Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[OH-:9].[Na+].N#N>O>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:9]
Reactant: [OH-]
Reactant: O=C(O)/C=C\C(=O)O
Agent: N#N
Agent: [Na+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
A reaction solution containing maleic acid (116 g) and 5N sodium hydroxide (200 ml) (having a total volume of 1,000 ml by adding water), which had been previously subjected to N2 substitution by carrying out agitation while blowing N2 gas in it for 30 minutes, was transferred into a jar fermenter having a volume of 3 L. The microbial cells of the both species (IFO 12669 strain: 20 g, AB-41 strain: 50 g), which had been recovered in Example 1 and in the item (1) described above, were added thereto, followed by agitation while supplying N2 at a velocity of 0.02 vvm to carry out a reaction at 30° C. for 36 hours with sealing. L-Malic acid was obtained in an amount of 104 g/L. Calcium chloride was added to the obtained solution of sodium L-malate to precipitate calcium malate, followed by washing with water. After that, L-malic acid was separated by using an ion exchange resin, and dried. Thus crystals of L-malic acid were obtained. The obtained crystals had an amount of 90 g.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C@H:5]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.COC(=O)[C@H](NS(C1C=CC(Br)=CC=1)(=O)=O)[C@H](OCC1C=CC(C)=CC=1)C1SC=CN=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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.O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C@H:5]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[C@@H:4]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)(=[O:22])=[O:23])[C:3]([OH:38])=[O:2])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(-c2ccc(SC)cc2)cc1)[C@H](OCc1ccc(C)cc1)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)[C@H](NS(=O)(=O)c1ccc(Br)cc1)[C@H](OCc1ccc(C)cc1)c1nccs1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: CSc1ccc(-c2ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](OCc3ccc(C)cc3)c3nccs3)cc2)cc1
Temperature: 25 °C

Procedure:
(2R,3S)-3-(4-Methyl-benzyloxy)-2-(4′-methylsulfanyl-biphenyl-4-sulfonylamino)-3-thiazol-2-yl-propionic acid methyl ester. The (2R,3S)-2-(4-bromo-benzenesulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid methyl ester 1e (660 mg, 1.26 mmol) and 4-thiomethoxyphenylboronic acid (320 mg, 1.88 mmol) are taken up in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water in the presence of Pd(PPh3)4 (44 mg, 0.03 mmol) and 267 mg of Na2CO3 and brought to reflux for 4 hours. The mixture is cooled to room temperature, poured into water, and extracted with methylene chloride. The organic layer is dried over Na2SO4, filtered and evaporated. The crude product is purified by silica gel chromatography using 8/2 hexane/EtOAc to give the desired product as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.Br[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:11]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 20 ml of N,N-dimethylformamide, 2.291 g (15.108 mM) of 4-piperidylmethanol hydrochloride, 4.48 g (18.1 mM) of bromodiphenylmethane, and 6.26 g (45.3 mM) of potassium carbonate were stirred together at 100° C. for 3.5 days and, then, at 150° C. for 2 hours. After cooling to room temperature, this reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1 to 1/1) to provide the title compound.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1C=CC=C[CH:4]=1.C([C:15]1[CH:19]=[C:18]([CH:20]=[CH2:21])[S:17][C:16]=1C=C)CCCCC>ClC1C=CC=CC=1>[CH2:20]([C:18]1[S:17][CH:16]=[CH:15][CH:19]=1)[CH2:21][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1cc(CCCCCC)c(C=C)s1
Reactant: C=Cc1ccccc1
Solvent: Clc1ccccc1
Product: CCCCCCc1cccs1
Temperature: 124 °C
Reaction time: 16 h

Procedure:
A mixture of the polymeric macroinitiator, 6 (2.0 g, 0.30 mmol, Mw) 7200, PDI) 1.09), styrene (0.258 g, 2.48 mmol), and 5 (0.916 g, 4.15 mmol) was dissolved in chlorobenzene (2.9 mL), degassed by four freeze/pump/thaw cycles, and sealed under argon. The polymerization mixture was then stirred at 124° C. for 16 h and allowed to cool, and the star polymer, 16, was obtained after precipitation into methanol (3.1 g, 90%, Mw) 49400, PDI) 1.58). 1H NMR (CDCl3): δ (ppm) 6.32-7.2 (br m), 0.81-2.12 (br m).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([S:16][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: Cc1ncccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1SCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65 g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 4 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a yellow solid (yield 742 mg, 59%).
Reaction SMILES: [C:1]1(C2C=CNN=2)C=CC=CC=1.[C:12]([CH:15]([NH:28]C(CC(C)C)C(O)=O)[CH2:16][C:17]1[CH:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)([OH:14])=[O:13].C1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:1][O:14][C:12](=[O:13])[CH:15]([NH2:28])[CH2:16][C:17]1[CH:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: CC(C)CC(NC(Cc1ccn(-c2ccccc2)n1)C(=O)O)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(N)Cc1ccn(-c2ccccc2)n1
Reaction time: 2 h
Yield: 100 %

Procedure:
2-[1-carboxy-2-(1phenyl-1H-pyrazol-3-yl)-ethylamino]-4-methyl-pentanoic acid Phenyl pyrazole 54-3 was prepared as described by R. M. Adlington et al. from 54-1 (J. Chem. Soc. Perkin Trans I 2000, 2311–2316). This reaction with phenyl hydrazine provided a single isomer whose structure was confirmed with 2D NMR methods (NOESY, HMBC, and HMQC). Phenyl pyrazole 54-3 (380 mg, 0.98 mmol) was dissolved in dichloromethane (4 mL) and a solution of HCl (2.45 mL, 9.80 mmol, 4 N in dioxane) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature, and a precipitate formed. The reaction mixture was concentrated to give a brown oil (290 mg, 100% yield). 1H NMR was consistent with the desired amino acid (with some tert-butyl ester). This oil was dissolved in methanol (5 mL) and toluene (5 mL) and a solution of trimethylsilyldiazomethane (2 mL, 3.92 mmol, 2 M in hexane) was added (gas evolution and precipitate formation). After 2 hours, the reaction mixture was concentrated to a brown oil. This oil was redissolved in ethyl acetate and the solution was extracted with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give 2-amino-3-(1-phenyl-1H-pyrazol-3-yl)-propionic acid methyl ester (54-4) as a brown oil (262 mg, >100% yield, contaminated with some tert-butyl ester). This ester was alkylated with triflate 54-5 as described above. The resulting diester was hydrolyzed to 2-[1-carboxy-2-(1phenyl-1H-pyrazol-3-yl)-ethylamino]-4-methyl-pentanoic acid 54-6 (Compound OD) as described above. 1H NMR (300 MHz, CD3OD) δ 8.17 (d, 1H, J=2.4 Hz); 7.76 (d, 2H, J=7.7 Hz); 7.46 (dd, 2H, J1=7.7 Hz, J2=8.1 Hz); 7.30 (t, 1H, J=7.3 Hz); 6.45 (d, 1H, J=2.4 Hz); 4.08 (dd, 1H, J1=4.5 Hz, J2=7.3 Hz); 3.97 (dd, 1H, J1=J2=6.9 Hz); 3.43 (dd, 1H, J1=4.7 Hz, J2=16.1 Hz); 3.34 (dd, 1H, J1=7.3 Hz, J2=16.3 Hz); 1.90–1.98 (m, 1H); 1.78–1.84 (m, 2H); 1.01 (d, 3H, J=5.3 Hz); 0.99 (d, 3H, J=5.7 Hz). Anal. Calc'd. for C18H23N3O4.H2O: % C, 59.49; % H 6.93; % N, 11.56. Found: % C, 59.85; % H, 6.96; and % N, 11.46.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.C([Li])CCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[B:11]([OH:16])[OH:12])#[N:5]
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)ccc1B(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Bromo-5-fluorobenzonitrile (6.00 g, 30.0 mmol) and triisopropyl borate (8.28 mL, 36.0 mmol) were dissolved in a mixture of toluene (48 mL) and tetrahydrofuran (12 mL), and the solution was cooled in a dry ice/acetone bath. A solution of n-butyllithium in hexanes (2.5M, 14.4 mL, 36.0 mmol) was added drop-wise over 1 hour, and the reaction was then allowed to warm to room temperature with stirring over 18 hours. The mixture was cooled in an ice bath and treated with a 2N aqueous hydrochloric acid solution until the pH reached 1, then allowed to warm to room temperature, at which time the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-heptane to provide (2-cyano-4-fluorophenyl)boronic acid as a white solid. Yield: 2.20 g, 13.3 mmol, 44%. 1H NMR (400 MHz, CD3OD) δ 7.43 (ddd, J=8.6, 8.6, 2.5 Hz, 1H), 7.55 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)[C:10]3[C:11]([N:22]=2)=[N:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)[C:10]3[C:11]([N:22]=2)=[N:12][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(-c4ccncc4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc3nc(C4CCNCC4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 69.5 %

Procedure:
2-(4Fluorophenyl)-1-(2cyclopentylamino-pyrimidinyl)-5-(4-pyridinyl)imdazo[4,5-b]pyridine (example 7; 100 mg; 0.22 mmol) is dissolved in HOAc (120 ml) and hydrogenated over Pd/C (10%, 200 mg) in a Parr apparatus for 48 h at room temperature. The reaction mixture is filtered and evaporated to dryness delivering the title compound as yellow crystals, which are recrystallised from MeOH and gave the title compound as colorless crystals (70 mg; 65%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][N:27]1[C:31](=[O:32])[CH2:30][S:29][C:28]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH2:25][CH2:26][N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[O:33])[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CSC(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)CSC1=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 42.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (800 mg, 2.64 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL), 3-(2-bromoethyl)-1,3-thiazolidine-2,4-dione (890 mg, 3.97 mmol, 1.50 equiv) and cesium carbonate (1.72 g, 5.26 mmol, 2.00 equiv). The resulting solution was stirred for 10 h at 80° C. in an oil bath. The reaction mixture was cooled with a water bath, diluted with 150 mL of ethyl acetate and washed with brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 500 mg (42%) of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-1,3-thiazolidine-2,4-dione as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3.N1C=CN=C1.[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C=O)C.CCOCC>[CH3:23][N:2]([CH3:1])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][Si:33]([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)N=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CN(C)N=C1CC[C@H]2[C@@H]3CCc4cc(O[Si](C)(C)C(C)(C)C)ccc4[C@H]3CC[C@]12C
Reaction time: 16 h

Procedure:
To a solution of 15.5 gr. of 3-hydroxyestra-1,3,5(10)-trien-17-one dimethylhydrazone (34) in 200 ml of DMF was added 13 gr. of imidazole, followed by dropwise addition of 15 gr. of TBDMSCl in 20 ml of ether. After stirring for an additional 16 hr the reaction mixture was poured onto 2 liters of water and the resulting mixture was stirred for an additional 10 minutes. The precipitate was filtered and dried in vacuo, to provide 20 g of 35, M.p. 100-103° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccc(F)cc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2ccc(F)cc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 0.80 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (331 mg, 0.78 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (1.0 g, 4.97 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (448 mg, 0.96 mmol) in chloroform (10 mL). DIEA (700 μL, 4.01 mmol) was added and the reaction stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (249 mg, 0.36 mmol, 46%): LC-MS (ES) m/z=507 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][C:7]([Br:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16].[H-].[Na+]>>[Br:11][C:7]1[C:6]([F:12])=[CH:5][C:4]([C:2]([CH2:1][C:13]([O:14][CH2:15][CH3:16])=[O:17])=[O:3])=[C:9]([F:10])[CH:8]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(F)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(F)c(Br)cc1F
Temperature: 80 °C

Procedure:
To a stirred mixture of 18 g 4-bromo-2,5-difluoroacetophenone and 233 ml diethyl carbonate cooled in an ice-bath was slowly added 6.4 g sodium hydride (60% in oil). The reaction mixture was heated at 80° C. for 90 min. and then added to 700 ml ice containing 25 ml acetic acid. The aqueous mixture was extracted with ether, and the ether extracts were washed with sodium chloride solution, dried (magnesium sulfate) and concentrated. The residue was distilled, collecting the material (15.33 g) boiling at 85°-135° C. (0.05 mm). The latter material was chromatographed on 185 g silica gel (Kieselgel 60) using 20% ether in hexane as eluant to give 6.69 g ethyl 4-bromo-2,5-difluorobenzoylacetate as the first product to be eluted.
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([CH3:20])([CH3:19])[O:11][CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN([CH:24]=[O:25])C>O1CCCC1>[Si:10]([O:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([CH:24]=[O:25])=[CH:17][CH:18]=1)([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5M in hexanes, 30 mL) was added dropwise to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane (example 4, step a) (16 g) in tetrahydrofuran (250 mL) at −78° C. The reaction mixture was allowed to warm to 0° C. and stirred for 1 h. The reaction was then cooled to −78° C. and DMF (34 mL) was added over 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, filtered and the solvent evaporated in vacuo. Purification was by silica gel chromatography, eluting with 93:7 isohexane:ethyl acetate to give the subtitled compound as a colourless oil. Yield 15.4 g.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[C:48]1([C:54]2([OH:59])[CH2:58][CH2:57][NH:56][CH2:55]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:56]1[CH2:57][CH2:58][C:54]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([OH:59])[CH2:55]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Reactant: OC1(c2ccccc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(O)(c2ccccc2)C1
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidin-3-ol hydrochloride (10 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1481.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:42])[O:5][CH2:6][CH:7]([NH:18][C:19](=[O:41])[CH2:20][N:21]1[C:25](=[O:26])[N:24]([CH2:27][C@H:28](O)[C:29]([F:32])([F:31])[F:30])[C:23]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[N:22]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:2].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([NH:3][C:4](=[O:42])[O:5][CH2:6][CH:7]([NH:18][C:19](=[O:41])[CH2:20][N:21]1[C:25](=[O:26])[N:24](/[CH:27]=[CH:28]/[C:29]([F:32])([F:31])[F:30])[C:23]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[N:22]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:2]
Reactant: CCNC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 230 mg (0.37 mmol) of the compound from Example 145 and 54 mg (0.44 mmol) of DMAP in 5 ml of pyridine was admixed dropwise with 155 μl (0.92 mmol) of trifluoromethanoic anhydride and the resulting mixture was stirred at RT overnight. Subsequently 2 ml of 1N hydrochloric acid were added and the volatile components were removed on a rotary evaporator. The residue was dissolved in a little DMSO and purified by preparative HPLC [Method 10]. The product-containing fraction was freed from the solvents on a rotary evaporator and the residue was dried in an HV. This gave 168 mg (75% of theory) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])[CH3:13]
Reactant: CCOC(=O)C1(CC)CCCC1O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-ethyl-cyclopentane carboxylate (4.90 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.22 ml) was slowly added, then 2-methyl-benzoyl chloride (5.28 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 8.99 g of yellow liquid. MS: m/e 304(M+″), 261, 244, 139, 119(base), 91.