Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5]([CH2:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])[CH3:11]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
NaH (13.8 g, 0.6 mole) was washed twice with hexane (2×50 ml) and suspended in 250 ml of freshly distilled THF. Next ethyl acetoacetate (75 ml, excess) was added dropwise carefully while the receiving flask was cooled at -10° C. After the addition was complete, it was stirred at -10° C. for 2 hours and at room temperature for 30 min. Benzylbromide (51.0 g, 0.3 mole) in THF was added dropwise at room temperature to the above solution. The reaction mixture was stirred overnight at room temperature. The reaction was terminated the next day by pouring into ice cold water, brought to neutral pH, and extracted with ether/ethylacetate. The combined ether/ethylacetate extracts were rinsed over brine and dried over Na2SO4. Removal of the solvent followed by careful vacuum distillation gave ethyl-benzylacetoacetate, bp 276° C. IR: (neat), cm-1 : 2900-3050, 1690-1760 (broad), 1655. NMR (CDCl3):δ:1.25 (t1 3H, CH2CH3); 2.25 (s, 3H, COCH3); 3.20 (d, 2H, benzylic CH2); 3.8 (t, 1H, COCHCO); 4.20 (q, 2H, OCH2CH3); 7.15-7.35 (m, 5H, Ar-H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH:31]=O>ClCCCl.ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:29]=2[Cl:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
Alternatively, add sodium triacetoxyborohydride (1.6 g, 7.6 mmol) to a mixture of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.4 mmol) and 2,4-dichlorobenzaldehyde (2.8 g, 16.2 mmol) in 1,2-dichloroethane (10 mL) and stir overnight at room temperature. Dilute with dichloromethane and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and chromatograph on silica gel to give (S)-3-(2,4-dichlorobenzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (865 mg, 33%). 1H NMR (400 MHz, CDCl3) 7.33-7.38 (2H, m), 7.23 (1H, d, J=7.82 Hz), 3.85 (2H, d, J=1.96 Hz), 3.45-3.56 (2H, m), 3.30-3.40 (2H, m), 3.19-3.10 (1H, m), 2.04 (1H, m), 1.74 (1H, m), 1.46 (9H, s), MS (ES): m/z=345 [M+].
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]([N:17]([CH:36]([CH3:38])[CH3:37])[C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:16])[CH3:15]>CC(C)=O>[CH:36]([N:17]([CH:14]([CH3:16])[CH3:15])[C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:3])=[O:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)([CH3:38])[CH3:37]
Reactant: CC(C)=O
Reactant: CC(C)N(C(=O)COc1ccc(-c2ccc(C=O)cc2)cc1)C(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)N(C(=O)COc1ccc(-c2ccc(C(=O)O)cc2)cc1)C(C)C
Reaction time: 7 h

Procedure:
0.85 ml of Jones' reagent were introduced under an inert gas atmosphere into a solution of 741 mg of the product of stage B in 10 ml of acetone and the mixture was stirred for 7 hours. The precipitate formed was filtered off and dried to obtain 620 mg of the expected product with a Rf=0.5 (dichloromethane/methanol 9/1).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:17]1)=[O:11]
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
To a 25 mL round-bottomed flask equipped with magnetic stirring was added methyl 2-(4-{(2R)-2-[(tert-butoxy)carbonylamino]-3-(4-chlorophenyl) propanoyl}-piperazinyl)benzoate (3.2 g, 6.4 mmol). A satd soln of HCl in EtOAc (15 mL) was added, and the mixture was stirred at RT for 1 h. The title compound, as the hydrochloride salt, was isolated by filtration as a white solid (2.6 g). MS (ESI, pos. ion) m/z: 402 (M+H). Calc'd for C21H24ClN3O3: 401.15.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:7][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:5]1)#[N:2].Br[C:40]1[C:41]([CH3:46])=[N:42][NH:43][C:44]=1[CH3:45].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:40]3[C:41]([CH3:46])=[N:42][NH:43][C:44]=3[CH3:45])[CH:27]=[N:26]2)[CH2:5][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:7]1)#[N:2]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
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: O
Solvent: C1COCCO1
Product: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
A mixture of 4-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (329 mg, 0.610 mmol, from Example 4, step 5), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (320 mg, 3.0 mmol) in 1,4-dioxane (10 mL)/water (5 mL) was purged with nitrogen and stirred at 110° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, concentrated. The residue was purified first with silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane), and then by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (30 mg, 9.7%). 1H NMR (500 MHz, DMSO-d6) δ 12.17 (1H, s), 8.45 (1H, d, J=8.0 Hz), 8.10 (1H, s), 7.70 (1H, s), 7.34 (1H, m), 6.61 (1H, s), 4.77 (1H, m), 4.62 (2H, d, J=9.0 Hz), 4.39 (1H, d, J=9.0 Hz), 3.64 (2H, s), 2.22 (6H, s), 1.31 (6H, d, J=7.0 Hz) ppm. LCMS calculated for C23H23F5N7O (M+H)+: m/z=508.2. Found: 508.0.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14][C:13]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1
Yield: 77.9 %

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (2.8 g, 5.7 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid (5 mL) and stir for 1 hour. Evaporate to dryness in vacuo and recrystallize the residue (ethyl acetate/hexane) to give the title compound as white needles (1.8 g, 82%); mp 195°-97° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:8]=1[O:9][CH3:10])=[O:2].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:19]([NH:22][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1ccccc1-c1cc(S(N)(=O)=O)cc(C=O)c1OC
Reactant: O=C(Cl)CCc1ccccc1
Product: COc1ccccc1-c1cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc(C=O)c1OC

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6,2′-dimethoxy-biphenyl-3-sulfonamide and 3-phenylpropionyl chloride, gave 5-formyl-6,2′-dimethoxy-N-(3-phenylpropionyl)-biphenyl-3-sulfonamide.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[NH:58]1[CH2:61][CH2:60][CH2:59]1>CN(C)C=O>[N:58]1([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:61][CH2:60][CH2:59]1
Reactant: C1CNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC1
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) were added triethylamine (0.130 ml) and azetidine hydrochloride (60 mg) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and residue was dried under reduced pressure to provide the titled compound as white powder (41.7 mg, 69%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[Na+]>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])([CH3:18])[CH2:13]1
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.92 g, 3.31 mmol) in DCM (40 ml) at 0° C. was added methanesulfonyl chloride (0.51 ml). The reaction mixture was stirred at RT for 12 h. The reaction mixture was made basic with 2 M NaOH and then extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CCOCC>[N:17]([CH:6]1[CH2:10][O:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[N+:18]=[N-:19]
Reactant: CS(=O)(=O)OC1COC(c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1COC(c2ccccc2)C1

Procedure:
14.7 g (61 mmol) of 4-methanesulfonyloxy-2-phenyltetrahydrofuran and 5.13 g (79 mmol) of sodium azide were heated for 3 hours in 120 ml of DMF at 90° C. After the mixture had cooled, it was diluted with ether, washed with water and saturated NaCl solution, dried and concentrated in vacuo. This gave 9.4 g (quant.) of a colorless oil, which was further reacted directly.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH2:25])=[N:22][C:21]=2[CH:26]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH:25][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:22][C:21]=2[CH:26]=1
Reactant: Nc1nc2cc(F)ccc2s1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc(F)ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-fluoro-benzothiazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[C:36]([F:37])=[C:35]([O:38][CH2:39][CH3:40])[CH:34]=[CH:33][C:32]=1[CH:41]1[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1.O>C1COCC1>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:41]2[CH2:46][CH2:45][C:44](=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]2)=[C:31]([F:30])[C:36]=1[F:37])[CH3:40]
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC(=COC)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (166.1 g) was mixed with THF (500 ml) under an atmosphere of nitrogen, and the solution was cooled to −30° C. Potassium t-butoxide (t-BuOK; 54.4 g) was added in two portions in the temperature range of −30° C. to −20° C. After 30 minutes of stirring at −20° C., the compound (s9) (102.7 g) dissolved in THF (100 ml) was added dropwise in the temperature range of −30 to −20° C. After 30 minutes of stirring at −10° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by column chromatography with a mixed solvent of heptane and toluene (heptane:toluene=1:1 by volume) as an eluent and silica gel as a stationary phase powder to give 1-(4-ethoxy-2,3-difluorophenyl)-4-methoxymethylenecyclohexane. The compound was mixed with formic acid (87%; 55.8 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of heptane and toluene (heptane:toluene=2:1 by volume) to give trans-4-(4-ethoxy-2,3-difluorophenyl)-cyclohexanecarboxaldehyde (s10) (54.6 g). The yield based on the compound (s9) was 50.4%.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[CH2:20]([OH:23])[CH:21]=[CH2:22].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>O.C1(C)C=CC=CC=1>[CH2:20]([O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=[CH2:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOCC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
Tetrabutylammonium hydrogenosulfate (470 g, 1.40 mol) is added to a solution of sodium hydroxide (6.6 Kg, 165 mol) in water (14 L) and toluene (14 L) at 20° C. Allyl alcohol (801.5 g, 13.8 mol) is added and the mixture is stirred at 20° C. for 1 h. The mixture is cooled to 5° C., and tert-butyl 2-bromoacetate (4 Kg, 20.5 mol) is added slowly maintaining the internal temperature below 15° C. The reaction mixture is stirred at room temperature for 16 h. The mixture is diluted with water (12 L) and hexanes (12 L) and the organic phase is separated. The aqueous phase is extracted with MTBE (5 L). The combined organic phase is dried over magnesium sulfate, filtered, and concentrated to afford the title compound as colorless oil (2.6 Kg, 100%). ES/MS m/e: 173 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: BrCc1ccccc1
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1ccccc1
Yield: 90.7 %

Procedure:
2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (2.02 g, 7.77 mmol) was reacted with benzyl bromide (1.20 mL, 10.1 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-benzyl-2-(2.6-difluorophenyl)-4-methoxylbenzimidazole (2.47 g, 7.05 mmol, 90% yield). M.p. 139-141° C. 1H-NMR (200 MHz, CD2Cl2) δ7.48 (m, 1H, H4′), 7.25-6.96 (m, 8H), 6.86 (dd, J=0.8, 8.3 Hz, 1H, H5), 6.72 (dd, J=8.0, 0.8 Hz, 1H, H7), 5.24 (s, 2H, CH2Ph), 4.01 (s, 3H, OCH3).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7](Cl)[N:6]=1.O.[C:14](OCC)(=[O:16])C>CO>[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:16][CH3:14])[N:6]=1
Reactant: CCOC(C)=O
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3.24 g of sodium methoxide dissolved beforehand in 13 ml of methanol are added dropwise to a solution of 11 g of 2,4,6-trichloropyrimidine in 140 ml of methanol cooled to 0° C. in an ice bath. The ice bath is withdrawn. The reaction medium is stirred at 0° C. for 45 minutes, and then the cooling bath is removed so as to allow the temperature to rise to ambient temperature. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 30 ml of water and 100 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give an oil which is left to crystallize for 24 hours at ambient temperature. The product crystallizes in the form of needles in the middle of an oil. The needles are separated so as to give 3.94 g of 2,4-dichloro-6-methoxypyrimidine, the characteristics of which are the following:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:67][C@@H:68]1[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=2)=[O:74])[C@H:70]([C:86]([N:88]2[CH2:94][CH2:93][CH2:92][N:91]([CH3:95])[CH2:90][CH2:89]2)=[O:87])[CH2:69]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([S:67][C@@H:68]3[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=4)=[O:74])[C@H:70]([C:86]([N:88]4[CH2:94][CH2:93][CH2:92][N:91]([CH3:95])[CH2:90][CH2:89]4)=[O:87])[CH2:69]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 46.5 %

Procedure:
340 mg of 4-nitrobenzyl (1R, 5R, 6S)-6[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 3.5 ml of anhydrous acetonitrile, and the solution was placed on an ice bath. Whilst the solution was still on the ice bath, 210 μl of diphenylphosphoryl chloride and 180 μl of diisopropylethylamine were added dropwise to it, and the resulting mixture was stirred for 1 hour at this ice-cooled temperature. 580 μl of diisopropylethylamine and 5 ml of an anhydrous acetonitrile solution containing 640 mg of (2S, 4S)-4-mercapto-2-(4-methyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine bis(trifluoromethanesulfonate) [prepared as described in step (1) above] were then added dropwise to the reaction mixture, still on an ice bath, and the resulting mixture was stirred overnight at this ice-cooled temperature. At the end of this time, the mixture was treated and purified by means similar to those described in Example 1(2), to give 316 mg of the title compound.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].[I:16][CH2:17]I>C1COCC1>[CH3:6][O:7][C:8]([C:10]1([CH2:17][I:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COC(=O)C1CCCCC1
Reactant: ICI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1(CI)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.8 %

Procedure:
To a −78° C. of Diisoprpyl amine (132 mmol, 18.65 mL) in THF (100 mL) was added n-BuLi (120 mmol, 75 mL). Cold bath was removed and put back after 30 minutes. Cyclohexane carboxylic acid methyl ester 1261-A (15.57 g, 109 mmol) was added dropwise in THF (50 mL). After 1 h, Diiodomethane (109 mmol, 8.78 mL) was added while keeping temperature below 10° C. After addition, reaction was warmed to RT and stirred overnight. After 18 h, reaction was quenched with NH4Cl and extracted with EtOAc. Washed with brine, dried over MgSO4, filtered and concentrated down to provide 35 g of product 1261-B.