Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25])=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.Cl>O>[OH:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[CH:10]([NH:13][C:14](=[O:15])[CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reaction time: 4.25 h

Procedure:
This substance was prepared according to German Offenlegungsschrift No. 2,103,014 as follows. A suspension of 8.0 g of cephalothin (1), available semi-synthetically, in 120 ml. of H2O treated with 8.6 g of K2CO3 and the resulting solution was stirred at 36° for 4.25 hours, then at 30° for 18 hours. The resulting mixture was layered with 500 ml of ethyl acetate and a solution of 10.0 ml of conc. HCl in 50 ml of H2O was added. The ethyl acetate was dried (MgSO4) and removed in vacuo in yield 3.84 g (54%) of 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid, mp 138°-145° d. Crystallization from ethyl acetate yielded material, mp 149°-151° d (lit. mp 151.5°-152° d); ir (nujol mull): 3600-2400 (carboxyl -OH), 3450 (amide N-H), 1790 (β-lactam C=O), 1745 (acid C=O), 1650 (amide C=O), and 1510 ("amide II" band) cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35][C:18](=[O:19])[C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:16][CH2:15]2)=[O:21])=[CH:36][CH:37]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 2.5 g, 8.61 mmol), 4-(benzyloxy)aniline hydrochloride (2.06 g, 10.3 mmol), triethylamine (1.8 mL, 12.9 mmol), EDCI (1.6 g, 10.3 mmol) and HOBt (1.58 g, 10.3 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 65:35) to give the title compound (3.64 g, 90%) as a white amorphous.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O>[F:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=C(O)c1csc(Br)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1csc(-c2ccc(F)nc2)c1
Temperature: 120 °C
Yield: 83 %

Procedure:
A mixture of 5-bromo-thiophene-3-carboxylic acid (0.71 g, 4.4 mmol), 2-fluoropyridine-5-boronic acid (0.619 g, 4.4 mmol), caesium carbonate (2.9 g, 8.8 mmol), and palladium tetrakis(triphenylphosphine) (0.470 g, 0.44 mmol) in DME (40 mL), IMS 20 mL) and water (10 mL) was divided across three microwave vials and each was heated by microwave irradiation to 120° C. for 20 minutes. The batches were combined and concentrated and the residue was partitioned between saturated aqueous sodium carbonate and DCM. The aqueous phase was isolated and acidified using dilute HCl (pH 2) giving a precipitate which was collected by filtration to afford the title compound as a white solid (0.815 g). LCMS m/z 224.07 [M+H]+ R.T.=2.83 min (Analytical Method 8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:31]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCCCc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 4-heptylbenzoyl chloride as a yellow oil (94%). HPLC, Rt: 6.8 min (Purity: 96.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:19][C:18]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=3[Cl:16])[CH:10]=2)=[N:4][CH:3]=1
Reactant: Oc1cccc(Oc2ncc(Cl)cn2)c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1cnc(Oc2cccc(OCc3ccc(Cl)cc3Cl)c2)nc1
Yield: 76.2 %

Procedure:
A solution of 3-[5-chloro-2-pyrimidyloxy]phenol (1.11 g), 2,4 dichlorobenzylchloride (0.98 g), potassium carbonate (0.76 g) and sodium iodide (0.075 g) in methyl ethyl ketone (25 ml) was refluxed for four hours. After dilution with water, the reaction mixture was extracted into chloroform and the extracts dried over anhydrous magnesium sulphate. Removal of the solvent under vacuum gave a white solid which was recrystallised from ethanol to give 1.45 g (77%) of the title compound, mp 110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C1(C)C=CC=CC=1>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.C(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][N:22]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2ccc(F)nc2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2.51 g (14.29 mmol) of 4-fluorophenylboronic acid, 0.825 g (0.71 mmol) of Pd(PPh3)4 and 50 mL of 1M sodium carbonate solution are added to a solution of 2.0 g (14.29 mmol) of 5-bromo-2-fluoropyridine in 140 mL of a 4/1 mixture of toluene and ethanol. The mixture is stirred at 90° C. for 2 hours.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=2[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]1)[CH3:10]>N1C=CC=CC=1>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([N:7]3[CH2:6][CH2:5][NH:4][CH:3]([CH2:2][F:1])[CH2:8]3)[C:19]=2[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]1)[CH3:10]
Reactant: FCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)c(F)c21
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
A mixture of 650 mg of 2-(fluoromethyl)piperazine, 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was stirred under nitrogen in a capped bottle at for 2.5 hours. The solvent was removed and the residue triturated with methanol. The solid was collected, washed twice with methanol and dried, giving 376 mg of racemic 1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([N:49]1[C:58]2[C:53](=[CH:54][C:55]([C:59]([NH:61]O)=[NH:60])=[CH:56][CH:57]=2)[C@H:52]([NH:63][C:64](=[O:69])[O:65][CH:66]([CH3:68])[CH3:67])[CH2:51][C@@H:50]1[CH3:70])(=[O:48])[CH3:47]>CN(C)C=O.CCOC(C)=O>[CH3:68][CH:66]([O:65][C:64](=[O:69])[NH:63][C@H:52]1[C:53]2[C:58](=[CH:57][CH:56]=[C:55]([C:59]3[N:61]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[O:12][N:60]=3)[CH:54]=2)[N:49]([C:46](=[O:48])[CH3:47])[C@@H:50]([CH3:70])[CH2:51]1)[CH3:67]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3noc(CNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A flask was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (72.4 mg, 0.413 mmol) and HATU (170 mg, 0.448 mmol) then filled with N,N-dimethylformamide (DMF) (2 mL). DIPEA (0.180 mL, 1.033 mmol) was added and the resulting pale yellow solution was stirred for 5 min. 1-Methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (120 mg, 0.344 mmol) in N,N-dimethylformamide (DMF) (2 mL) was then added via syringe and the resulting mixture was stirred at room temperature for 1 h. The mixture was then stirred at 100° C. under nitrogen for 3.5 h then cooled to room temperature and dissolved in AcOEt. The organic phase was washed with water. The aqueous phase was extracted with AcOEt. The combined organic phases were washed three times with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 on a 10 G silica cartridge (gradient 23 to 63% AcOEt in Hexanes) gave 1-methylethyl((2S,4R)-1-acetyl-6-{5-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (132 mg, 0.271 mmol, 79% yield) as a white foam. LCMS (method A): Retention time 1.07 min, [M−H]−=486.23
Reaction SMILES: [C:1]12([NH:11][C:12]3[S:13][CH:14]([CH2:18][CH2:19][OH:20])[C:15](=[O:17])[N:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]12([NH:11][C:12]3[S:13][CH:14]([CH2:18][CH:19]=[O:20])[C:15](=[O:17])[N:16]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C1N=C(NC23CC4CC(CC(C4)C2)C3)SC1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCC1SC(NC23CC4CC(CC(C4)C2)C3)=NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(1-adamantylamino)-5-(2-hydroxyethyl)thiazol-4(5H)-one (0.25 g, 0.85 mmol) in CH2Cl2 (10 mL) was added to Dess-Martin periodinane (0.56 g, 1.28 mmol, Aldrich) in CH2Cl2 (10 mL). After stirring at ambient temperature for 1 h, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium thiosulfate and aqueous sodium bicarbonate. The organic portion was separated, washed with brine, and conc. in vacuo to give the title compound as a light yellowish solid. MS m/z: 293.6 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14]>CN(C=O)C>[CH3:12][S:11][C:8]1[S:9][C:10]2[C:2]([C:13]#[N:14])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: N#C[Cu]
Reactant: CSc1nc2cccc(Br)c2s1
Solvent: CN(C)C=O
Product: CSc1nc2cccc(C#N)c2s1

Procedure:
The title compound was prepared from 7-bromo-2-methylsulfanyl-1,3-benzothiazole by heating with CuCN (1.0 eq.) in DMF at 160° C. for 12 h.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[CH3:28][N:29]([CH2:31][C:32](O)=[O:33])[CH3:30].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), dimethylaminoacetic acid (47 mg, 0.455 mmol), HOAt (62 mg, 0.455 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (87 mL, 0.455 mmol) and 4-methylmorpholine (0.10 mL, 0.911 mmol) in anhydrous DCM (4 mL) was stirred at RT for 20 h. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) then triturated with diethyl ether affording 134 (55 mg, 30%). LCMS: RT 1.79 min [M+H]+ 448.1. 1H NMR (DMSO, 400 MHz): δ 8.23-7.93 (3H, m), 7.90-7.78 (1H, m), 7.68-7.58 (1H, m), 7.21-7.12 (2H, m), 4.80-4.69 (1H, br), 4.53-4.30 (1H, m), 4.22 (0.6H, bd, J=12.25 Hz), 4.03 (0.4H, bd, J=12.25 Hz), 3.85 (0.6H, t, J=12.08 Hz), 3.44-3.26 (1.4H, t, J=12.08 Hz), 3.21-3.10 (1H, m), 2.99 (0.4H, bd, J=13.04 Hz), 2.90-2.64 (1.6H, m), 2.44-2.26 (1H, m), 2.25-2.11 (6H, m), 1.85-1.58 (5H, m), 1.13-0.97 (1H, m). Signals split due to presence of rotamers
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([C:13]2[C:24]([CH2:25]O)=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([C:13]2[C:24]([CH2:25][C:5]#[N:6])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: OCc1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (186 μL, 1.47 mmol) and trimethylsilyl cyanide (260 μL, 1.95 mmol) in dichloromethane (5 mL) was added a solution of (2-phenyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (130 mg, 0.488 mmol) in dichloromethane (10 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (117 mg, yield 87%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.[C:19](O)(=[O:22])[CH:20]=[O:21]>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[C:10]2[O:11][C:20](=[O:21])[CH:19]([OH:22])[C:9]=2[CH:8]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC(=O)O
Reactant: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reaction time: 7 h
Yield: 100 %

Procedure:
23.6 g of methyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate, 10.1 g of glyoxylic acid monohydrate and 0.08 g of p-toluenesulfonic acid are boiled in 80 ml of 1,2-dichloroethane under a water separator for 7 h. The reaction solution is then cooled down, washed 3 times with 50 ml of water each time and freed of solvent in a rotary evaporator to leave 29.2 g of methyl 3-(7-tert-butyl-3-hydroxy-2-oxo-2,3-dihydrobenzofuran-5-yl)propionate in the form of a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:16]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:20][C:15]3=[N:14][CH:13]=1)[CH:8]=[CH:7]2.[NH2:26][C@@H:27]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].ClCCl>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:19]1[CH:18]=[CH:17][N:16]2[C:12]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:2]([NH:26][C@H:27]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]5)[CH:3]=[CH:4][CH:5]=4)[N:10]=3)=[CH:13][N:14]=[C:15]2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(Br)c4n3)cnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCOc1ccn2c(-c3ccc4cccc(N[C@H]5CCN(C(=O)OC(C)(C)C)C5)c4n3)cnc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A stream of argon was passed through a mixture of 8-bromo-2-(7-(2-methoxyethoxy)-imidazo[1,2-a]pyridin-3-yl)quinoline (0.100 g, 0.2511 mmol), (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.05537 ml, 0.3264 mmol), Cs2CO3 (0.1145 g, 0.3515 mmol), Pd(OAc)2 (0.01127 g, 0.05022 mmol) and rac-BINAP (0.01564 g, 0.02511 mmol) in toluene (1 mL) for 15 minutes. The mixture was heated to 100° C. for 18 hours. The mixture was then allowed to cool to ambient temperature and dichloromethane was added. After stirring 30 minutes, the resulting mixture was filtered and the filtrate was concentrated to yield the title compound as an oil. MS APCI (+) m/z 504.1 (M+1) detected.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2C(C)(C)C)cc1

Procedure:
88 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(2,4-dimethylphenyl)piperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[Br:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30]Br)[N:29]=1>C(#N)C.C(OCC)(=O)C>[Br:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:29]=1
Reactant: BrCc1csc(Br)n1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (2.54 g, 12.5 mmol) in acetonitrile (75 mL), were added cesium carbonate (8.55 g, 26.2 mmol), sodium iodide (187 mg, 1.25 mmol) and 2-Bromo-4-bromomethyl-thiazole (3.53 g, 13.7 mmol). The resulting suspension was stirred at 25° C. for 30 minutes, then at 40° C. for 90 minutes. After cooling, the suspension was diluted with ethyl acetate (80 mL), filtered over a plug of celite, the solvents were evaporated in vacuo. Purification on silica gel afforded N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-methanimine as an oil that solidified on standing after 2 days (4.19 g, yield 88%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:11]O>C(O)(=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][S:8](=[O:11])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1COC2(CCSCC2)O1
Reactant: OO
Solvent: CC(=O)O
Product: O=S1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A room temperature mixture of 13.8 g of product from Example 392 dissolved in 100 ml of acetic acid is treated, dropwise over 20 minutes, with 9.0 ml of 30% hydrogen peroxide. The reaction mixture is stirred at room temperature for 1 hour, concentrated in vacuo at 50° C., and extracted with ethyl acetate. The organic layer is washed 2× with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The aqueous washes are combined and concentrated in vacuo to about 25 ml. The residue is saturated with solid potassium carbonate and extracted 2× with 200 ml of ethyl acetate. The organic phase is concentrated in vacuo to a solid which is triturated with hexane and collected to give 13.1 g of the desired product.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:29]2[N:33]=[C:32]([NH:34]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:31][N:30]=2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl>C(O)=O>[NH2:34][C:32]1[S:31][N:30]=[C:29]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:33]=1
Reactant: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2[C@H](NC(=O)C(=NOC3CC3)c3nsc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: Cl
Solvent: O=CO
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)ns1
Reaction time: 3.5 h
Yield: 60.4 %

Procedure:
To a solution of 7β-[2-(cyclopropyloxyimino)-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in formic acid (11 ml) was added concentrated hydrochloric acid (0.29 ml) under ice-cooling. The mixture was stirred for 3.5 hours at the same temperature. The mixture was concentrated in vacuo and poured into a mixture of ethyl acetate and water. After the mixture was adjusted to pH 7.2 with saturated aqueous solution of sodium bicarbonate, the aqueous layer was separated, adjusted to pH 3 with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with diethyl ether to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (459 mg) as a solid.