization reaction in a stream of nitrogen at 70° C. for 12 hr, to obtain a copolymer of stearyl acrylate, n-butyl acrylate and hydroxyacrylate (hereinafter sometimes referred to “PSABAHEA”. The resulting PSABAHEA had a weight average molecular weight of 170,000.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=3[O:15][CH3:16])[CH2:14][CH2:13]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Agent: Cl
Product: COc1ccc(Cl)cc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 b from 1-(5-chloro-2-methoxy-phenyl)-piperazine hydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH:9]3[CH2:14][CH:10]3[C:11]=2[NH:12][N:13]=1)=O)C.[OH-].[NH4+:16]>O1CCOCC1>[CH2:14]1[CH:9]2[CH2:8][C:7]3[C:6]([C:4]([NH2:16])=[O:3])=[N:13][NH:12][C:11]=3[CH:10]12
Reactant: [NH4+]
Reactant: CCOC(=O)c1n[nH]c2c1CC1CC21
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1n[nH]c2c1CC1CC21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of the ester from Step C (14.2 g, 73.9 mmol) in dioxane (140 mL) was added ammonium hydroxide (28% NH3 in H2O, 750 mL). The mixture was placed in a 1000 mL pyrex bottle and agitated on a shaker plate for 22 h at rt. The mixture was concentrated in vacuo to a total volume of 100 mL at which time a light yellow precipitate was evident. The mixture was filtered and the solid was washed with H2O (2×100 mL). Further drying of the solid in vacuo gave 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide [HPLC/MS: Discovery® C18 column (5μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.09 min, ESI+=164.0 (M+H)] as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1.[I-].[Na+]>CN(C=O)C>[CH:38]1([NH:43][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCNC4CCCC4)CC3)n[nH]c12
Temperature: 120 °C
Reaction time: 0.02 h
Yield: 26.1 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide (Intermediate 22) (19 mg, 0.0413 mmol) in DMF (1 mL) was added K2CO3 (25 mg, 0.165 mmol), cyclopentylamine (22 uL, 0.2065 mmol) and sodium iodide (1.0 mg). The reaction mixture was heated to 120° C. for 14 hrs. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (5.5 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][O:21][C:22]2=[O:27]>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:17]/[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][O:21][C:22]3=[O:27])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 81.6 %

Procedure:
To a stirred mixture of 4-fluorobenzaldehyde (3 g, 20.4 mmol) and anhydrous sodium sulfate (29 g, 20.4 mmol) in anhydrous dichloromethane (200 mL) was added 4-aminoisobenzofuran-1(3H)-one (3.04 g, 24.5 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (4.25 g, yield 81%); LC-MS (ESI) m/z: 256 (M+1)+. A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (2.53 g, 10 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (1.21 g, 11 mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then a solution of sodium ethanoxide in ethanol [sodium (1 g, 44 mmol) in ethanol (30 mL)] was added drop-wise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg, yield 5%). LC-MS (ESI) m/z: 394 (M+1)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][C@H:6]([CH2:7][CH2:8]1)[CH2:5][C:4](=O)[CH2:3]2.Cl.[NH2:12]O.O.O.O.C([O-])(=O)C.[Na+].[Na]>CS(C)=O.C(O)C>[ClH:1].[ClH:1].[N:2]12[CH2:9][C@H:6]([CH2:7][CH2:8]1)[CH2:5][C@@H:4]([NH2:12])[CH2:3]2
Reactant: NO
Reactant: O=C1C[C@H]2CCN(C1)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: N[C@@H]1C[C@H]2CCN(C1)C2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a flask containing (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol), and ethanol (130 mL) is added sodium acetate trihydrate (9.23 g, 67.8 mmol). The mixture stirred for 3 h and is filtered and concentrated. The resulting white solid is taken up in n-propanol (100 mL) and sodium (˜13.6 g, 618 mmol) is added in 20-25 portions. The reaction spontaneously begins to reflux, and the reaction is heated in an oil bath (100° C.). The addition is complete in ˜20 min and the mixture solidifies after ˜40 min. The oil bath is removed and n-propanol (2×25 mL) is added dissolving the remaining sodium metal. The mixture is carefully quenched through the dropwise addition of H2O (100 mL). Saturated aq. NaCl (20 mL) is added, and the layers are separated. The organic layer is dried (MgSO4), filtered, treated with freshly prepared MeOH/HCl, and concentrated. The resulting solid is triturated with 30 mL EtOH, filtered and dried in vaccuo to afford 3.51 g as a white solid: [α]25D=−3 (c 0.94, DMSO); 1H NMR (400 MHz, DMSO-d6) δ 3.60-3.80, 2.95-3.10, 2.65-2.75, 1.90-2.15, 1.70-1.90; HRMS (FAB) calcd for C7H14N2 (M+H+) 127.1235, found 127.1235.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:22]=[C:21]([NH:32][CH3:33])[N:20]=1>CC#N>[CH3:33][NH:32][C:21]1[N:22]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:24]=[C:19]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)[N:20]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNc1nc(Cl)nc(N2CCN(C)CC2)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Temperature: 80 °C

Procedure:
trans-4-Aminocyclohexylcarboxylic acid (472 mg, 3.30 mmol, 8 equivalents) and triethylamine (0.46 ml, 3.30 mmol, 8 equivalents) was added to the solution of 4-Chloro-N-methyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (100 mg, 0.412 mmol, 1 equivalent) in CH3CN (8 ml). The reaction mixture was heated at 80° C. for 16 hours. The solvent was evaporated and the crude product was purified with RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 2-45% CH3CN/H2O, 0.1% TFA, 25 min) to give the product (18.4 mg, 10%). MS (ES+): m/e 350.13 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[Si:11]([O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH:31]=[O:32])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixture of DMSO (53 g, 0.68 mol) and oxalylchloride (43 g, 0.34 mol) in dry dichloromethane (1.51) at −78° C. was added tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (75 g, 0.226 mol) drop-wise. After stiring at −78° C. for 1 h, was added triethylamine (158 ml, 1.13 mol) drop-wise and warmed the reaction mixture slowly to RT. The reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with brine and dried. The solvent was removed under vacuum to give tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-formylpyrrolidine-1-carboxylate (70 g) as pale yellow liquid. Yield: 94%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)NC(=O)c1cccc(N)c1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
3-Nitro-N-(methanesulfonyl)phenylcarboxamide (1.6 g) was dissolved in 50 ml of ethanol, treated with 510 mg of 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 30 psi for 15 minutes. The reaction mixture was filtered through Celite and concentrated to give the title compound (1.1 g) as a white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+].[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35]Br)[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13].CN(C=O)C>CC(C)=O.C(OCC)(=O)C.O>[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35][O:8][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 64 %

Procedure:
In 30 ml of acetone is dissolved 2.6 g of n-heptanoic acid, and 10 ml of 2N-NaOH, 4.2 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one, 30 ml of DMF and 10 ml of water are serially added to the above solution. The mixture is refluxed for 5 hours. After cooling, 400 ml of ethyl acetate is added and the mixture is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following 400 ml of diisopropyl ether-n-hexane (2:3), elution is carried out with 1000 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 3.0 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])/[C:19](/[C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20]\[O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].[C:36]([O:39][CH2:40]Br)(=[O:38])[CH3:37].[Br-].[K+].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl>CN(C)C=O.C(OCC)(=O)C.CC(C)=O.C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])/[C:19](/[C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20]\[O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O:14][CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:13])(=[O:3])[NH2:2]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: CC(=O)OCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A solution (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (12.00 g) in N,N-dimethylformamide (70 ml) was stirred for 10 minutes with potassium carbonate (1.95 g), during which time the mixture became darker and the solid almost completely dissolved. A solution of acetoxymethyl bromide (5.0 g) in N,N-dimethylformamide (15 ml) was then added, whereupon precipitation of potassium bromide occurred almost immediately. The reaction mixture was stirred at 21° for 30 minutes, after which it is shown by t.l.c. (developing with chloroform:acetone=2:1 and observing the spots under u.v. light and by spraying with ninhydrin and heating to 120°) to contain no unreacted cephalosporin starting material. The reaction mixture was then poured into a mixture of 2 N-hydrochloric acid (350 ml) and ethyl acetate (350 ml), and the aqueous phase was extracted with further ethyl acetate (2×200 ml). The organic extracts were combined and were washed successively with 2 N-hydrochloric acid (2× 300 ml), water (2×300 ml), aqueous sodium bicarbonate solution (3%, 300 ml), water (3×300 ml), and saturated sodium chloride solution (2×300 ml), and dried (MgSO4), and the solvent was removed in vacuo to give a yellow froth (13.87 g). This product was absorbed onto a column of silica gel (Hopkin and Williams, 100 to 200 mesh-330 g) which was eluted with chloroform:acetone=2:1; 25 ml fractions were collected. Evaporation of fractions 11 to 32 gave crude title ester, which crystallised during the evaporation. The resulting solid (7.217 g) was triturated with ether to give the title ester (6.58 g) as a white powder, m.p. 181° to 183° (Kofler); [α]D +58° (c 0.98, DMSO), [α]D +72° (c 1.32, dioxan); λmax (EtOH) 276 nm (ε 19,750). The nmr and infrared data are shown in Table 1 hereinafter. The structure of the product was also confirmed by microanalysis.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[Cl:7][C:8]1[C:13]([N:14]([S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[C:2]([C:1]([N:14]([C:13]2[C:8]([Cl:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])=[O:5])=[O:3])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(Nc1cccnc1Cl)C(F)(F)F
Solvent: ClCCl
Product: O=C(C(=O)N(c1cccnc1Cl)S(=O)(=O)C(F)(F)F)N(c1cccnc1Cl)S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.762 gram; 0.006 mole) is added dropwise to a suspension of N-(2-chloro-3-pyridyl)trifluoromethanesulfonamide (2.61 grams; 0.01 mole) and powdered molecular sieves (5.0 grams; Molecular Sieve, Type 3A) in methylene chloride (75 mls) at 0° C. under a nitrogen atmosphere. The mixture is then heated to 60° C., held thereat for 3 hours, and then stirred at room temperature for 60 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The resulting residue is extracted with diethyl ether, and the combined ethereal extracts are dried over anhydrous sodium sulfate. The dried ethereal extract is then separated and evaporated to obtain 2.33 grams (81% of theoretical) of crude product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@@H](O)C2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
(R)-Pyrrolidin-3-ol (0.276 g, 3.17 mmol) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 2.11 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.61 g, 3.17 mmol) in dichloromethane (7 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with DCM (10 mL) and washed with water (1×15 mL), 10% aqueous citric acid solution (2×15 mL) and brine (2×15 mL), and dried over sodium sulfate. The solvents were reduced in vacuo to afford the title compound as colourless oil (0.42 g, 74%). 1H NMR (400 MHz, CDCl3): δ 4.54-4.52 (1 H, m), 4.11-4.09 (4 H, m), 3.50-3.48 (5 H, m), 2.01-2.00 (2 H, m), 1.43 (9 H, d, J=0.78 Hz)