Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14]C=2)[C:6]1=[O:18].[NH2:20][O:21][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([NH:20][OH:21])=[O:19])[C:6]1=[O:18])[C:11]1[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CC1CCN(CCc2ccccc2)C1=O
Reactant: NO[K]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CC1CCN(Cc2ccccc2)C1=O)NO
Temperature: 0 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
12 mg of (2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetic acid methyl ester (25r) prepared by the above Step 1 was dissolved in methanol solution (0.04 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.07 ml, 0.12 mM) was added thereto at 0° C. and the resulting mixture was stirred for 4 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 1.6 mg of 2-(1-benzyl-2-oxo-pyrrolidin-3-yl)-N-hydroxy-acetamide (25s) (yield: 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[Cl-].[Cl:11][C:12]1[S:13][S+:14]=[C:15](Cl)[C:16]=1[Cl:17]>>[Cl:17][C:16]1[C:15](=[N:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=2)[S:14][S:13][C:12]=1[Cl:11]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: Clc1s[s+]c(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cc(Cl)cc(N=c2ssc(Cl)c2Cl)c1

Procedure:
If 3,5-dichloro-aniline is reacted with 3,4,5-trichloro-1,2-dithiolium chloride to give 4,5-dichloro-3-(3,5-dichlorophenylimino)-1,2-dithiolene, the course of the reaction can be represented by the following equation: ##STR6##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[N:19]=[C:18]([CH2:20][NH:21][C:22](=[O:33])[C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH:17]=[CH:16][CH:15]=2)[N:12]=[C:11]([C:34]([F:37])([F:36])[F:35])[CH:10]=1)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:25][C@@H:23]([CH3:24])[C:22]([NH:21][CH2:20][C:18]1[N:19]=[C:14]([N:13]2[C:9]([C:7]([NH:6][CH2:5][C:4]3[CH:38]=[CH:39][CH:40]=[CH:41][C:3]=3[O:2][CH3:1])=[O:8])=[CH:10][C:11]([C:34]([F:35])([F:37])[F:36])=[N:12]2)[CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)[C@H](C)N)n1
Temperature: 21 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a stirred solution of 50 (28 mg, 0.049 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.056 mL, 0.728 mmol). The resulting solution was allowed to stir at 21° C. for 2 h and evaporated to dryness. Water was added and the precipitate was removed by filtration. The aqueous phase was then lyophilized. The title product 51 (16.1 mg, 56.1% yield) was isolated as a white solid. 1H NMR: (CD3OD) o(ppm): 7.99 (t, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.26 (d, 2H, J=7.6 Hz), 7.09 (s, 1H), 6.96 (d, 1H, J=7.6 Hz), 6.91 (t, 1H, J=7.6 Hz), 4.51 (dd, 2H, J=15.2, 23.6 Hz), 4.32 (dd, 2H, J=16, 54.4 Hz), 3.95 (q, 1H, J=7.2 Hz), 3.80 (s, 3H), 1.51 (d, 3H, J=6.8 Hz). LRMS (ESI): calc. 476.5; found 477.5 (MH)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16](CO)[N:17]=1)[CH2:10][CH2:11][CH3:12].C(O)C>O1CCOCC1>[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16]([Cl:1])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C

Procedure:
1.45 Grams (10.9 mmol) of an N-chlorosuccinimide was added to a solution consisting of 1.91 g (10.4 mmol) of a 2-butyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane maintained at room temperature. The mixture was reacted for 18 hours with stirring and, then, the solvent was distilled off under reduced pressure. The resulting reaction product was washed with water and was recrystallized from acetonitrile to obtain a pale yellowish scale-like crystalline 2-butyl-4- chloro-5-(hydroxymethyl) imidazole in an amount of 1.00 g (yield, 51%). Recrystallization was further effected with acetonitrile to obtain the milk-white crystalline compound in pure form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@H]4CCCC[C@@H]4O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@H]4CCCC[C@@H]4O)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a solution of methyl 6-chloro-5-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added aq. 1.0M NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (12.6 mg, 16% yield) as a white solid. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, DMSO-d6): δ 12.40-11.90 (br. s, 1 H), 11.85 (s, 1 H), 8.10 (s, 1 H), 7.90 (s, 1 H), 7.61 (m, 1 H), 7.32 (d, 2 H), 7.00 (d, 2 H), 4.93 (m, 1 H), 4.10 (m, 1 H), 3.57 (m, 1 H), 2.05 (m, 1 H), 1.88 (m, 1 H), 1.53 (m, 2 H), 1.40-1.10 (m, 4 H).
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH3:9][C:5]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:6][CH2:7][OH:8].[C:10]([O-:17])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C([O-])c1ccccc1
Reaction time: 8 h

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol in benzene was added 0.09 Mol benzoylchloride and stirred overnight. The benzene was evaporated and the residue was stirred with sat. sodiumbicarbonate solution and extracted with ether. The oily product was purified by column chromatography, yielding the product as a slight yellow liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH:7]=1.C([O-])(=[O:15])C.[Na+]>>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[O:6][CH:7]=[C:3]([CH2:2][OH:15])[N:4]=1
Reactant: ClCc1coc(-c2cccs2)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: OCc1coc(-c2cccs2)n1
Yield: 80 %

Procedure:
In substantially the same manner as in Reference Example 77, 4-chloromethyl-2-(2-thienyl)oxazole was allowed to react with sodium acetate, and then hydrolyzed to give 2-(2-thienyl)oxazolylmethanol. The yield was 80%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 98-99° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH2:6][CH2:5]2.[C:13](=[O:16])([O-])[O-].[K+].[K+]>C(N)C1C=CC=CC=1>[CH2:8]([NH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:11]=1)[C:13](=[O:16])[NH:7][CH2:6][CH2:5]2)[C:9]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: NCc1ccccc1
Product: O=C1NCCc2cc(NCc3ccccc3)ccc21
Yield: 35 %

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (300 mg, 1.81 mmol) and potassium carbonate (550 mg, 3.98 mmol) in benzylamine (1.5 ml) was stirred at 180° C. in a microwave for 2 hrs. The solvent was evaporated and the resulting residue partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with brine (10 ml), then dried (MgSO4) and evaporated in vacuo. The crude residue was purified by preparative HPLC (Method A) to yield the title compound as a colourless solid (80 mg, 18%). HPLC retention time 3.81 min. Mass spectrum (ES+) m/z 253 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@:10]([C:14](Cl)=[O:15])([CH2:11]2)[C@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:33]=[C:34]([C@@H:42]([NH:44][CH3:45])[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(=O)(O)[O-].[Na+]>[F:30][C:31]([F:46])([F:47])[C:32]1[CH:33]=[C:34]([C@@H:42]([N:44]([CH3:45])[C:14]([C@:10]23[CH2:11][CH:12]2[CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:9]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH3:43])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: CN[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)[C@]12CC1CN(Cc1ccccc1)[C@@H]2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)[C@]12CC1CN(Cc1ccccc1)[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To racemic Intermediate 40, one enantiomer being (1R,2R)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (0.17 g, 0.56 mmol) in MC (5 mL) was added triethylamine (0.23 mL, 1.7 mmol) and (S)-1-(3,5-bis(trifluoromethyl)phenyl)-N-methylethanamine 0.15 g, 0.56 mmol) in MC (1 mL). The reaction was allowed to stir at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and the phases separated. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. This material was flash chromatographed on silica using a gradient of 5 to 10% EtOAc/Hexanes to afford the title compound (0.056 g, 18% yield).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]([O:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:28]([CH3:37])[CH2:27][CH2:26]4)[CH:20]=[N:19]2)[CH:15]1[CH3:46])(C1C=CC=CC=1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>C(OCC)(=O)C>[F:45][C:42]1[CH:41]=[CH:40][C:39]([O:38][C:24]2[C:23]([C:21]3[CH:20]=[N:19][N:18]([CH:16]4[CH2:17][NH:14][CH:15]4[CH3:46])[CH:22]=3)=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][C@H:28]([CH3:37])[N:29]3[C:33]([O:35][CH3:36])=[O:34])=[CH:44][CH:43]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CN(C(c5ccccc5)c5ccccc5)C4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Agent: CC(Cl)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CNC4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 50-mL round-bottom flask was charged with (2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.020 g, 0.03 mmol), 1,2-dichloroethane (5 mL) and 1-chloroethyl chloroformate (1 mL), and the resulting solution stirred for 3 h at 80° C. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (20 mL). The organic phase was separated and washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting 25% ethyl acetate-petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV254&220. This afforded methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0021 g, 14%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.40 Hz, 3H), 0.85-0.97 (m, 1H), 1.10-1.18 (m, 3H), 1.29-1.39 (m, 3H), 1.52-1.65 (m, 1H), 1.99-2.25 (m, 2H), 2.41-2.75 (m, 2H), 3.82 (s, 3H), 4.05-4.17 (m, 2H), 4.26-4.35 (m, 1H), 4.62-4.73 (m, 1H), 5.16-5.23 (m, 1H), 6.73-6.81 (m, 2H), 6.93-6.99 (m, 2H), 7.51-7.62 (m, 2H), 7.85 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 451 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[C:3]=1[CH2:13][C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH3:22]O>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[C:3]=1[CH2:13][C:14]([O:16][CH3:22])=[O:15]
Reactant: CO
Reactant: O=C(O)Cc1c(O)ccc2cc(Br)ccc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(O)ccc2cc(Br)ccc12

Procedure:
126.5 Grams of 2-hydroxy-6-bromo-1-naphthylacetic acid, 700 ml of methanol and 2 ml of concentrated sulfuric acid were stirred at room temperature for 24 hours. Then, the reaction mixture was concentrated under reduced pressure. The precipitate was collected by filtration and washed with small amounts of methanol and water to obtain 125.5 g of the desired product.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C:27]([C:29]1[S:33][C:32]([CH2:34]Br)=[N:31][CH:30]=1)=[O:28])[CH3:25]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:34][C:32]4[S:33][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][N:31]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: CCOC(=O)c1cnc(CBr)s1
Product: CCOC(=O)c1cnc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)s1

Procedure:
The subtitle compound was prepared from the product of example 1 step (iii) (1.0 g) and 2-(bromomethyl)-5-thiazolecarboxylic acid ethyl ester (0.9 g) according to the method of example 1 step (iv). The reaction mixture was evaporated to dryness under reduced pressure and the crude product was recrystallised from ethyl acetate/methanol. Yield 0.78 g.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1.ClCCl.CO>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 1.50 g (3.43 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl)-1-piperazine-carboxylate, obtained in step 3.4., and 8.6 ml (17.15 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 1.18 g of product are obtained in the form of a white solid.
Reaction SMILES: C(OC(NC1SC=C(C(=O)C(NC2C(=O)N3C(C(O)=O)=CCS[C@H]23)=O)N=1)=O)(CC)(C)C.[S:32]1[CH:36]=[N:35][N:34]=[C:33]1[S:37][CH2:38][C:39]1[CH2:40][S:41][C@@H:42]2[CH:49]([NH:50][C:51](=[O:68])[C:52]([C:54]3[NH:55][C:56](=[N:59][C:60]([O:62][C:63]([CH2:66][CH3:67])([CH3:65])[CH3:64])=[O:61])[S:57][CH:58]=3)=[O:53])[C:48](=[O:69])[N:43]2[C:44]=1[C:45]([OH:47])=[O:46].[OH-].[Na+].[BH4-].[Na+]>CO.O>[S:32]1[CH:36]=[N:35][N:34]=[C:33]1[S:37][CH2:38][C:39]1[CH2:40][S:41][C@@H:42]2[CH:49]([NH:50][C:51](=[O:68])[CH:52]([OH:53])[C:54]3[N:55]=[C:56]([NH:59][C:60]([O:62][C:63]([CH2:66][CH3:67])([CH3:65])[CH3:64])=[O:61])[S:57][CH:58]=3)[C:48](=[O:69])[N:43]2[C:44]=1[C:45]([OH:47])=[O:46]
Reactant: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1

Procedure:
To a solution of 3-(1,3,4-thiadiazol-2-yl)thiomethyl)-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.1 g.) in methanol (30 ml.) was added 1 N sodium hydroxide aqueous solution (5.2 ml.) under ice-cooling and stirring. To the mixture was dropwise added a solution of sodium borohydride (0.074 g.) in water (2 ml.) over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature. After the reaction, the reaction mixture was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the aqueous layer was separated. The aqueous layer was adjusted to pH 5 to 6 with 10% hydrochloric acid and then washed with ethyl acetate. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and then treated with activated charcoal. After distillation of the solvent from the ethyl acetate layer, the remaining residue was pulverized in diethyl ether, collected by filtration and then dried to give pale yellow powder of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acidc (2.2 g.).
Reaction SMILES: [CH:1](=[C:3]1/[C@@H:4]2[N:12]([C:13]/1=[O:14])[C:11]([C:15]([O:17]CC=C)=[O:16])=[C:10]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9]1)/[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:50].C(OCC)C>O1CCCC1.ClCCl.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>[CH:1](=[C:3]1/[C@@H:4]2[N:12]([C:13]/1=[O:14])[C:11]([C:15]([O-:17])=[O:16])=[C:10]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9]1)/[CH3:2].[Na+:50]
Reactant: C=CCOC(=O)C1=C2CCCC[C@@H]2[C@@H]2/C(=C\C)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C=C1/C(=O)N2C(C(=O)[O-])=C3CCCC[C@@H]3[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Allyl (8S,9R)-10-((E)-ethylidene)-11-oxo-1-azatricyclo-[7.2.0.03,8]undec-2-ene-2-carboxylate (73 mg; 0.267 mmole) prepared according to the process disclosed in Example 11a was dissolved in a mixture (0.5 ml) of tetrahydrofuran/dichloromethane 1:1 (v/v). To the obtained mixture there were added first a solution of triphenylphosphine (24 mg; 0.08 mmole) and then a solution of sodium 2-ethylhexanoate (46.8 mg; 0.28 mmole) and tetrakis(triphenylphosphine)palladium(0) (32 mg; 0.024 mmole) (prepared according to the process disclosed in D. R.Coulson, Inorganic Synthesis 13, 121 (1972)) in a mixture (2 ml) of tetrahydrofuran/dichloromethane (1:1). The obtained solution was stirred for 30 minutes at room temperature. To the obtained mixture diethyl ether (4 ml) was added and it was cooled to the temperature of 0° C. The separated product was filtered off, washed with an anhydrous mixture of diethyl ether/tetrahydrofuran and dried in vacuo. The title compound (32 mg; 47%) was obtained in the form of brownish crystals and with m.p. 222-225° C. with decomposition (DMF-diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1(P([C:25]2[CH:30]=[CH:29]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(O)CC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:29]2[CH2:30][CH2:25]2)=[C:4]([Cl:11])[N:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OC1CC1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CC3)c2n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
2,6-Dichloropurine (1 mmol), triphenylphosphine (1.3 mmol), tetrahydrofurane (5 ml) and cyclopropanol (5 mmol) were stirred at rt under nitrogen to give clear yellowish solution, which was then cooled to 0° C. and diisopropyldiazadicarboxylate (DIAD; 1.3 mmol) was added via syringe. The reaction mixture was then stirred at rt for 12 h. After evaporation of the solvents the product was extracted with diethylether and purified by column chromatography (silicagel, 1% MeOH in CHCl3). Crystallization from methanol gave the product in yield 35%, mp 121-124° C.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8]>C(OCC)C.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]([CH2:3][CH2:4][O:5][CH:7]([O:9][CH2:10][CH3:11])[CH3:8])=[CH2:6]
Reactant: C=C(Br)CCO
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(Br)CCOC(C)OCC
Reaction time: 1 h
Yield: 91.6 %

Procedure:
While cooling a solution of 10.38 g (0.0687 mol) of 3-bromo-3-buten-1-ol in 20 ml of diethyl ether with 50 mg (0.000263 mol) p-toluene sulfonic acid monohydrate in an ice water bath, 19 ml (0.199 mol) of ethyl vinyl ether was added slowly dropwise to maintain an internal temperature of <10° C. After 1 hour at 0° C., a few drops of triethylamine was added. The reaction mixture was poured onto water. The resulting mixture was transferred to a separatory funnel and the phases were separated. The isolated organic layer was washed with brine then dried over potassium carbonate and filtered. The solvent was removed from the filtrate in vacuo to yield 14.04 g of 2-bromo-4-(1-ethoxy-ethoxy)-but-1-ene as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-carboxylate and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, m.p. 77-78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42-7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H).