Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][CH:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CC(=O)Oc1ccc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To an ice-cooled solution of product obtained in Step 4 of Example 8 (5.3 g) in dimethylformamide (18 ml) was added (2-aminothiazol-4-yl)glyoxylic acid (2.03 g), and the mixture was stirred overnight at room temperature. The resulting solution was poured into ice water (100 ml), and the mixture was acidified (pH 2) with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether, giving 6.30 g of the objective compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([NH:19][C@@:20]12[CH2:27][C:26](=[CH2:28])[CH2:25][C@@H:24]1[CH2:23][N:22]([C@@H](C1C=CC=CC=1)C)[CH2:21]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[CH2:5]([O:4][C:2]([N:22]1[CH2:23][C@@H:24]2[C@@:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])([CH2:27][C:26](=[CH2:28])[CH2:25]2)[CH2:21]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C1C[C@@H]2CN([C@H](C)c3ccccc3)C[C@]2(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: C=C1C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@]2(NC(=O)OC(C)(C)C)C1
Temperature: 40 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
Benzyl chloroformate (0.250 ml, 1.75 mmol) was added to a solution of the residue containing (1S,5R)-1-tert-butoxycarbonylamino-7-methylene-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (200 mg, equivalent to 0.437 mmol) in dichloromethane (1.94 ml) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours and at 40° C. for four hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→87:13→86:14→83:17→80:20→75:25) to give 95.1 mg of the title compound as a transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.Cl>O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A methanol (2.0 ml) solution containing (2RS,3RS)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.05 g), methyl 3-mercaptopropionate (0.11 ml) and a 28% sodium methylate-methanol solution (0.14 ml) was refluxed for 1.0 hour. The reaction mixture was cooled, to which was added water (10 ml). The mixture was neutralized with 1N aqueous solution of hydrochloric acid, followed by extraction with methylene chloride (5.0 ml×twice). The extract solution was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was subjected to a silica gel chromatography (2.5 cm×5 cm), followed by elution with ethyl acetate-hexane (1:2). The object fraction was concentrated, to which was added ethyl acetate to give (2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-[(1H)-1,2,4-triazol-1-yl]-2-butanol (0.030 g) as colorless needles.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[ClH:26].[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[O:19][C:17]1[CH:16]=[CH:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: Clc1cccc(Oc2ccc3c(n2)OCCN(Cc2ccccc2)C3)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Cl
Product: Clc1cccc(Oc2ccc3c(n2)OCCNC3)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 183.3 %

Procedure:
To a solution of the compound obtained in step 2 (0.23 g) in dichloroethane (3 mL) was added 1-chloroethyl chloroformate (0.074 mL), and the resulting mixture was stirred at 90° C. for 2 hr. The solvent was evaporated under reduced pressure, and methanol (3 mL) was added. The mixture was stirred at 80° C. for 1 hr. Diisopropyl ether (3 mL) was added, and the precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.18 g, 89%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 67.6 %

Procedure:
54.2 g of 4-hydroxymethylbenzaldehyde, together with 40 g of triethylamine, are dissolved in 350 ml of dichloromethane. After the dropwise addition of 31.2 g of acetyl chloride at 0° to 5° C., the reaction mixture is allowed to stand overnight at room temperature. Thereafter, the precipitated triethylammonium chloride is filtered off under suction, and the filtrate is extracted 3 times with saturated bicarbonate solution. After it has been dried with sodium sulphate, the residue is distilled in a high vacuum. 47.9 g of a colorless solid are obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([CH2:28][OH:29])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:30][CH3:31])=[CH:7][CH:6]=2.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[CH:9][C:8]([O:30][CH3:31])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(Cl)c(CCCC3(CO)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(Cl)c(CCCC3(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 0 °C

Procedure:
A mixture of 24.8 g of tert-butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-4-hydroxymethyl-piperidine-1-carboxylate in 400 cm3 of dichloromethane and 12.9 cm3 of triethylamine was cooled to about 0° C. with stirring and under an inert atmosphere. Methanesulfonyl chloride, dissolved beforehand in 125 cm3 of dichloromethane, was added dropwise and the reaction mixture was then stirred for 18 hours at a temperature in the region of 20° C. 200 cm3 of water were added to the reaction mass, followed by a further addition of 3 000 cm3 of water. The phases were separated by settling and the aqueous phase was extracted with 200 cm3 of dichloromethane. The organic extracts were washed with 300 cm3 of aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45° C. 30.6 g of tert-butyl 4-[3-(3-chloro-6-methoxy-quinolin-4-yl)propyl]-4-methanesulfonyloxymethylpiperidine-1-carboxylate were obtained in the form of an orange-colored oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[S:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2>C(#N)C>[Br-:1].[N:5]([CH2:4][CH2:3][CH2:2][N+:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)=[C:6]=[S:7]
Reactant: S=C=NCCCBr
Reactant: C1CN2CCC1CC2
Solvent: CC#N
Product: S=C=NCCC[N+]12CCC(CC1)CC2
Product: [Br-]
Temperature: 50 °C

Procedure:
To a solution of 55 mg of 3-bromopropyl isothiocyanate in 1 ml of acetonitrile was added 33 mg of quinuclidine, and the mixture was heated at 50° C for 19 hours. The reaction solution was concentrated and the residue was washed 3 times with 1 ml of ether to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O)(=O)C.[Na].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH2:6][CH2:5]2
Reactant: C1COCCN1
Reactant: O=C1CCc2c(ccc(Br)c2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1c(Br)ccc2c1CCC(N1CCOCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To 6-bromo-5-fluoro-tetralin-2-one (1 g, 4.11 mmol) and morpholine (0.36 mL, 4.11 mmol) in dichlormethane is added glacial acetic acid (0.52 mL, 9.05 mmol). The reaction mixture is cooled with an ice bath and sodium triacetoxyborhydride (1.74 g, 8.23 mmol) is added. The reaction mixture is stirred at r.t. overnight. Morpholine (0.2 mL) is added and stirred again at r.t. overnight. The reaction mixture is basified with potassium carbonate solution (20%) and stirred for 15 min. The organic layer is separated and the aq. layer is washed two times with dichlormethane. The organic layers are dried and concentrated. The crude product is purified by reversed phase HPLC Yield 57%, m/z 314/316 [M+H]+, rt 0.68 min, LC-MS Method X011_S03.
Reaction SMILES: [H-].[Na+].[CH:3](=[C:5](/[C:10]1[CH:35]=[C:34]2[C:13]([NH:14][C:15]3[C:16]2=[CH:17][CH:18]=[C:19]2[C:27]=3[NH:26][C:25]3[C:20]2=[CH:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=3)=[CH:12][CH:11]=1)\[CH:6]=[CH:7]/[CH:8]=C)\[CH3:4].C1OCCOCCOCCOCCOC1.[Br:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](Cl)=[O:55]>C1COCC1>[Br:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54]([N:26]1[C:27]2[C:19](=[CH:18][CH:17]=[C:16]3[C:34]4[C:13](=[CH:12][CH:11]=[C:10]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:4][CH:3]=5)[CH:35]=4)[NH:14][C:15]3=2)[C:20]2[C:25]1=[CH:24][CH:23]=[C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]=2)=[O:55]
Reactant: C=C/C=C\C(=C/C)c1ccc2[nH]c3c(ccc4c5cc(-c6ccccc6)ccc5[nH]c43)c2c1
Reactant: O=C(Cl)c1ccccc1Br
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Br)n1c2ccc(-c3ccccc3)cc2c2ccc3c4cc(-c5ccccc5)ccc4[nH]c3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (52.5 mmol) of NaH (60% in mineral oil) are dissolved in 500 ml of THF under a protective atmosphere. 20 g (50 mmol) of 3-[(Z)-1-eth-(E)-ylidenepenta-2,4-dienyl]-8-phenyl-11,12-dihydro-11,12-diazaindeno[2,1-a]-fluorene and 11.5 g (52.5 mmol) of 15-crown-5 dissolved in 200 ml of THF are added. After 1 h at room temperature, a solution of 12 g (55 mmol) of 2-bromobenzoyl chloride in 250 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 18 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([C:42](=[O:44])[CH3:43])=[CH:41][C:28]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([C:42](=[O:44])[CH3:43])=[CH:41][C:28]3=4)[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)C(=CCCN1CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the (S)-4-(4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol (5.50 g, 22.94 mmol) in acetonitrile (200 mL) and water (50 mL) was added potassium carbonate (7.17 g, 51.9 mmol) followed by solid 1-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-ethanone (6.30 g, 17.3 mmol). The heterogeneous mixture was stirred at room temperature 4 hours, warmed to 50° C. and stirred 13 hours. The mixture was cooled to room temperature and acetonitrile was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (750 mL) and the extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (3:1 ethyl acetate:hexanes) to afford (S)-1-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl)-ethanone as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#N.CC(C[AlH]CC(C)C)C.ClCCl.[O:33]1CCCC1>>[CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=[O:33]
Reactant: C1CCOC1
Reactant: Cc1c(C#N)cccc1NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
To a solution of benzyl 3-cyano-2-methylphenylcarbamate (6.41 g, 24.07 mmol) in tetrahydrofuran (250 mL) at −78° C. was added DIBAL-H in dichloromethane (96 mL, 96 mmol) over 1 hr. The mixture was stirred at −78° C. for 45 min and then at room temperature for 5 hr. It was poured into ice cold water (300 mL) and the resulting mixture was stirred at room temperature for 30 min. The mixture was filtered through CELITE®, and the filtrate was concentrated to remove most of the THF. The remaining aqueous solution was extracted with ethyl acetate (4×150 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (5.65 g, 20.98 mmol, 87% yield) as a pale yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:18]1[S:22][C:21]([NH:23][C:24]([N:26]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:25])=[N:20][C:19]=1[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(Cl)Cl>[CH:27]1([N:26]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:24](=[O:25])[NH:23][C:21]2[S:22][C:18]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)=[C:19]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
DIPEA (60 μl, 0.35 mmol) and N-methylpiperazine (33 μl, 0.298) were added to a solution of ethyl {5-chloro-2-[3,3-dicyclohexylureido]-thiazol-4-yl}-acetate (100 mg, 0.234 mmol) in methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 48 h, filtered and evaporated to dryness in vacuo. The crude product was purified by HPLC to give ethyl {2-[3,3-dicyclohexylureido]-5-[4-methylpiperazin-1-yl]-thiazol-4-yl}-acetate. Yield: 13 mg (11%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7].[NH2:14][CH:15]1[C:29](=[O:30])[N:17]2[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:13])[CH2:9][C:10]([NH:14][CH:15]1[C:29](=[O:30])[N:17]2[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]12)=[O:12])=[O:7]
Reactant: CC(CC(=O)O)S(=O)c1cccs1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(CC(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)S(=O)c1cccs1

Procedure:
436 mg. of 3-(2-thienylsulfinyl)butyric acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 292 mg. of 7-[3-(2-thienylsulfinyl)butyramido]-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:34]>C(Cl)Cl>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33](=[O:34])[N:21]([C@H:10]2[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH3:22])=[CH:37][CH:38]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3.35 g (10 mmol) (3S,4R)-1-benzyl-4-(3,4-dichlorophenyl)-N-methylpyrrolidin-3-amine (example 159, h), 1.61 g (12.5 mmol) DIPEA and 1.92 g (11 mmol) 4-fluorophenyl chloroformate in 50 mL DCM at 0-5° C. was stirred at 0° C. for 1 h and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from heptane and t-butyl-methylether to yield after evaporation of the product containing fractions 3.07 g (65%) of the title compound as colourless viscous oil. MS m/e: 473.1 [M+H]+.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]([CH2:29][CH2:30][CH:31]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([S:40]([CH:31]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[CH2:30][CH2:29][N:21]([CH2:20][CH2:19][OH:18])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:42])=[O:41])=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate (1.13 g, 1.55 mmol). Under ice cooling, a tetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. Water (2 ml) was added to the reaction mixture. The residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure, whereby the title compound (651 mg, 1.32 mmol, 85%) was obtained as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of 4-(heptyloxy)benzoic acid (1.0 g, 4.23 mmol) in DCM (10 mL) were added DMF (1 drop) and oxalyl chloride (0.47 mL, 5.5 mmol). The reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated under high vacuum. DCM (10 mL) was added and the reaction mixture evaporated again to dryness. The residue was dissolved in DCM (10 mL) then added to a stirring mixture of 4-hydroxy benzaldehyde (0.56 g, 4.6 mmol) and TEA (0.706 mL, 5.07 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was quenched with NaHCO3 (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO4 and concentrated to give 977 mg (62%) of 4-formylphenyl 4-(heptyloxy)benzoate INT-12 which was used in the next step without purification. LCMS-ESI (m/z) calculated for C21H24O4: 340; found 341 [M+H]+, tR=11.91 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.19-7.91 (m, 4H), 7.63-7.41 (m, 2H), 7.24-7.01 (m, 2H), 4.09 (t, J=6.5 Hz, 2H), 1.86-1.62 (m, 2H), 1.50-1.07 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:27][CH:26]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1.O1CCCC1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:29][CH:30]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1
Reactant: [H][H]
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1

Procedure:
To the solution of the compound obtained from step k above (0.3 g) in a solvent mixture of tetrahydrofuran:methanol (10 mL, 1:1), 10% palladium on charcoal (0.15 g) was added at room temperature and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.3 g).