Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([N:34]1[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]1)=[O:23])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
21.31 g of N-benzyloxycarbonyltyrosine and 11.79 of N-(tert-butoxycarbonyl)piperazine were dissolved in a mixed solvent of 200 ml of methylene chloride and 100 ml of ethyl acetate, and to the solution was added 14 g of DCC. After stirring at a room temperature for 40 hours, precipitated insoluble matter was filtered off, and the filtrate was concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (1:1) to obtain 23.9 g of the title compound in a colorless amorphous form
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([OH:35])=O)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:38][NH:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([N:39]([CH3:40])[CH3:38])=[O:35])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CNC
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)O)O3)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)N(C)C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylic acid (154 mg, 0.299 mmol) synthesized in Example (28a) was dissolved in dichloromethane (10 mL), and dimethylamine hydrochloride (75.0 mg, 0.920 mmol), WSCI•HCl (115 mg, 0.600 mmol) and 4-dimethylaminopyridine (110 mg, 0.900 mmol) were added, followed by stirring at room temperature for 2 days under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (107 mg, yield 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[NH:18][C:19](=[NH:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:28]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(Cl)c1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(Cl)c3)n2)cc1
Temperature: 122.5 °C

Procedure:
N,N-Dicyclohexylcarbodiimide (4 g, 0.019 mol) is added to a solution of 2-chlorobiphenyl-4-carboxylic acid (3 g, 0.013 mol), N-hydroxy-4-hydroxymethyl benzamidine (2.9 g, 0.017 mol) and N-hydroxybenzotriazole monohydrate (2.9 g, 0.019 mol) in N,N-dimethylformamide (40 mL). The reaction mixture is heated at 120-125° C. for 3 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×15 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (2×20 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 1:9) to give {4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-phenyl}-methanol.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: COc1ccccc1-c1ccnc(F)c1
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1ccnc(Nc2ccccc2)c1
Temperature: 150 °C

Procedure:
A mixture of A3 (80 mg, 0.39 mmol) and aniline (102 mg, 1.1 mmol) was heated for 20 minutes at 150° C. in a microwave oven. The title compound B1 was obtained from the residue by preparative HPLC (water/ACN gradient) as an amorphous solid (20 mg, 19%). MS (ES) C18H16N2O requires: 276. found: 277 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:10][C:11]1[C:15]2=[N:16][C:17]3[C:23](=[O:24])[O:22][C:20](=[O:21])[C:18]=3[CH:19]=[C:14]2[S:13][CH:12]=1>C1COCC1>[C:3]([C:2]([NH:1][C:23]([C:17]1[N:16]=[C:15]2[C:11]([Cl:10])=[CH:12][S:13][C:14]2=[CH:19][C:18]=1[C:20]([OH:22])=[O:21])=[O:24])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3c(Cl)csc3cc21
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2c(Cl)csc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
2-Amino-2,3-dimethylbutyramide (0.71 g) all in one portion is added to a stirred solution of 3-chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid anhydride, (1.2 g) in THF (1.0 mL). After standing for five minutes, the ice bath is removed and the reaction stirred at room temperature for 28 hours. THF (5 mL) is added and the mixture heated at reflux for two hours and then set aside overnight. The cooled mixture is filtered and the collected solid washed with ether to give 1.4 g of the desired 5-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-chlorothieno[3,2-b]pyridine-6-carboxylic acid.
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH2:16]O)[S:13]/[C:12]/3=[N:18]\[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:10][C:4]=2[O:3]1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH2:16][F:35])[S:13]/[C:12]/3=[N:18]\[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:10][C:4]=2[O:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CN(C)C(=O)/N=c1\sc(CO)cn1-c1ccc2c(c1)OC(F)(F)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)/N=c1\sc(CF)cn1-c1ccc2c(c1)OC(F)(F)O2
Reaction time: 4 h

Procedure:
A solution of N′-[(2Z)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-(hydroxymethyl)-1,3-thiazol-2(3H)-ylidene]-N,N-dimethylurea (Example 87, 0.2 g, 0.56 mmol) in dry CH2Cl2 (10 mL) was treated with bis(2-methoxyethyl)aminosulfur trifluoride (0.148 g, 0.67 mmol). After 4 hours at room temperature, the mixture was neutralized by dropwise addition of a saturated solution of sodium bicarbonate. The mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over silica using CH2Cl2 as mobile phase. 1H NMR (CDCl3) δ ppm 3.00 (6H), 5.20 (1H), 5.38 (1H), 7.00 (1H), 7.30 (2H), 7.38 (1H); MS (ESI) 360(M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1(O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:12]1([O:1][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OC1CCCC1
Reactant: COc1ccc(C#N)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (90 mg, 0.60 mmol, example 9), cyclopentanol (55 mg, 0.64 mmol) and triphenylphosphine (167 mg, 0.64 mmol) in THF (3 mL) at −78° C. was added diethyl azodicarboxalate (0.16 mL, 0.860 mmol, 85%). The cooling bath was removed and the reaction was allowed to warm up to room temperature over 1.5 h. The reaction mixture was concentrated in vacuo, and purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-8% diethyl ether in hexanes yielded 2-cyclopentyloxy-4-methoxy-benzonitrile as a clear liquid (125 mg, 90%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:10]([OH:12])[CH3:11])[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Sodium borohydride (1.182 g, 51.4 mmol) was added to a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanone (10 g, 42.8 mmol) in methanol at 0° C., The resulting bubbling white mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with acetone (50 mL) and concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated to yield the title compound (10 g, 42.5 mmol, 99% yield) as a white solid: 1H NMR (CDCl3): δ 7.75 (d, 1H), 7.32 (m, 1H), 7.19 (m, 1H), 5.23 (q, 1H), 1.95 (d, 1H), 1.48 (d, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH2:23]([CH:27]([Sn])C=C(CCCC)CCCC)[CH2:24]CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1)[CH:23]=[CH2:24]
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(-c2cccnc2)cc2nc(NC(=O)NCC)sc12
Temperature: 120 °C

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.14 g, 0.37 mmol) in DMF (2 mL) was added tributylallyltin (0.15 g, 0.45 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.0371 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 20 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-MeOH (95:5) to provide the title compound as off white solid (0.034 g, 27%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13](=[O:18])[C@@H:14]([CH3:17])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:18])[C@@H:14]([CH3:17])[CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: COC(=O)[C@@H](C)CO
Reactant: N#Cc1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)COc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1.0 g, 7.3 mmol), (S)-3-hydroxy-2-methyl-propionic acid methyl ester (0.8 mL, 7.3 mmol) and triphenylphosphine (2.3 g, 8.8 mmol) at room temperature, diethyl azodicarboxylate (1.4 mL, 8.8 mmol) was added dropwise. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed successively with dilute aqueous sodium hydroxide, dilute aqueous hydrochloric acid, brine, and dried (MgSO4). Solvents were stripped in vacuo. The resulting oil was washed with diethyl ether and the precipitate was filtered off. The mother liquor was adsorbed onto silica gel and the product purified by flash column chromatography (40% ethyl acetate/hexane), affording 0.14 g of a yellow oil (8% yield).
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C=O)C>[Si:9]([O:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In 10 ml of DMF was dissolved 1.2 g of methyl (R)-β-hydroxybutyrate, and 1.8 g of t-butyldimethylsilyl chloride and 1.0 g of imidazole were added to the solution and reaction was carried out at room temperature overnight. Water was added to the solution and the mixture was extracted with ether. The extract was subjected to distillation to obtain 2 g of methyl (R)-β-t-butyldimethylsilyloxybutyrate. The obtained compound was dissolved in anhydrous ether and the solution was added dropwise into a suspension of 0.5 g of lithium aluminum hydride in anhydrous ether. After the dropwise addition, the mixture was refluxed for 3 hours. After the reaction, 0.5 ml of water, 0.5 ml of 15% NaOH and 1.5 ml of water were added in turn to the reaction mixture, 20 ml of THF was further added, and the mixture was stirred for 30 minutes. The precipitate was removed by filtration, and the filtrate was dried over magnesium sulfate and concentrated under a reduced pressure. The residue was subjected to distillation under reduced pressure to obtain
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][C:13]=2[OH:26])=O)=[CH:7][CH:6]=1)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[OH:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]2[O:26][C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][C:12]=3[N:11]=2)=[CH:7][CH:6]=1
Reactant: CCCCCCCCc1ccc(O)c(NC(=O)c2ccc(OC(C)=O)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCCCCCCc1ccc2oc(-c3ccc(O)cc3)nc2c1
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 200 ml-round-bottomed flask, 4.00 g (10.4 mM) of 2-(4-acetoxybenzoylamino)-4-octylphenol, 0.40 g of p-toluenesulfonic acid monohydrate and 40 ml of o-dichlorobenzene were placed, followed by stirring for 1 hour at 188°-192° C. After the reaction, odichlorobenzene in the reaction mixture was distilled off under reduced pressure. To the residue, 1.98 g (30.0 mM) of potassium hydroxide and 60 ml of ethanol was added and stirred for 1 hour on a water bath kept at about 75° C. After the reaction, ethanol in the reaction mixture was distilled off under reduced pressure. Water was added to the resultant residue, followed by addition of 6.0 ml (34.0 mM) of concentrated hydrochloric acid under stirring on an ice bath to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from ethanol to obtain 2.70 g of 2-(4-hydroxyphenyl)-5-octylbenzoxazole (Yield: 80.0%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)#N.C(O)(=[O:20])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:20]
Reactant: CC(=O)O
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C#N)c2C
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of methyl (R)-(5-cyano-4-methyl-indan-1-yl)acetate (1.00 g, 4.36 mmol, from EXAMPLE 110, Step J) in pyridine (28 mL), acetic acid (15 mL), H2O (15 mL) and NaH2PO2 (3.07 g, 34.9 mmol) Rainey nickel was added (1.0 g) and the mixture was heated to 50° C. After 5 hr, the reaction was concentrated in vacuo and filtered through Celite®. The filtrate was concentrated in vacuo and partitioned between EtOAc (150 mL) and H2O (50 mL). The organic layer was washed with 5.0 N HCl (7×50 mL), sat. NaHCO3 (2×50 mL), brine (1×50 mL) and dried (MgSO4). The mixture was filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/hexanes) to give 882 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.76-1.84 (m, 1H), 2.41-2.51 (m, 2H), 2.57 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.6 Hz), 2.81-2.87 (m 1H), 2.93-2.99 (m, 1H), 3.61-3.67 (m, 1H), 3.72 (s, 3H), 7.16 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, 7.8 Hz), 10.2 (s, 1H).
Reaction SMILES: [S:1]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH2:4][CH:3]=[CH:2]1.S1[C@@H]2CC(=[O:18])N2C=CC1>>[S:1]1(=[O:18])[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH:4]=[CH:3][CH2:2]1
Reactant: O=C1C[C@H]2SC=CCN12
Reactant: O=C1C[C@H]2SCC=CN12
Product: O=C1C[C@@H]2N1C=CCS2=O

Procedure:
A ceph-2-em or ceph-3-em reaction product may also be oxidised to yield the corresponding ceph-3-em 1-oxide, for example by reaction with a peracid, e.g. peracetic or m-chloroperbenzoic acid; the resulting sulphoxide may if desired, subsequently be reduced as described hereinafter to yield the corresponding desired ceph-3-em sulphide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)CCC(CC=Cc1cccnc1)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 34 mg of 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-2-propenyl]octanoic acid in 2 mL of ethanol is added 5 mg of 10% palladium on carbon. The mixture is hydrogenated at 1 atmosphere pressure of hydrogen at room temperature for 48 hours. Then the mixture is filtered, washed and evaporated to give an oil which is purified by preparative thin layer chromatography using petroleum ether, ethyl acetate, acetic acid (80:18:2) as solvent to yield 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid of Example 5a.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:15][CH2:16][CH2:17][N:18]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]1[CH3:24]>COCCOC>[CH3:24][C:19]1[N:18]([CH2:17][CH2:16][NH:15][C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[S:14])[C:22]([CH3:23])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Solvent: COCCOC
Product: CCOC(=O)c1ccc(NC(=S)NCCn2c(C)ccc2C)cc1

Procedure:
8.3 g (0.04 mol) of 4-ethoxy carbonylphenyl isothiocyanate in 20 ml of ethylene glycol dimethyl ether are added dropwise at room temperature to 5.5 g (0.04 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole in 20 ml of ethylene glycol dimethyl ether. The precipitated product is filtered off with suction and recrystallized from methanol. Yield: 5.1 g (37% of theory) Melting point: 155°-156° C. Elemental analysis: C18H23N3O2S (345.47) calculated: C 62.6 H 6.7 N 12.2 0. 9.3 S 9.3 found: C 62.0 H 6.7 N 11.6 0 10.0 S 9.2
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[C:28]([F:42])([F:41])[CH2:27]1)=O)(C)(C)C>>[F:42][C:28]1([F:41])[CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:8]5[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=5)[N:17]4[N:16]=3)=[C:34]([O:39][CH3:40])[CH:33]=2)[CH2:30][CH2:31][NH:26][CH2:27]1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2(F)F)ccc1N
Reactant: COc1ncccc1-c1ccc2cnc(O)nn12
Product: COc1cc(C2CCNCC2(F)F)ccc1Nc1ncc2ccc(-c3cccnc3OC)n2n1

Procedure:
7-(2-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (prepared as described in U.S. Pat. No. 8,471,005/Appl. WO2010071885; 65 mg, 0.27 mmol) and (±)-4-(4-amino-3-methoxy-phenyl)-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) were converted to the title compound by a procedure similar to Example 4, to afford a yellow foam (86 mg, 69% yield). 1H NMR (CDCl3): 8.72 (s, 1H), 8.49 (d, J=7.4 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (m, 1H), 7.51 (s, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.08 (m, 1H), 6.86 (m, 3H), 4.02 (s, 3H), 3.92 (s, 3H), 3.30 (m, 1H), 3.21 (m, 1H), 3.02 (m, 1H), 2.90 (dd, J=30.8 (F_H vic. coupling), 13.7 Hz, 1H), 2.75 (m, 1H), 2.10 (m, 1H), 1.95 (m, 2H); LC/MS (ESI+): 467.0 (M+H).