Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(=O)(=O)(O)O.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(Br)c1

Procedure:
The required aldehyde, 5-bromopyridine-3-carboxaldehyde, can be prepared from 5-bromonicotinic acid (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc.). The 5-bromonicotinic acid can be treated with ethyl chloroformate to form a mixed anhydride, which can then be reduced, for example, with lithium aluminum hydride in tetrahydrofuran (THF) at −78° C., to afford 5-bromo-3-(hydroxymethyl)pyridine, as reported by Ashimori et al., Chem. Pharm. Bull. 38 (9): 2446 (1990). Alternatively, the 5-bromonicotinic acid can be esterified, for example, in the presence of sulfuric acid and ethanol and the intermediate ethyl ester reduced with an excess of sodium borohydride to yield 5-bromo-3-(hydroxymethyl)pyridine, according to the techniques reported in Nutaitis et al., Org. Prep. and Proc. Int. 24: 143 (1992). The resulting 5-bromo-3-(hydroxymethyl)pyridine can then be converted to 5-bromo-3-pyridinecarboxaldehyde by Swern oxidation using oxalyl chloride and dimethylsulfoxide, according to the methods of Stocks et al., Tetrahedron Lett. 36 (36): 6555 (1995) and Mancuso et al., J. Org. Chem. 44 (23): 4148 (1979). The aldehyde, 4-bromopyridine-3-carboxaldehyde can be synthesized according to methodology described in PCT WO 94/29893 by Chin et al. or by methodology described by Ojea et al., Synlett. 6: 622 (1995). 6-Bromopyridine-3-carboxaldehyde can be prepared according to procedures described in Windschief and Voegtle, Synthesis 1: 87 (1994) or German Patent No. 93/4320432 to Fey et al.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]([O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH3:35])[C:31](O)=[O:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]([CH:8]1[C:16]([CH3:17])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[C:31](=[O:32])[C@@H:30]([NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28])[CH2:34][CH3:35])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C1Nc2ccccc2C1(C)C
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCNC(=O)C1N(C(=O)[C@H](CC)NC(=O)OCc2ccccc2)c2ccccc2C1(C)C
Temperature: 0 °C
Reaction time: 22 h

Procedure:
3,3-Dimethylindoline-2(R/S)-carboxylic acid butylamide (1.000 g, 4.08 mmol) and N-benzyloxycarbonyl-2(S)-aminobutyric acid (1.451 g, 6.12 mmol) were dissolved in dry tetrahydrofuran (25 ml). The solution was cooled to 0° C. and triethylamine (2.44 ml, 13.78 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (2.338 g, 9.183 mmol) were added. The mixture was stirred at room temperature for 22 hours and ethyl acetate (40 ml) was then added, and the mixture was washed with 3N hydrochloric acid (3×50 ml), 5% sodium bicarbonate (3×50 ml) and water (50 ml) and dried over sodium sulphate. After removing the solvent, several successive purifications by chromatography on a column of silica gel gave the product in the form of an off-white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:24]=[C:25]([CH3:30])[CH:26]=[CH:27][C:28]=1Cl)([O-:22])=[O:21].Cl>CN(C=O)C.O.CCOCC>[C:1]([CH:3]([C:28]1[CH:27]=[CH:26][C:25]([CH3:30])=[CH:24][C:23]=1[N+:20]([O-:22])=[O:21])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
benzyl cyanoacetate (3.50 g; 20 mmol) is added to a suspension of potassium carbonate (6.08 g; 44 mmol) in 5 mL of DMF. The carbonate is washed with 2 mL of DMF. A solution of 3-nitro-4-chlorotoluene (3.41 g, 20 mmol) in 5 mL of DMF is added and the resulting reaction mixture is stirred at 70° C. for 24 hours. After cooling down to ambient temperature, it is treated with a 5N aqueous solution of HCl (12.5 mL). The mixture is divided between ether (100 mL) and water (50 mL) then the organic phase is re-extracted with ether. The ethereal phases are washed with water, dried over anhydrous MgSO4, filtered under vacuum and evaporated. The residue is purified by chromatography on silica gel (eluent: CH2Cl2/pentane, 1/1) in order to produce benzyl 2-cyano-2-(2-nitro-4-methylphenyl)ethanoate with a yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH:30]([F:32])[F:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.[I-].[Na+].Cl>O.C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH:30]([F:32])[F:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][N+:38]4[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COc1ccncc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(N)n4)[C@H]3SC2)cc1
Yield: 13 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.0 g), 4-methoxypyridine (4.0 g), sodium iodide (8.0 g), acetonitrile (4.0 ml) and water (1.0 ml) was heated for 2.0 hours at 65° to 68° C., and then water (100 ml) was added thereto. The mixture was adjusted to pH 3.0 with 1N-hydrogen chloride and the resultant precipitates were filtered off. The aqueous layer was subjected to column chromatography on macroporus nonionic adsorption resin "Diaion HP-20" and the elution was carried out with 30% aqueous methanol. The fractions containing the object compound were collected, concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.43 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[CH:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: OC1CCCC1
Agent: [Rh]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (489 mg, 1.69 mmol) in dichloromethane (10 mL) at 25° C. was treated with cyclopentanol (0.38 mL, 4.23 mmol) followed by rhodium (II) acetate dimer (15 mg, 0.034 mmol). After the resulting solution was stirred at 25° C. for 1 h, it was diluted with dichloromethane (10 mL), poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) to afford rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid methyl ester (395 mg, 67% yield) as a colorless oil: EI-HRMS m/e calcd for C15H19ClSO5 (M+) 346.0642, found 346.0643.
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:3](=[O:5])[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[F:1])[CH3:13]
Reactant: O=C(O)C(F)c1ccccc1
Reactant: CCOC(=O)[C@H](C)N
Product: CCOC(=O)[C@H](C)NC(=O)C(F)c1ccccc1

Procedure:
Following General Procedure F above, and using α-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.75 in 1:1 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[N:10]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[N:10]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:42][CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]4[C:47](=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46]3=[O:55])[CH:26]=2)[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2c(C#N)n(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2c(C#N)n(C(=O)OC(C)(C)C)c(=O)n2-c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a suspension of 0.12 g (0.28 mmol) of the product from step c) and 0.15 g (1.1 mmol) of K2CO3 in dry 5 ml of DMF was added 0.083 g (0.30 mmol) of N-(3-bromopropyl)-phthalimide. The mixture was stirred at room temperature overnight and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, brine, dried over Na2SO4 and evaporated. Chromatography on SiO2 (heptan-ethyl acetate) gave the title compound (152 mg, 86%).
Reaction SMILES: Cl.C(O[C:7]([N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:10])=[O:8])(C)(C)C.[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC(OC(Cl)=O)(Cl)Cl>C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:7]([N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:10])=[O:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CN(CCc1ccccn1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4N-hydrogen chloride in ethyl acetate (5 ml) was added to 2-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]pyridine at 0° C. The solution was stirred at 0° C. for 1 hour and concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml). Triethylamine (304 mg) and (1S)-1-benzyloxycarbonyl-2-phenylethyl isocyanate (281 mg) prepared by reacting L-phenylalanine benzyl ester with trichloromethylchloroformate was added to this solution at 0° C. The solution was stirred at the same temperature for 1 hour and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give N-[N-(2-pyridyl)ethyl-N-methylaminocarbonyl]-L-phenylalanine benzyl ester (400 mg) as an oil. Rf: 0.50 ( chloroform:methanol, 20: 1, V/V)
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1CBr
Product: O=[N+]([O-])c1cccnc1COc1ccc(Cl)cc1
Yield: 90 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 4-chlorophenol, the titled compound was obtained as yellow solid. (Yield: 90%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC[C@H]1C(N)=O
Reaction time: 17 h
Yield: 33.8 %

Procedure:
A mixture of 6.28 g (0.0332 m) of N-tert.-butoxycarbonyl-β-alanine, 5.0 g (0.0332 m) of L-proline amide hydrochloride, 8.96 g (0.0664 m) of 1-hydroxybenzotriazole, 12 ml of N-methylmorpholine, 75 ml of tetrahydrofuran, 40 ml of dimethylformamide and 6.84 g (0.0332 m) of dicyclohexylcarbodiimide was stirred at 25° for 17 hours. The solvents were evaporated in vacuo and the residue dissolved in ethyl acetate and water. The separated organic layer was washed with small volumes of dilute hydrochloric acid, brine, 5% bicarbonate and brine. The dried extract was concentrated to give 3.2 g of syrupy N-tert.-butoxycarbonyl-β-alanyl-L-proline amide. The methane chemical ionization mass spectrum was in agreement with the dipeptide structure.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH2:26]([NH:30][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CCCCN
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNCc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. Butylamine (0.543 mL, 5.5 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 89:10:1 chloroform/methanol/ammonium hydroxide) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.24 (br s, 1H), 4.42 (d, J=9 Hz, 2H), 3.90 (s, 3H), 3.16 (m, 2H), 2.38 (s, 3H), 1.64 (s, 2H), 1.44 (m, 9H), 1.27 (m, 2H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.Cl>O.C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:16]([OH:17])[OH:15])=[CH:3][C:4]=1[O:10][CH3:11])#[N:7]
Reactant: COc1cc(Br)ccc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(B(O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A 3-necked 1 L round-bottomed flask was equipped with an overhead stirrer, and a nitrogen line. The flask was charged with 45.56 g (215 mmol) of 4-bromo-2-methoxybenzonitrile, 64 mL (277 mmol) of tri-isopropylborate and 500 mL of THF. The solution was cooled to −78° C. in a dry-ice/acetone bath. n-Butyllithium (2.5M, 110 mL, 275 mmol) was added dropwise via addition funnel. The mixture was stirred for 30 minutes and 2N HCl was added. The mixture was stirred for an hour and poured into water. The mixture was extracted with Et2O. The organic solution was backextracted with 1N NaOH. The aqueous layer was washed with Et2O and acidified with conc. HCl. The mixture was extracted with Et2O. The organic extract was dried (MgSO4) and evaporated in vacuo to afford 20.77 g (55%) of the product as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.68 (d, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: [Na].C(S)C.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1>CN(C)C=O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc(CC(CC(=O)O)CC(=O)O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C(O)CC(CC(=O)O)Cc1ccc(O)cc1
Temperature: 165 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a stirred suspension of 57% sodium hydrideparaffin (1.4 g) in dry dimethylformamide (30 ml) is added dropwise a solution of ethanethiol (4.0 ml) in dry dimethylformamide (10 ml). After 15 minutes, a solution of 3-[(4-methoxyphenyl)methyl]glutaric acid (800 mg) in dry dimethylformamide (20 ml) is added. The resulting slurry is heated in a bath at 165° C. for 20 hours and evaporated in vacuo. The residue is acidified with 20% hydrochloric acid, extracted with ether and the extracts are discarded. The aqueous solution is saturated with salt and extracted with ethyl acetate. The extracts are combined, washed once with brine, dried, evaporated and the residue crystallized from a mixture of ethyl acetate-chloroform-hexane to give 600 mg of 3-[(4-hydroxyphenyl)methyl]glutaric acid, melting point 117°-119° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 116.1 %

Procedure:
To a suspension of solution of (S)-1,4bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (18.3 g, 45 mmol) and potassium carbonate (8.2 g; 59 mmol) in DMF (150 ml) cooled to 0° C. under N2, was added dropwise a solution of iodomethane (7.36 ml; 118 mmol). The reaction mixture was left to stir at room temperature for 18 h. It was diluted with ethyl acetate, washed with water and brine. The organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid (18 g; 95%). 1H NMR (CDCl3) 1.46-1.50 (18H, d), 1.65 (3H, s), 2.80-2.90 (1H, m), 3.10-3.40 (2H, m), 3.75-4.10 (2H, m), 4.60-4.70 (2H, m).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1C=[CH:22][CH:21]=[C:20]1[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].Cl.C1C[O:44][CH2:43]C1>>[F:32][C:33]([F:35])([F:34])[CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:20]1[CH:21]=[CH:22][O:44][CH:43]=1)[OH:27]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1-c1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: OC(c1ccccc1-c1ccoc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml of 1M in THF) was added to a solution of 2-furan-2-yl-benzaldehyde (123 mg, 0.71 mmol) and trifluoromethyl trimethylsilane (120 mg, 0.86 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 3 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.150 g of 2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethanol, which was directly used in next step without purification (yield: 90%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(CCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCNC(=O)c2ccccc2)C1

Procedure:
3-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.50 g) as starting compound was reacted and treated in the same manner as in Example 1 using benzoyl chloride (0.68 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (1.17 g) to give 4-amino-N-((3S)-1-(3-benzoylaminopropyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [B:1](OC1CCC(C)C(C)C1)([O:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH3:19])[CH2:13]1)[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]([CH3:10])[CH2:4]1.[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:34]=1[OH:44])([CH3:32])([CH3:31])[CH3:30]>>[B:1]([O:44][C:34]1[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:38][C:37]([CH3:39])=[CH:36][C:35]=1[C:40]([CH3:43])([CH3:42])[CH3:41])([O:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH3:19])[CH2:13]1)[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]([CH3:10])[CH2:4]1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1CCC(OB(OC2CCC(C)C(C)C2)OC2CCC(C)C(C)C2)CC1C
Product: Cc1cc(C(C)(C)C)c(OB(OC2CCC(C)C(C)C2)OC2CCC(C)C(C)C2)c(C(C)(C)C)c1

Procedure:
Bis(3,4-dimethylcyclohexyl) 2,6-di-t-butyl-4-methylphenyl borate was prepared by transesterification of tri(3,4-dimethylcyclohexyl) borate (1.5 mole) with 2,6-di-t-butyl-4-methylphenol (0.5 mole). The reaction mixture was slowly distilled to remove 3,4-dimethylcyclohexanol and the product was obtained as a viscous oil.