Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(#N)C.CO>[CH2:7]([O:6][CH2:5][C@H:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@H](CO)COCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCl)N[C@H](CO)COCc1ccccc1
Temperature: -10 °C
Reaction time: 20 h

Procedure:
(2R)-2-Amino-3-(benzyloxy)propan-1-ol (2.18 g) was dissolved in acetonitrile (38 ml) and methanol (7 ml), and triethylamine (2.0 ml) was added. The atmosphere was replaced with nitrogen, and then the mixture was cooled to −10° C. A solution of chloroacetyl chloride (1.05 ml) in acetonitrile (9 ml) was added dropwise thereto, and the mixture was stirred for 20 hours to be gradually warmed to room temperature. The reaction solvent was distilled off, and the residue was directly purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.26 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13]C(=O)C(C)(C)C)=[N:11][CH:12]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]1([CH3:20])[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](c2cnc(NC(=O)C(C)(C)C)cn2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 61.7 %

Procedure:
A mixture of N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (8.4 g, 30.7 mmol) and potassium carbonate (4.32 g, 31.2 mmol) in methanol (150 mL) was stirred at 25° C. for 16.5 h, at which time, thin layer chromatography suggested partial conversion to a more polar product. In an effort to avoid epimerization at the stereogenic center, the reaction was discontinued before completion. Therefore, the solvent was removed under reduced pressure at 25° C. The resulting residue was again concentrated in vacuo from ethyl acetate (50 mL). The material was purified using Biotage chromatography (FLASH 40 L, Silica, ethyl acetate). The early fractions collected allowed for the recovery of unreacted starting pivaloylamide as a white solid (2.0 g, 24%). The later fractions were concentrated in vacuo to provide 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (3.7 g, 63%) as a pale yellow oil. High-performance liquid chromatography analysis with a chiral column indicated 100% ee.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccn2C)c(F)c2oc(C3CC3)nc2c1C#N
Yield: 78.7 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol) was dissolved in toluene (4 ml), then 2-tributylstannyl-1-methylpyrrole (300 mg, 0.81 mmol) and 2,6-di-tert-butylcresol (2 mg) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) were added, followed by heating under reflux for 19 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (10:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(1-methyl-1H-pyrrol-2-yl)-1,3-benzoxazole-4-carbonitrile (158 mg, 79%) as a pale yellow transparent oily substance. Apart of this (157 mg, 0.53 mmol) was dissolved in dimethyl sulfoxide (3 ml), triethylamine (187 μl, 1.33 mmol) and (3S)-3-(dimethylamino)pyrrolidine (101 μl, 0.80 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 13 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v). The resulting residue was recrystallized and purified with a mixed solvent of diethyl ether-n to obtain the entitled compound (104 mg, 50%) as a white solid.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:44])=[CH:14][CH:13]=1)=[O:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[CH3:31][O:30][C:28]([C:27]1[N:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([NH:9][NH2:8])=[O:11])=[CH:17][CH:16]=2)[C:19](=[O:44])[C:20]2[C:25]([C:26]=1[C:32]1[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:29]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)NN)cc1
Temperature: 25 °C

Procedure:
The compound obtained in Example 23 is dissolved in dioxane (2 ml), and thereto is added a 4M solution of hydrogen chloride in dioxane (5 ml), and the mixture is stirred at room temperature. To the reaction mixture is further added a 4M solution of hydrogen chloride in dioxane (5 ml), and the mixture is stirred for three hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; chloroform:methanol=30:1) to give 3-methoxycarbonyl-2-[4-(hydrazinocarbonyl)phenyl]-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone hydrochloride as listed in Table 4.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([N:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]1=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c([N+](=O)[O-])c(OCc2ccccc2)ccn1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 4.68 g (30 mmol) of 2,4-dihydroxy-3-nitro-pyridine in 100 ml of dimethylformamide was combined batchwise at ambient temperature with 2.88 g (60 mmol) of a 50% suspension of sodium hydride in paraffin oil and stirred for 15 minutes. Then 8.91 ml (75 mmol) of benzylbromide were added and the mixture was stirred for 24 hours at 80° C. The solution was then carefully stirred into approx. 250 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and evaporated down in vacuo. The residue was triturated with diethyl ether, suction filtered and dried. The product thus obtained was further processed without any purification.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].Cl[C:6]([O:8][CH2:9][Cl:10])=[O:7].N1C=CC=CC=1>CCOCC>[CH:2]([O:4][C:6](=[O:7])[O:8][CH2:9][Cl:10])([CH3:3])[CH3:1]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)OC(=O)OCCl
Temperature: 0 °C
Yield: 91.9 %

Procedure:
2-Propanol (73.14 mmole, 5.6 mL) was added to a solution of chloromethyl chloroformate (73.85 mmole, 6.5 mL) in ether (100 mL). The reaction mixture was cooled to 0° C. and pyridine (74.18 mmole, 6 mL) was dropwise added with stirring. Thereafter, the reaction mixture was stirred at ambient temperature for 20 hours. The formed solids were filtered and the filtrate was washed with citric acid (1% aqueous), water, sodium bicarbonate solution (1%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 10.26 g (92%) of a colorless oil. MS (ES+): m/e 152 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(O)C(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: COc1ccc(N)cc1
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Nc2nccn3c(Br)cnc23)cc1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
3,5-Dibromo-imidazo[1,2-a]pyrazine (intermediate D) (200 mg, 0.7 mmol) was added to a mixture of anisidine (445 mg, 5 eq.), trifluoroethanol (3.6 ml), DIPEA (diisopropylethylamine) (0.629 ml, 5 eq). The mixture was heated at 75–85° C. in sealed tube for 12 hr. The mixture was then cooled to room temperature, diluted with DCM and water. The organic layer was washed with 1N HCl, brine, dried and concentrated. The residue was purified on a silica gel column to give 56.6 mg (yield 50%) of the title compound as faint orange solid.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O)(=O)=[O:10].[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[NH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO.I([O-])(=O)(=O)=O.[Na+]>O>[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[NH:21])=[O:10])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N=S(c1ccccc1)c1cccs1
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: N=S(=O)(c1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g. Phenyl-(2-thienyl)-sulphimide mesitylene-sulphonate are dissolved in 200 ml. methanol. A solution of 7 g. sodium periodate in 150 ml. water are added dropwise thereto, whereafter the reaction mixture is stirred for 24 hours at ambient temperature. The reaction mixture is then rendered alkaline and evaporated on a rotary evaporator. The residue obtained is partitioned between water and dichloromethane and the organic phase is evaporated. There are obtained 3.7 g. phenyl-(2-thienyl)-sulphoximide which, after recrystallisation from ethyl acetate/isopropanol, melts at 133° C.
Reaction SMILES: CN(C)C1C=CC=CC=1.C[Si](Cl)(C)C.C1(CC([NH:24][CH:25]2[C:46](=[O:47])[N:27]3[C:28]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=4)=[O:34])=[C:29]([OH:32])[CH2:30][S:31][C@H:26]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.O.CO.C(N(CC)CC)C>[NH2:24][CH:25]1[C:46](=[O:47])[N:27]2[C:28]([C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])=[C:29]([OH:32])[CH2:30][S:31][C@H:26]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Triethylamine (2.37 g.), dimethylaniline (7.12 g.) and trimethylsilyl chloride (3.93 g.) were added to a stirred suspension of 4-nitrobenzyl 7-(2-phenylacetamido)-3-hydroxy-3-cephem-4-carboxylate (10 g.) in methylene chloride (200 ml.) in turn, and the solution was stirred at room temperature for an hour. Phosphorus pentachloride (4.88 g.) was added to the solution at -30° to -25° C. and stirred at -25° to -20° C. for 3 hours. Methanol (42 ml.) was added to the solution at -25° to -20° C., and stirred for an hour. To the solution was added water (35 ml.) at -25° to -20° C., and the solution was stirred at room temperature. The precipitates were collected by filtration, washed with methylene chloride and diethyl ether in turn, and dried to give 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (5.2 g.), mp 148° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=O)[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=[CH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.5 %

Procedure:
7-(Benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (3.6 g, 12.98 mmol) and (tert-butoxycarbonylmethylene)triphenylphosphorane (5.86 g, 15.58 mmol) were dissolved in toluene (40 mL) and the reaction mixture was heated under reflux and stirred for 24 h. The solution was cooled to room temperature. The precipitate was collected by filtration. The filtrate was concentrated under reduced pressure to yield additional white solid. The process was repeated to provide the title compound (1.391 g). LCMS m/z=376.4 [M+H]+.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[N:4]=1.CCCC(C)C.[CH2:16]([OH:18])[CH3:17]>>[Br:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:18][CH2:16][CH3:17])[N:4]=1
Reactant: CCO
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CCCC(C)C
Product: CCOc1cccc(Br)n1

Procedure:
Sodium (0.48 g, 20.9 mmol) was dissolved in ethanol (50 ml) under an atmosphere of nitrogen at ambient temperature. 2,6-Dibromopyridine (10.0 g, 41.4 mmol) was added and the solution heated to reflux. After 6 h the cooled reaction mixture was partitioned between diethyl ether (150 ml) and water (100 ml). Diethyl ether extracts were washed with water and saturated brine then dried over magnesium sulphate, filtered and evaporated in vacuo to give a semi-solid. Addition of isohexane, filtration and concentration in vacuo gave a residue that was purified by chromatography on silica gel eluting with 80% dichloromethane-isohexane to give 2-bromo-6-ethoxypyridine (1.7 g) as a colourless liquid: δH (400 MHz, CDCl3) 1.38 (3H, t, J 7), 4.34 (2H, quartet, J 7), 6.65 (1H, d, J 8), 7.02 (1H, d, J 7), 7.40 (1H, dd, J 7 and 8); m/z (ES+) 202/204 (M++H).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:23][CH2:24][C:25]1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrC(O)C>>[CH2:16]([O:23][CH2:24][CH2:25][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: CC(O)Br
Product: O=C(c1ccccc1)C(CCOCc1ccccc1)c1ccccc1

Procedure:
This compound is prepared from 19.6 g of desoxybenzoin and 21.5 g of benzylether-protected bromoethanol according to the procedure described in Example 1(a).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:11]=2[C:12]([NH:30][C:28]2[CH:27]=[N:26][O:25][CH:29]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)O)c2)cn1
Reactant: Nc1cnoc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3cnoc3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid (may be prepared as described in Description 121; 100 mg, 0.31 mmol), isoxazol-4-amine (38.6 mg, 0.46 mmol), HOBT (70.4 mg, 0.46 mmol) and EDC (88 mg, 0.46 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Water (50 ml) was added. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by a prep-HPLC (instrument: Gilson GX-281; Column: Shimadzu PRC-ODS, 15.0 um, 19 mm*250 mm; Mobile Phase: A: 0.05% NH3H2O/H2O; B: CH3CN; Gradient 0-8 min 42-54% B; 8-12 min 95%; Flow Rate (ml/min) 30.00; Detective Wavelength (nm) 214; Retention Time (min) 7.5) to yield the title compound as a white solid. 17 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:65]([NH:68][CH2:69][CH2:70][NH2:71])(=[O:67])[CH3:66]>CN(C=O)C.CCOCC>[C:65]([NH:68][CH2:69][CH2:70][NH:71][C:22](=[O:24])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)(=[O:67])[CH3:66]
Reactant: CC(=O)NCCN
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCc1cc(-c2nc(-c3cccc(CC(=O)NCCNC(C)=O)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of crude (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (preparation described in Example 24, Step 1, 308 mg; 0.74 mmol) in DMF (6 mL) at 0° C. was added DIEA (267 4, 1.5 mmol) and HATU (282 mg; 0.74 mmol). After 10 min, a solution of N-acetylethylenediamine (75 mg, 0.74 mmol) in DMF (2 mL) was added and the reaction mixture was stirred at RT overnight. Et2O was added and the mixture was washed with water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by preparative HPLC affording the title compound as a white fluffy solid. LC/MS (Method B): 499.3 (M+H)+. HPLC (Method A) Rt 4.89 min (Purity: 100.0%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:18][CH2:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:50](I)([CH3:52])[CH3:51]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:18][CH2:19][C:20]([N:22]1[CH2:23][CH2:24][C:25]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:26]=2[CH2:27][CH2:28]1)=[O:21])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:17][CH:50]([CH3:52])[CH3:51])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)I
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(O)ccc31)C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(OC(C)C)ccc31)C(=O)OC(C)(C)C)CC2
Reaction time: 24 h

Procedure:
1.4 g (2.7 mmoles) of the product of Step 1 are dissolved in 15 mL of DMF. There are then added 740 mg (2 equivalents) of potassium carbonate, 160 mg (0.18 equivalent) of caesium carbonate and 0.54 mL (2 equivalents) of isopropyl iodide. Heating is then carried out at 40° C. for 24 hours. The DMF is evaporated off using a rotary evaporator. The residue obtained is then diluted with water and extracted with CH2Cl2. The organic phase is then dried over MgSO4, filtered and evaporated to dryness. An oil is obtained which is purified by flash chromatography over 100 g of silica (eluant: CH2Cl2/ethyl acetate: 80/20) to yield the expected product in the form of a sticky meringue.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([C@H:39]([CH2:44][C:45]#[CH:46])[C:40]([O:42][CH3:43])=[O:41])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O>[CH:31]1[C:32]2[CH:33]([CH2:35][O:36][C:37]([CH:39]([CH2:44][C:45]3[N:3]=[N:2][N:1]([C@H:4]4[C:13]5[C:8](=[CH:9][C:10]([CH2:14][N:15]6[CH2:16][CH2:17][CH:18]([F:21])[CH2:19][CH2:20]6)=[CH:11][CH:12]=5)[O:7][CH2:6][CH2:5]4)[CH:46]=3)[C:40]([O:42][CH3:43])=[O:41])=[O:38])[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: C#CC[C@H](C(=O)OC)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=N[C@@H]1CCOc2cc(CN3CCC(F)CC3)ccc21
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)C(Cc1cn([C@@H]2CCOc3cc(CN4CCC(F)CC4)ccc32)nn1)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of (R)-1-((4-azido-3,4-dihydro-2H-chromen-7-yl)methyl)-4-fluoropiperidine (0.83 g, 2.9 mmol) and (R)-methyl 2-(((9H-fluoren-9-yl)methoxy)-carbonyl)pent-4-ynoate (1.0 g, 2.9 mmol) in t-BuOH/H2O (1:1, 40 mL) was added a solution of sodium ascorbate (30 mg, 0.14 mmole) in H2O (300 μL), followed by CuSO4.5H2O (7 mg, 0.03 mmol) in H2O (300 μL). The reaction mixture was stirred for 72 h at RT. The reaction mixture was concentrated, extracted with CH2Cl2 (3×), dried over MgSO4, and concentrated. The residue was purified by SiO2 (2% MeOH/CH2Cl2) to give the title compound. MS (m/z): 640.4 (m+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:21])[CH:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]#[N:33])=[C:27](B(O)O)[CH:28]=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>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:32]#[N:33])=[C:25]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:21])[CH:3]=2)[CH:24]=1
Reactant: CCOC(=O)C(Cc1ccccc1)n1ccc(Br)cc1=O
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccccc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
572 mg (1.6 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate (racemate) and 330 mg (1.8 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 300 mg (purity 94%, 43% of theory)
Reaction SMILES: O.[C:2]([C:10]([OH:12])=[O:11])(=[O:9])C1C=CC=CC=1.[CH2:13](O)[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([O:12][CH2:16][CH2:15][CH:14]=[CH2:13])(=[O:11])[CH:2]=[O:9]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: C=CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCOC(=O)C=O
Temperature: 110 °C
Yield: 85.9 %

Procedure:
In a flask with a water separator, a mixture of 11.02 g of benzoylformic acid (glyoxalic acid), 6.62 g of 3-buten-1-ol and 0.42 g of p-toluenesulfonic acid in 130 ml of toluene is heated at 110° C. for 22 hours. The solution is washed with saturated NaHCO3 solution and water. The organic phases are dried over sodium sulfate. Filtration, evaporation of the solvent and distillation (b.p.=85° C. at 0.035 mbar) give but-3-enyl glyoxalate (8.08 g, 54%) as a pale yellowish liquid.