Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCC.O1CCCC1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1CN(Cc2ccccc2)CC1C(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -70 °C
Yield: 14.5 %

Procedure:
Benzyl (3RS,4SR)-1-benzyl-4-methylpyrrolidine-3-carboxylate obtained in Example 1f (30 g, 97.4 mmol) was dissolved in tetrahydrofuran (300 ml), which was cooled to −70° C. with stirring under nitrogen. A 1.11M lithium diisopropylamide/n-hexane-tetrahydrofuran solution (105 ml, 116 mmol) was added dropwise over 20 minutes so that the internal temperature did not exceed −64.3° C. The mixture was stirred at −70° C. for 1 hour, and tetrahydrofuran (30 ml) and tert-butyl bromoacetate (26.6 g, 136 mmol) were then added dropwise over 10 minutes so that the internal temperature did not exceed −60° C. The reaction mixture was stirred at −70° C. for further one hour, and a saturated aqueous ammonium chloride solution was then added to the reaction mixture. Immediately thereafter, the reaction mixture was diluted with water and ethyl acetate was added. The organic layer was washed with brine and a 5 N aqueous hydrochloric acid solution, and then dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The residue was further purified by NH silica gel column chromatography (elution solvent: heptane/ethyl acetate=98/2) to give the title compound (6 g, yield: 14.5%).
Reaction SMILES: Cl.[O-:2][Si:3]([O-:5])=[O:4].[Na+:6].[Na+].[OH2:8]>>[Si:3]([O-:8])([O-:5])([O-:2])[O-:4].[Na+:6].[Na+:6].[Na+:6].[Na+:6]
Reactant: O
Reactant: O=[Si]([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]
Yield: 18.5 %

Procedure:
Heimann (U.S.D. Pat. No. 2,316,241 dated Apr. 13, 1943) uses a gel that contains more water than the gels used in this invention. The patentee uses concentrated hydrochloric acid (the commercial product generally has 36% HCl) diluted with an equal volume of water, yielding approximately 18% acid. He neutralizes this with 40° Baume waterglass solution (37% sodium silicate) which is also diluted with an equal volume of water, resulting in an approximately 18.5% sodium silicate solution. The ingredients for the gel preparation used in a specific embodiment of the present invention are 41.5% sulfuric acid and 29% sodium silicate. The resulting reaction mixture of the present invention has approximately half the amount of water compared with Heimann's mixture. Those skilled in the art know that this difference in concentration causes the solidification of a gel to take approximately ten times longer for the more dilute system. This is the reason Hiemann makes his gel by one of three methods. (1) Precipitation with ammonia, or (2) by letting the mixture stand for several days or (3) by heating the mixture to 90 or 100 degrees C. The gel used in the present invention gelatinizes in 30 to 60 minutes. (Data for this difference of gelation time are given in "The chemistry of silica" by Ralph K. Iler, John Wiley & Sons, 1979, page 368). The differences in the character of gels is given by Heimann in his patent. On page one, left side line 53, he mentions that the stabilizing effect of his product "cannot be attained when employing an ordinary silica gel prepared with an acid". The gel of this invention is an ordinary silica gel prepared with acid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[NH2:20][C:21]1[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[CH:24]=[C:23]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1.[CH3:36][C:37](=O)[CH2:38][C:39](=O)[CH2:40][CH3:41].[OH-].[Na+]>>[CH:30]1([C:23]2[C:22]3[C:21](=[N:20][C:39]([CH2:40][CH3:41])=[CH:38][C:37]=3[CH3:36])[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[CH:24]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCn1c(N)cc(C2CCCCC2)cc1=O
Reactant: CCC(=O)CC(C)=O
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CCc1cc(C)c2c(C3CCCCC3)cc(=O)n(CC)c2n1
Temperature: 140 °C

Procedure:
A mixture of 5.0 g of diphosphorus pentoxide and 2.5 ml of phosphoric acid was stirred at 140° C. until it became transparent. Then, 1.1 g of 6-amino-4-cyclohexyl-1-ethyl-2(1H)-pyridone and 0.6 ml of 2,4-hexanedione were added to this solution, and the mixture was stirred at 140° C. for 3 hours. The reaction solution was poured into ice water, made alkaline by adding 1 N sodium hydroxide aqueous solution and then extracted with ethyl acetate. After drying the ethyl acetate layer over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (toluene-ethyl acetate) to give 1.2 g of 4-cyclohexyl-1,7-diethyl-5-methyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[N:11]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:10]=2)O1.Br[C:34]1[CH:39]=[N:38][CH:37]=[C:36]([CH:40]2[CH2:42][CH2:41]2)[N:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:40]1([C:36]2[N:35]=[C:34]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=4)[N:11]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=4)(=[O:24])=[O:23])[CH:10]=3)[CH:39]=[N:38][CH:37]=2)[CH2:42][CH2:41]1
Reactant: COC(=O)c1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: Brc1cncc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(-c1cncc(C3CC3)n1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A brown mixture of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole-5-carboxylate (2.32 g, 5.10 mmol), 2-bromo-6-cyclopropylpyrazine (CombiPhos Catalysts, Inc., Princeton, N.J.; 1.116 g, 5.60 mmol), Pd2(dba)3 (0.140 g, 0.153 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos; 0.146 g, 0.306 mmol), and potassium phosphate (3.24 g, 15.29 mmol) in a mixture of dioxane (45 mL) and H2O (4.50 mL) was sparged with argon then heated at 100° C. for 3 h. Additional 2-bromo-6-cyclopropylpyrazine (CombiPhos Catalysts, Inc., Princeton, N.J.; 550 mg, 2.80 mmol) was added, and the resulting mixture was stirred at 100° C. for 2 h. The reaction was cooled to RT, diluted with DCM (50 mL), and concentrated onto silica gel. Chromatographic purification (silica gel, 0-80% EtOAc/Hex) furnished methyl 3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indole-5-carboxylate (2.22 g, 4.96 mmol, 97%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 448.1 (M+1).
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[CH3:54][NH2:55]>C1(C)C=CC=CC=1>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]2[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11][CH:10]2[O:9][CH2:8][C:7]2[CH:46]=[CH:47][C:4]([C:2](=[O:3])[NH:55][CH3:54])=[C:5]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:6]=2)=[CH:17][CH:18]=1
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC
Reaction time: 0.25 h

Procedure:
The solution of 0290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 69b) in 1.0 ml of toluene is slowly added dropwise to 1.5 ml of methylamine solution (approx. 10M in ethanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (2:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[O:25].O>ClCCl>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[O:25])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (250 mg, 1.01 mmol), and triethylamine (0.56 mL, 4.03 mmol) in dichloromethane (10 mL) was added methyl 4-(chlorocarbonyl)benzoate (220 mg, 1.11 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (30 mL). This was extracted with dichloromethane (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with n-hexane/ethyl acetate=3/1) to give 329 mg (87% yield) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C)C=O>ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(1,4-dihydroindeno-[1,2-c]pyrazol-3-yl)phenol (2.4 g), anhydrous potassium carbonate (1.2 g), ethyl 2-bromoacetate (1.2 ml) and dry dimethylformamide (20 ml) was stirred at ambient temperature for 24 hours. The mixture was diluted with dichloromethane (200 ml), washed with water, then 1N sodium hydroxide solution. The organic layer was separated, dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate/petroleum ether b.p. 60-80° C. (1:2 as the mobile phase). Appropriate fractions were combined and evaporated to give ethyl 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxyacetate, m.p. 134-136° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6](=O)[CH3:7].[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].C(O)(=O)C.N1CCCCC1.N1CCCCC1>C(O)C.O.C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH3:7])[NH:14][C:12](=[O:13])[C:11]=1[C:9]#[N:10]
Reactant: N#CCC(N)=O
Reactant: COCC#CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: COCc1cc(C)[nH]c(=O)c1C#N
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 8.7 %

Procedure:
To a solution of 5-methoxypent-3-yn-2-one (1.2 g, 10.7 mmol) in 90% ethanol (22 mL), cyanoacetamide (1.08 g, 12.85 mmol) and piperidine acetate {prepared by the addition of piperidine to a solution of acetic acid (0.5 mL) in water (1 mL) till pH 8} were added and reaction heated at 90° C. for 16 h. On completion, ethanol was evaporated and water was added to residue. Solid obtained was filtered and washed with water. Then this solid was stirred with acetonitrile for 10 min and filtered again to obtain the desired intermediate (0.165 g, 8.68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20](O)=[O:21])=[C:11]2[C:10]([C:28]([O:30][CH3:31])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:23]1([C@@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]=[C:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]=23)[C:20]([NH:46][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45]2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CCCC3)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C3CCCC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopentylacetic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C27H38N4O5, 499; found, 499.6.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5])[CH3:2].O1CCOCC1.[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>P(Cl)(Cl)(Cl)=O.O>[CH2:1]([C:3]1([C:19]2[C:18]([CH:17]=[O:24])=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][CH:4]1[OH:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCc1c(O)cccc1O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCC1(c2ccccc2C=O)C(O)=CC=CC1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 629 g. of 2-ethylresorcinol in 1 l. of dioxane were added 530 g. of benzaldehyde and 30 g. of phosphorus oxychloride as a catalyst. The resulting mixture was stirred at room temperature for 24 hours and thereafter poured into 5 l. of a cold water with stirring to give a pale brown powdery resin.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]#[CH:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]#[C:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:25]
Reactant: O=Cc1ccccc1
Reactant: C#Cc1ncc[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: OC(C#Cc1ncc[nH]1)c1ccccc1
Temperature: 25 °C

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) under argon atmosphere and cool to 0° C. Add 2-imidazolylacetylene (276 mg, 3 mmol) in tetrahydrofuran (20 mL) and stir at 0° C. until anion formation is complete. Add a solution of benzaldehyde (297 mg, 2.8 mmol) in tetrahydrofuran, remove the ice bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([OH:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccnn3-c3ccccc3)CS[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccnn3-c3ccccc3)CS[C@H]12
Reaction time: 2 h
Yield: 83 %

Procedure:
To a stirring solution of (7R)-7-[(phenylacetyl)amino]-3-(1-phenylpyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (80 mg, 0.12 mmol) and anisole (0.02 mL) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). After 2 h at 0° C., the solvent was removed with a rotary evaporator, and the residue was subjected to chromatography on silica gel (3% acetic acid/ethyl acetate), affording 49 mg (83%) of the title compound.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]([CH2:15][O:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25])(=O)[NH2:13].Cl>O1CCCC1.CO>[NH2:13][CH2:12][CH2:15][O:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1)=[O:25]
Reactant: NC(=O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a suspension of sodium borohydride (0.30 g) in tetrahydrofuran (15 ml) was added boron trifluoride etherate (3.5 ml) in a nitrogen stream with stirring at 0°-10° C. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-(carbamoylmethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.40 g) in tetrahydrofuran (3 ml) at 0°-10° C. The mixture was stirred at 0°-10° C. for 3 hours and at ambient temperature overnight. Methanol (10 ml) was added to the reaction mixture at 0°-10° C. After 2 hours, insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a residue. A solution of the residue in a mixture of concentrated hydrochloric acid (3 ml) and methanol (30 ml) was stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure to give a syrup. A solution of the syrup in ethyl acetate (30 ml) was extracted with 1N hydrochloric acid (30 ml×3). The aqueous solution was adjusted to pH 10 with aqueous sodium hydroxide and extracted with chloroform (30 ml×3). The organic solution was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (5:95 and then 10:90 V/V) to give (2S,4R)-2-(2-aminoethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.13 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[F:11][C:12]1[CH:24]=[CH:23][C:15]([CH:16]=[N+:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=1.FC1C=CC(C=O)=CC=1.N1CCCCC1>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:2]2[N:1]([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: OCCCn1cccc1
Reactant: Fc1ccc(C=[N+]2CCCCC2)cc1
Agent: O=Cc1ccc(F)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Product: OCCCn1cccc1C(c1ccc(F)cc1)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 3-pyrrol-1-yl-propanol and 1-(4-fluorobenzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 4-fluorobenzaldehyde and piperidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.CC(C)(O)C#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH:16]([OH:17])[C:18]#[N:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)(O)C#N
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 143 %

Procedure:
To a solution containing N-benzyloxycarbonyl-L-valinal 22.2 g, 0.094 mol) in methylene chloride (500 mL) and triethylamine (5.81 g, 8.0 mL, 0.057 mol) was added acetone cyanohydrin (24.23 g, 26.0 mL, 0.2847 mol). The reaction was allowed to stir at room temperature overnight and then concentrated under reduced pressure. The residue was taken up into ether and washed with brine (3×). The solvent was removed under reduced pressure and purified by column chromatography (silica gel; 1:2 acetone:hexane) to give 21.38 g (86.6%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile as a pale yellow oil; TLC Rf =0.33 (silica gel; 1:2 acetone:hexane).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.CCN(C(C)C)C(C)C.[F:24][C:25]([F:43])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[F:43][C:25]([F:24])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37]([N:8]([C:7]2[C:2]([Cl:1])=[C:3]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:4]3=[N:5][CH:6]=2)[CH3:9])=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1
Reactant: CCn1ncc2c(Cl)c(NC)cnc21
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(Cl)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc21
Temperature: 40 °C
Yield: 94.7 %

Procedure:
To a solution of (4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methyl-amine (2.24 g, 10.63 mmol) in CH2Cl2 (50 mL) was added iPr2NEt (3.69 mL, 21.20 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 4.38 g, 13.70 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 4.96 g (95%) of the title compound as a light yellow solid. ES-MS m/e: 493.2 (M+H+).