Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].FC1C([Mg]Br)=C(F)C(F)=C(F)C=1F.[Al:18]([C:41]1C(F)=C(F)C(F)=C(F)C=1F)([C:30]1C(F)=C(F)C(F)=C(F)C=1F)[C:19]1[C:28]([F:29])=[C:26]([F:27])[C:24]([F:25])=[C:22]([F:23])[C:20]=1[F:21].[Al](Cl)(C)C.C1([Li])C(F)=C(F)C(F)=C(F)C=1F>C(OCC)C>[Al:18]([C:19]1[C:28]([F:29])=[C:26]([F:27])[C:24]([F:25])=[C:22]([F:23])[C:20]=1[F:21])([CH3:30])[CH3:41]
Reactant: Fc1c(F)c(F)c([Al](c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: C[Al](C)Cl
Agent: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Agent: [Al+3]
Solvent: CCOCC
Product: C[Al](C)c1c(F)c(F)c(F)c(F)c1F
Yield: 64 %

Procedure:
O(CH2CH3)2} from reaction of aluminum trichloride (AlCl3) and pentafluorophenylmagnesiumbromide (BrMgC6F5) in diethyl ether is also known. However, attempts at removing the coordinated ether resulted in explosion. The synthesis of base free Al(C6F5)3 was not possible until much later. The first disclosure of a method for making base free Al(C6F5)3 was provided by researchers in 1995. This was accomplished by reaction of Me2AlCl with C6F5Li in hexanes to initially form Me2AlC6F5 which is then heated to 180° C. in vacuo to liberate AlMe3 and generate crude Al(C6F5)3. Recrystallization of the crude reaction product from THF gave the adduct THF.Al(C6F5)3 in 64% yield. This procedure is dangerous to conduct as C6F5Li is thermally unstable and the produced Al(C6F5)3 is energetic and exploded on occasion. An alternative route for the synthesis of Al(C6F5)3 involves the exchange reaction between B(C6F5)3 and trimethylaluminum which is typically conducted in an aromatic hydrocarbon (i.e., toluene). This strategy purportedly gives rise to high yields of base free Al(C6F5)3 (stable in toluene) but involves the requisite use of pyrophoric Al(CH3)3 in addition to consuming valuable B(C6F5)3.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOC(C)=O.CO.N>>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc[n+](Cc2ccccc2)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1=CCN(Cc2ccccc2)CC1

Procedure:
The product was obtained analogously to IP 5b starting from 10.0 g (45.5 mmol) of 1-benzyl-4-methylpyridinium chloride. Yield: 7.15 g (84% of theoretical); C13H17N (M=187.281); calc.: molpeak (M+H)+: 188; found: molpeak (M+H)+: 188; Rf value: 0.95 (silica gel, EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH3:16][C:17]1[S:18][C:19]([CH:22]=O)=[CH:20][N:21]=1>>[CH3:16][C:17]1[S:18][C:19]([CH:22]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:20][N:21]=1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: Cc1ncc(C=O)s1
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1cnc(C)s1)C2=O
Yield: 60 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 2-methyl-1,3-thiazole-5-carbaldehyde (220 mg, 2.0 mmol) according to Method A3 in 60% yield. ES-MS m/z 314 (M+H)
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].I[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][N:4]([CH:26]([CH3:28])[CH3:27])[C:3]1=[O:24]
Reactant: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1C(=O)N(C(C)C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (75 mg, 0.220 mmol, Compound 32), in N,N-Dimethylformamide (DMF) (1 mL) was added 2-iodopropane (0.024 mL, 0.242 mmol) and sodium hydride (8.81 mg, 0.220 mmol). The resulting reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 equivalent of 2-iodopropane and 0.5 equivalent of sodium hydride and stirred for an additional 24 h at room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 2N NaOH solution (10 mL). The aqueous phase was extracted with ethyl acetate (2×10 mL). All of the organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The crude product was purified by MDAP. The relevant fractions were combined, concentrated and dried to give the title compound as a colourless oil (8 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1(C)C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:14])([F:16])[F:15])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]3)[CH:7]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
300 mg (0.97 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 184 mg (1.16 mmol) of 5-amino-2-methylquinoline are heated in 10 ml of acetic acid over 6 hours to 125° C. After cooling to room temperature, it is mixed with 320 mg (1.51 mmol) of sodium triacetoxy borohydride, and it is allowed to stir for 16 hours. After the addition of another 320 mg (1.51 mmol) of sodium triacetoxy borohydride and 2 hours of stirring, toluene is added, and it is concentrated by evaporation in a vacuum. The residue is taken up in ethyl acetate, the organic phase is washed with saturated sodium bicarbonate and saturated sodium chloride solution, and it is dried on sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-60%), 221 mg of the product is obtained.
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[CH:13]=1)=[O:8])C.Cl>C(O)C>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 72.6 %

Procedure:
Water (5 ml) and 4N aqueous solution of sodium hydroxide (5 ml) were added at room temperature to a solution of 1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (544 mg) in ethanol (10 ml), and stirred at 80° C. for 3.5 hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (21 ml) was added. The precipitated solid was collected by filtration to give the titled compound (356 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:2]3[C:7]([CH:8]=[O:9])=[C:6]([N:10]4[CH:22]=[CH:21][N:13]5[C:14]6[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=6[CH:20]=[C:12]5[C:11]4=[O:23])[N:5]=[CH:4][CH:3]=3)[CH:48]=2)=[N:40][CH:41]=1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ccn6c7c(cc6c5=O)CCCC7)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 80 °C
Yield: 26.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (150 mg, 1.0 eq., 0.46 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 155a (228 mg, 0.46 mmol), K3PO4 (195 mg, 0.92 mmol), PdCl2(dppf) (37 mg, 0.046 mmol), sodium acetate (75 mg, 0.92 mmol), water (8 drops), and acetonitrile (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/ethanol to afford 160a as yellow solid (80 mg, 26%). MS-ESI: [M+H]+ 661.4.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][N:24]([CH:22]=[O:23])[CH2:25][CH2:26]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=CN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: c1ccncc1
Product: O=CN1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (2.0 g), 4-formylpiperazine (0.75 g), and pyridine (30 ml) was stirred at 50° C. for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with water and extracted with chloroform. The extract was dried, and chloroform was evaporated. Ethanol was added to the residue, and the precipitated crystals were collected by filtration. Recrystallization from chloroform-ethanol gave 1-cyclopropyl-5,6,8-trifluoro-7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.58 g), m.p. 290°-297° C.
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCC1.[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26]N=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:9]1([C:14]([NH:16][C:17]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([O:33][C:24]3[C:23]4[C:28](=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=4)[N:27]=[CH:26][CH:1]=3)=[CH:35][C:36]=2[F:41])=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(Cl)C1CCCC1
Agent: O=C(N=C=S)C1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCC4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
1-Cyclopentanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopentanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopentanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 47%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([NH2:16])=O)=[CH:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[S:26])[NH2:16])=[CH:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1cc(C(N)=O)c2ccc(OC)cc21
Solvent: Cc1ccccc1
Product: CCn1cc(C(N)=S)c2ccc(OC)cc21
Yield: 71.4 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 90° C. for 90 min. The reaction mixture is concentrated and purified by silica gel chromatography (EtOAc/CH2Cl2, 1/9) to yield 1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).
Reaction SMILES: [Mg+2].[Cl-].[Cl-].C(O)C(N)(CO)CO.Cl.[P:13]([O:25][CH2:26][C@H:27]1[O:31][C@@H:30]([N:32]2[C:41]3[N:40]=[CH:39][N:38]=[C:36]([NH2:37])[C:35]=3[N:34]=[CH:33]2)[C@H:29]([OH:42])[C@@H:28]1[OH:43])([O:16][P:17]([O:20]P(O)(O)=O)([OH:19])=[O:18])(=[O:15])[OH:14]>>[P:13]([O:25][CH2:26][C@H:27]1[O:31][C@@H:30]([N:32]2[C:41]3[N:40]=[CH:39][N:38]=[C:36]([NH2:37])[C:35]=3[N:34]=[CH:33]2)[C@H:29]([OH:42])[C@@H:28]1[OH:43])([O:16][P:17]([OH:19])([OH:20])=[O:18])(=[O:14])[OH:15]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Next, 50 μl of a reaction mixture containing 0.16 μg of the apyrase-treated PPK-ADK, 10 μM AMP, 400 μM polyphosphate, 8 mM MgCl2, and 60 mM Tris-HCl (pH 7.4) were prepared. Then, 5 μl of the reaction mixture were sampled and mixed with 40 μl of an ATP bioluminescence assay reagent (Roche), and luminescence was measured immediately by using a multiplate luminometer (ARVO, Wallac).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:27]([C:34]([NH:36][OH:37])=O)C1C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:26])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1)=[O:27]
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCNCC1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a solution of (5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.263 g, 0.71 mmol) in dry THF (7 mL) was added N-(phenoxycarbonyl)hydroxylamine (0.216 g, 1.41 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 241 mg (64%) of COMPOUND 264 as a white solid. 1H NMR (CDCl3) δ 0.99 (d, 6H, J=6.9 Hz), 1.60-1.66 (m, 2H), 1.92 (d, 2H, J=11.1 Hz), 2.14 (s, 3H), 2.66-2.88 (m, 4H), 3.78 (s, 2H), 3.81 (s, 2H), 4.04 (d, 2H, J=12.9 Hz), 6.65 (br s, 1H), 6.81 (br s, 1H), 7.16 (dd, 1H, J=7.8, 4.8 Hz), 7.42 (d, 1H, J=1.5 Hz), 7.52 (dd, 1H, J=7.8, 1.5 Hz), 8.32-8.34 (m, 2H); 13C NMR (CDCl3) δ 19.64, 24.80, 28.47, 28.74, 45.43, 55.31, 58.83, 124.66, 132.29, 135.42, 136.61, 139.11, 145.69, 146.12, 147.20, 156.93, 162.45; ES-MS m/z 432 (35Cl) & 434 (37Cl) (M+H). Anal. Calcd. For C22H30N5O2Cl.0.2CH2Cl2O.0.5H2O: C, 58.22; H, 6.91; N, 15.29; Cl, 10.84. Found: C, 58.51; H, 6.68; N, 15.29; Cl, 10.55.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[CH3:20]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)CCN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 5 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
10-chloro-2-cyclohexyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 267; 5.87 g, 20.91 mmol) was suspended in DMA (450 mL) under nitrogen. Methyl iodide (3.26 g, 23 mmol) was added and the suspension cooled to 5° C. on an ice-water bath. Sodium hydride (60% mineral oil dispersion; 920 mg, 23 mmol) was added in a single portion and the resulting mixture stirred on the ice-water bath for 30 minutes allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the solvent evaporated. The residue was partitioned between DCM (200 mL) and water (300 mL) and the aqueous phase re-extracted with DCM (100 mL). The combined organic phases were dried (MgSO4) and the evaporated. The residue was taken up in DCM and purified on a silica column eluting with a gradient of 10-50% EtOAc/isohexane over 10 column volumes. Fractions containing product were combined and evaporated to yield the title compound as a cream solid (5.02 g, 81%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](Cl)(Cl)Cl)[NH:5][C:6]=1[Cl:7].[NH3:12]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]#[N:12])[NH:5][C:6]=1[Cl:7]
Reactant: N
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)[nH]1
Yield: 90 %

Procedure:
25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole were introduced in small portions into 200 ml of ethanol saturated with ammonia, whilst cooling with ice and stirring vigorously. The mixture was stirred for a further 30 minutes at 50° C., the constituents which had not dissolved were then filtered off and the filtrate was evaporated under reduced pressure. The combined residues were dissolved in hot water. On acidifying the solution with dilute hydrochloride acid, the reaction product precipitated out. This was filtered off, washed with water and dried. In this way 14.6 g (90% of theory) of 4,5-dichloro-2-cyano-imidazole were obtained and after recrystallisation from toluene this had a melting point of 187°-189° C.
Reaction SMILES: [CH:1]([CH:14]1[C:19](=[O:20])[CH:18]2[CH2:21][CH2:22][N:15]1[CH2:16][CH2:17]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[H][H]>CC(O)C>[CH:1]([C@H:14]1[C@@H:19]([OH:20])[CH:18]2[CH2:17][CH2:16][N:15]1[CH2:22][CH2:21]2)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
397.7 mg (1.30 mmol) of a racemic mixture of 2-benzhydrylquinuclidin-3-one (1-2) and 1.2 mg (1.3 μmol) of (S)-1,1′-binaphthyl-2,2′-bis(diphenyl)phosphine ruthenium (II) dichloride (R,R)-hexane-2,5-diamine complex were placed in an autoclave in which the inside had been replaced with argon. After adding 6.4 ml of 2-propanol thereto and degassing, 0.13 mL (0.13 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 18 hours at 20 to 25° C. at a hydrogen pressure of 1.0 MPa. After concentrating the reaction solution, analysis of the crude purification product by 1H-NMR indicated that only the syn form had been formed. The reaction solution was then purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=3:1 (volume ratio)) to obtain 382 mg (1.30 mmol, yield: 96%) of (2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2). The optical purity of this substance as measured by high-performance liquid chromatography (eluent: acetonitrile:0.02 M aqueous disodium hydrogen phosphate=6:4 (volume ratio), column: CHIRALCEL OD-RH, Daicel Chemical Industries, Ltd.) was 96% ee.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:36][O:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:31]([O-:33])=[O:32])=[C:15]([CH2:18][N+:19]([CH3:30])([CH3:29])[CH2:20][C:21]4[NH:22][CH:23]=[C:24]([OH:28])[C:25](=[O:27])[CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:36][O:37][CH2:38][C:39]([OH:41])=[O:40])[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:31]([O-:33])=[O:32])=[C:15]([CH2:18][N+:19]([CH3:29])([CH3:30])[CH2:20][C:21]4[NH:22][CH:23]=[C:24]([OH:28])[C:25](=[O:27])[CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Yield: 56.6 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.54 g) in anisole (2 ml) was dropwise added trifluoroacetic acid (8 ml) under ice-cooling with stirring. After being stirred at ambient temperature, the mixture was poured into diisopropyl ether (100 ml). The resulting precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure. The precipitate was dissolved in water (30 ml) at pH 7.0 and acidified to pH 1.0 with 6N hydrochloric acid. After removal of precipitated materials, the aqueous solution was subjected to column chromatography on Diaion HP-20 (50 ml). The column was washed with water and the elution was carried out with 30% aqueous methanol. The active fractions were collected and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.28 g).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Cl:18][CH2:19][C:20]([O:22][CH:23]1[C:24]([O:66]C(OCC)C)([CH3:65])[CH2:25][CH2:26][CH:27]([O:59]C(OCC)C)[CH2:28][C:29]([O:31][CH:32](/[C:37](/[CH3:58])=[CH:38]/[CH:39]=[CH:40]/[CH:41]([CH3:57])[CH2:42][CH:43]2[O:56][CH:44]2[CH:45]([CH3:55])[CH:46]([O:49]C(OCC)C)[CH2:47][CH3:48])[CH:33]([CH3:36])[CH:34]=[CH:35]1)=[O:30])=[O:21]>CO>[Cl:18][CH2:19][C:20]([O:22][CH:23]1[C:24]([OH:66])([CH3:65])[CH2:25][CH2:26][CH:27]([OH:59])[CH2:28][C:29]([O:31][CH:32](/[C:37](/[CH3:58])=[CH:38]/[CH:39]=[CH:40]/[CH:41]([CH3:57])[CH2:42][CH:43]2[O:56][CH:44]2[CH:45]([CH3:55])[CH:46]([OH:49])[CH2:47][CH3:48])[CH:33]([CH3:36])[CH:34]=[CH:35]1)=[O:30])=[O:21]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)CCl)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)CCl)C=CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridinium p-toluenesulfonate (1 mg, 4.1 μmol) was added to a solution of (8E,12E,14E)-7-chloroacetoxy-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (3.2 mg, 4.06 μmol) in methanol (1 mL), followed by stirring at room temperature for one hour. The reaction solution was evaporated, and the resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; ethyl acetate-hexane=2:1) to obtain the title compound (1.6 mg, 70%) as a colorless oil.