Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18]([NH:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])[C:16]([C:17](=[CH:32][N:33]([CH3:35])[CH3:34])[C:18]([NH:20][CH3:21])=[O:19])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(OC)N(C)C
Reactant: CNC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: CNC(=O)C(=CN(C)C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 5 h
Yield: 98.5 %

Procedure:
A 100-mL round bottom flask was charged with 3-(3,5-ditert-butyl-4-hydroxy-phenyl)-N-methyl-3-oxo-propanamide (3.05 mg, 10 mmol) and toluene (20 mL). The mixture was heated and to the resulting hot solution was added N,N-dimethylformamide dimethyl acetal (1.50 mL, 11.3 mmol) with evolution of methanol. The mixture was stirred for 5 h without further heating then evaporated to an oil that was taken up in ethyl acetate (50 mL). The resulting solution was washed with water (4×50 mL) then with brine (20 mL), dried with sodium sulfate and evaporated to an oil and then further dried to a solid foam that was kept under high vacuum to reach a constant weight, then ground to a fine powder to afford 3.55 g of the title compound (98%). TLC (ethyl acetate) Rf 0.09. This material, and especially the equivalent material derived from N,N-dimethylacetamidine dimethyl acetal, is readily hydrolyzed to the starting material. It is therefore advisable to use the condensation product directly and immediately after solvent removal.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[N:5][N:6]=1.[H][H]>CO.C(OCC)(=O)C.[Ni]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccccc2[N+](=O)[O-])o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nnc(-c2ccccc2N)o1
Yield: 99.5 %

Procedure:
A mixture of 2-methyl-5-(2-nitro-phenyl)-[1,3,4]oxadiazole (0.73 g) and 50% Raney Ni (1 mL) in methanol (5 mL) and ethyl acetate (25 mL) was shaken under 50 psi of hydrogen for 3 hours. Filtration through celite and concentration of the filtrate provided 0.62 g of 2-methyl-5-(2-amino-phenyl)-[1,3,4]oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, 1H), 7.26 (dd, 1H), 6.76 (m, 2H), 5.81 (bs, 2H), 2.61 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[NH2:1][C@@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Solvent: O
Product: NC(=O)[C@H](N)Cc1ccccc1

Procedure:
In accordance with the process described in JP Patent Application Laying Open (Kokai) No. 62-55097, Enterobacter cloacae N-7901 (FERM BP-873) was cultured. This culture solution, 500 mL, was centrifuged, and the wet cells were then suspended in distilled water to prepare a 1,140 g cell suspension. D, L-phenylalanine amide, 60 g, was dissolved in this suspension, and the mixture was then allowed to react at 40° C. for 24 hours. After the reaction, cells were removed by centrifugation and 1,150 g of an aqueous solution containing 2.5% by mass each of L-phenylalanine and D-phenylalanine amide was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:4][C:3]=1[O:26][CH3:27].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[O:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12](=[O:24])[CH2:11][C:10](=[O:25])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:26][CH3:27])[CH:4]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OC(=O)N(C)C)c(OC)c2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To the solution of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (150 mg, 0.4 mmol, 1.0 eq.) in dry DCM (15 mL) were added TEA (81 mg, 0.8 mmol, 2.0 eq.) and dimethylcarbamic chloride (43.8 mg, 0.4 mmol, 1.0 eq.). The reaction mixture was stirred at rt overnight, then washed with water and extracted with CH2Cl2 (30 mL×2). The combined organic layers werewashed with H2O, dried over anhydrous Na2SO4 and concentrated. The resulting residue was separated by Prep-HPLC to provide 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (50 mg, 28% yield). LRMS (M+H+) m/z calculated 440.2. found 440.2. 1H NMR (CDCl3, 400 MHz) δ 7.56 (s, 1H), 7.52 (s, 1H), 6.98-7.07 (m, 6H), 6.87 (d, 1H), 6.40-6.49 (m, 2H), 5.76 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.06 (s, 3H), 2.95 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C@H:7]2[CH2:8][CH2:9][C@@H:4]([CH3:3])[CH2:5][CH2:6]2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[C@H]1CC[C@@H](O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@@H](Oc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.1 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.23 g of cis-4-methylcyclohexanol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes and then cooled to 0° C., to which 1 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.37 g of 4-chloro-6-(cis-4-methylcyclohexyloxy)pyrimidine.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:24]1[CH2:27][N:26]([CH:28]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25]1)(=O)=O>CN(C)C=O>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:26]2[CH2:27][CH:24]([NH:10][C:3]3[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:1](=[O:11])(=[O:12])[N:2]=3)[CH2:25]2)=[CH:37][CH:38]=1
Reactant: NC1=NS(=O)(=O)c2ccccc21
Reactant: CS(=O)(=O)OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(NC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c2ccccc21
Temperature: 100 °C
Reaction time: 9 h
Yield: 11.2 %

Procedure:
182 mg of 1,2-benzisothiazol-3-amine 1,1-dioxide and 326 mg of cesium carbonate are added to 386 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-yl methylsulfonate in solution in 10 cm3 of dimethylformamide. The reaction medium is then stirred at 100° C. for 9 hours and then concentrated under reduced pressure (2.7 kPa). The residue is washed four times with 5 cm3 of boiling distilled water, disintegrated by stirring in 5 cm3 of distilled water at room temperature and then recovered by filtration and purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (98/2 by volume)]. 53 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1,1-dioxo-1H-1λ6-benzo[d]isothiazol-3-yl)amine are obtained in the form of a pasty product [[1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 3.17 (mt: 2H); 3.61 (broad t, J=7.5 Hz: 2H); 4.37 (s: 1H); 4.75 (mt: 1H); from 6.30 to 6.40 (unresolved complex: 1H); from 7.20 to 7.35 (mt: 8H); 7.62 (broad d, J=7.5 Hz: 1H); 7.69 (broad t, J=7.5 Hz: 1H); 7.76 (broad t, J=7.5 Hz: 1H); 7.93 (broad d, J=7.5 Hz: 1H)].
Reaction SMILES: [CH2:1]([N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH3:27])C(OC(C)(C)C)=O)[CH2:2][CH3:3].[ClH:49]>C(OCC)C>[ClH:49].[ClH:49].[ClH:49].[ClH:49].[CH2:25]([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:1][CH2:2][CH3:3])[CH2:26][CH3:27]
Reactant: CCCN(CCCN(C/C=C/CN(CCCN(CCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCNCCCNC/C=C/CNCCCNCCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1.26 g (1.84 mmol) of (E)-1,14-di-propyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 19 ml of 3N methanolic hydrochloric acid is stirred for 15 h at room temperature. The reaction mixture is then diluted with 19 ml of diethyl ether, the mixture is filtered, and the filtration residue is washed with diethyl ether. Drying under a high vacuum at 100° C. yields the crystalline title compound (m.p. >260° C.). 1H-NMR (D2O): δ0.95(t,6H); 1.62-1.75(m,4H); 2.05-2.16(m,4H); 3.02(t,4H); 3.11-3.18(m,8H); 3.76(d,4H); 6.04-6.06(m,2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([NH:18][C:19](=[O:22])[O:20][CH3:21])(=[O:17])[CH:13]=[CH:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]([CH2:15][CH3:16])[CH2:13][C:12]([NH:18][C:19](=[O:22])[O:20][CH3:21])=[O:17])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC=CC(=O)NC(=O)OC
Solvent: Cc1ccccc1
Product: CCC(CC(=O)NC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 4-trifluoromethylaniline (121 mg, 0.75 mmol) and methyl 2-pentenoylcarbamate (79 mg, 0.5 mmol) in toluene (2 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (13.3 mg, 0.0125 mmol) and the resulting mixture was stirred at 50° C. for 5 hours. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give the objective compound methyl 3-(4-trifluoromethylanilino)pentanoylcarbamate (143 mg, 45% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: OJ-R) to be 59% e.e. (S form).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>O>[C:1]1([CH:7]([CH3:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: NC=O
Solvent: O
Product: CC(CO)c1ccccc1

Procedure:
(1st step). 1,340 parts of 2-phenylpropanal, 450 parts of formamide, 95 parts of p-toluenesulfonic acid and 420 parts by volume of cyclohexane are refluxed for 41/2 hours at 95°-98° C. in a stirred apparatus equipped with a reflux condenser and water separator; 144 parts of water are separated off. The reaction mixture is subjected to fractional distillation. The distillate is extracted with 500 parts by volume of ether. Distillation of the ether extract under reduced pressure gives 118 parts of unconverted 2-phenylpropanol, whilst crystallization of the extraction residue and the distillation residue gives 947 parts of N-(2-phenyl-prop-1-enyl)-formamide, corresponding to a yield of 64.5% of theory, based on 2-phenylpropanol converted.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:10]([O:23][CH3:24])[C:9]=1[C:25](=[O:27])[NH2:26])(C)(C)C>CC(O)=O.Cl>[NH2:7][C:8]1[C:9]([C:25]([NH2:26])=[O:27])=[C:10]([O:23][CH3:24])[C:11]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(C(N)=O)c(OC)c1CN1CCOCC1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(N)c(C(N)=O)c(OC)c1CN1CCOCC1
Yield: 74.1 %

Procedure:
A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].C1(C)C=CC=CC=1.[ClH:27]>CC(O)C>[ClH:27].[NH2:1][C:2]([CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(CC(C)(N)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1ccc(CC(C)(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
Intermediate tert-butyl 2-amino-3-(4-methoxyphenyl)-2-methylpropanoate (0.60 g, 2.26 mmol) was mixed with toluene (6 mL) and a 5-6 N HCl solution in IPA (2 mL). A clear yellow solution was heated to reflux and kept at that temperature for 7 h. The resulting slurry was cooled to ambient temperature and filtered. The solid was washed with toluene (3 mL) on a filter and air-dried to afford 2-amino-3-(4-methoxyphenyl)-2-methylpropanoic acid hydrochloride [0.37 g; 67%] as a white solid [HPLC 71.8% (AUC; tR=3.71]. 1H NMR (500 MHz, DMSO-d6): δ 13.96 (br. s, 1H, COOH), 8.44 (br. s, 3H, NH3), 7.16 (d, J=8.7 Hz, 2H, Ar), 6.90 (d, J=8.7 Hz, 2H, Ar), 3.74 (s, 3H, CH3), 3.08 (s, 2H, CH2), 1.48 (s, 3H, CH3). Optical rotation (α25D, DMSO, c=1.10)+7.27°.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:13]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)#[N:12]
Reactant: O=C(O)c1ccncc1F
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(CNc2cnccc2C(=O)O)cc1
Temperature: 166 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol), 4-(aminomethyl)-benzonitrile hydrochloride (240 mg, 1.42 mmol), and DIEA (250 μL, 1.42 mmol) were combined in DMA (2 mL) and the reaction mixture was stirred at 166° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified by silica gel chromatography (10-20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a pale yellow precipitate, which was collected by filtration and dried under vacuum to give 32 mg (18%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11N3O2, 254. Found 254.
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:7])[C:3](OC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[NH2:1][C@@:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:7])[CH2:3][OH:4]
Reactant: COC(=O)[C@](C)(N)c1cc(Br)ccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: C[C@](N)(CO)c1cc(Br)ccc1F
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of (R)-methyl 2-amino-2-(5-bromo-2-fluorophenyl)propanoate (3.95 g, 14.3 mmol, Eq: 1.00) in diethyl ether (120 ml) was added at 0° C. lithium aluminum hydride (652 mg, 17.2 mmol, Eq: 1.2) in five portions. The icebath was removed and stirring continued at room temperature for 2 hours. To the cooled reaction mixture was added dropwise water (652 mg, 652 μl, 36.2 mmol, Eq: 2.53), NaOH (15% in water) (572 mg, 652 μl, 14.3 mmol, Eq: 1.00) and water (1.96 g, 1956 μl, 109 mmol, Eq: 7.59) via syringe (1:1:3 system) and the mixture was stirred for 20 min until a white suspension occurred. Three small spoons of Na2SO4 were added to the mixture, which was filtered after 5 min. The colourless ether solution was evaporated to give (R)-2-amino-2-(5-bromo-2-fluorophenyl)propan-1-ol (3.2 g, 12.9 mmol, 90.2% yield) as a white solid which was used in the next step without further purification. MS (ISP): m/z=248.1 [M+H]+ and 250.0 [M+2+H]+.
Reaction SMILES: [F:1][C:2]1([F:39])[CH2:6][CH2:5][N:4]([C:7]([C@@H:9]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:10]([CH:16]2[CH2:21][CH2:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH2:17]2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[O:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[C:47]1[CH:48]=[CH:49][C:50]2[N:51]([N:53]=[CH:54][N:55]=2)[CH:52]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:34]([O:33][C:32](=[O:38])[NH:31][C@H:9]([C:7]([N:4]1[CH2:5][CH2:6][C:2]([F:1])([F:39])[CH2:3]1)=[O:8])[C@H:10]([CH:16]1[CH2:21][CH2:20][C:19]([C:47]2[CH:48]=[CH:49][C:50]3[N:51]([N:53]=[CH:54][N:55]=3)[CH:52]=2)=[CH:18][CH2:17]1)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])([CH3:37])([CH3:36])[CH3:35]
Reactant: CN(C)C(=O)[C@@H](C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reactant: Brc1ccc2ncnn2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CN(C)C(=O)[C@@H](C1CC=C(c2ccc3ncnn3c2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Temperature: 80 °C

Procedure:
The material from Step B (2.0 g, 3.6 mmol) was combined with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.43 g, 0.53 mmol), potassium carbonate (1.5 g, 11 mmol), and 6-bromo[1,2,4]triazolo[1,5-a]pyridine (80% pure, 1.1 g, 4.3 mmol) and the flask was flushed with nitrogen. DMF (35 mL) was added, and the resulting mixture was heated at 80° C. for 14 h. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (anhydrous sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography twice (0-5% methanol in dichloromethane, then 0-5% methanol in ethyl acetate) to afford the title compound. LC/MS 547.3 (M+1).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=O)=[O:4].Cl.[NH2:21][C@H:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([NH:21][C@H:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCC[C@H](N)C(=O)OCC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Boc-Gly-Pro-OH (3.85 g, 0.014 mol), the HCl salt of Nleu-OEt (2.76 g, 0.014 mol) and HOBt (2.8 g, 0.02 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. on a water-ice bath. TEA (2.8 ml, 0.02 mol.) was added to the solution. After stirring the solution for 10 minutes, EDC (4.0 g, 0.021 mol.) was added. The stirring was continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 200 ml ethyl acetate. The organic layer was washed by H2O 2×30 ml, saturated NaHCO3 3×10 ml, brine 2×10 ml, saturated NaHSO4 3×15 ml and brine again until the pH value of the brine layer was approximately 7. The ethyl acetate solution was dried using Na2SO4 and the solvent was removed by distillation under reduced pressure. Column chromatography (elution solvents: E/H, 2:1) was performed to obtain the pure product (yellowish oil, 4.7 g, 81%). TLC Rf=0.54 (developing solvents: CMA, 85:15:3) and Rf=0.34 (developing solvents: E/H, 2:1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[F:10][Sb-:11]([F:16])([F:15])([F:14])([F:13])[F:12].[CH3:17][N:18]([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[N+](C)([O-])=O>[F:10][Sb-:11]([F:16])([F:15])([F:14])([F:13])[F:12].[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N+:18]([CH3:25])([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)cc1
Reactant: CN(C)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C[N+](C)(C)c2ccccc2)cc1
Yield: 55 %

Procedure:
12.21 g (0.1 mol) of 4-methylbenzylalcohol and 35.78 g (0.1 mol) of N,N-dimethylaniline hexafluoroantimonate were dissolved in 100 g of nitromethane and allowed to react at 80° C. for 8 hours. After the completion of the reaction, the mixture was concentrated, and the precipitated white solid was washed with ether and dried to give the titled compound. Yield: 55%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC(O)CO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCC(O)CO)n1
Temperature: 0 °C
Yield: 43 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 3.9 g (0.0424 mol) of racemic 3-aminopropane-1,2-diol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 2.19 g of yellow powder are obtained, ie a yield of 43%.