Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[C:19]([F:21])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]#[N:18])=[N:10]2)=[C:6]([F:22])[CH:5]=1)[CH3:2].C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:31]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:22])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17](=[NH:31])[NH2:18])=[N:10]2)=[C:19]([F:21])[CH:20]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(C#N)c3c2CCC3)c(F)c1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1cc(F)c(Cn2nc(C(=N)N)c3c2CCC3)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.73 g of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carbonitrile 1-1-1 (25.5 mmol, 1.00 eq) were suspended in 100 mL methanol. 7.65 mL sodium methanolate in methanol (2.23 g, 41.3 mmol, 1.62 eq.) were added at rt. The reaction mixture was stirred for 4 h at rt. 2.36 mL acetic acid (2.45 g, 41.3 mmol, 1.62 eq.) and 2.05 g ammonium chloride (38.2 mmol, 1.50 eq.) were added and the reaction mixture was stirred at 50° C. for two days. The mixture was concentrated in vacuo and the residue was filtered off and washed with methanol. The filtrate was suspended in water and aqueous hydrochloric acid (4N). DCM was added, the aqueous layer was washed with DCM twice. To the aqueous layer aqueous sodiumhydroxid solution (2N) was added to reach pH 12. The aqueous layer was extracted with DCM/isopropanol (4:1) three times. The united organic layers were dried over a silicone filter, concentrated in vacuo to provide 2.67 g (7.99 mmol, 31.3%) of analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Cl:7])[N:6]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Cl:7])[N:6]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a 0° C. solution of 2,4-dichloro-1,3-thiazole-5-carbaldehyde (1.0 g, 5.5 mmol) in anhydrous methanol (45 mL) was added sodium borohydride (340 mg, 9.0 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added and the methanol was evaporated. The resultant mixture was extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, to afford (2,4-dichloro-1,3-thiazol-5-yl)methanol (850 mg, 84% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]O)[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][Cl:18])[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCOc1ccnc(CCl)c1C

Procedure:
11.0 g (0.054 mol, 1.0 eq.) of 4-pentyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 620 mL of chloroform, and 24.9 g (0.281 mol, 4 eq.) of thionyl chloride was added dropwise at 22 to 30° C. Subsequently, the mixture was heated to reflux for one hour, and then concentrated, to obtain 4-pentyloxy-2-chloromethyl-3-methylpyridine as a brown oily matter.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])[CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])[CH:15]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2nn(C)cc2CC(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of methyl [1-methyl-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (686 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (471 mg, yield 71%), which was then recrystallized from acetone-hexane. melting point: 126–127° C.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]([CH3:25])([CH2:22][CH2:23][CH3:24])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.[Ni]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:10]([CH3:25])([CH2:22][CH2:23][CH3:24])[CH2:9][O:8][C:7]2[CH:26]=[CH:27][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: CCCC(C)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCCC(C)(COc1ccc(N)cc1)COc1ccc(N)cc1

Procedure:
300 g 1,3-bis-(4-nitrophenoxy)-2-methyl-2-propylpropane were hydrogenated as in Example 10 in 1500 ml DMF in the presence of 46 g Raney nickel. The crude product was recrystallized from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[CH:9][C:8](=[O:12])[C:7]=2[CH:13]=1.C(N(CC)CC)C>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH:8]([OH:12])[C:7]=2[CH:13]=1
Reactant: COc1ccc2occc(=O)c2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c(c1)C(O)CCO2

Procedure:
A solution of 6-methoxy-4-benzopyranone (31.6 g), triethylamine (4.9 ml) and 10% palladium on carbon (3.16 g) in absolute ethanol (1.7 l) is stirred under an atmosphere of hydrogen for 19 hours. The reaction mixture is filtered and evaporated in vacuo yielding the desired hydrogenated product as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[O:17][CH3:18])[CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.C(OCC)C.O>[F:19][C:20]([F:22])([F:21])[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[OH:14]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cc(C=O)ccc1Oc1cccc(F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 4-[(6-fluoropyridin-2-yl)oxy]-3-methoxy benzaldehyde (300 mg; 1.2 mmol) with trifluoro methyltrimethylsilane (228 μl; 1.46 mmol) in THF (3 ml) under argon at 0° C. was added a molar solution of TBAF in THF (10 μl; 0.012 mmol). The reaction mixture was allowed to stir at rt for 2 h and a molar aqueous solution of HCl was added dropwise (2.5 ml; 2.5 mmol). The reaction mixture was stirred for another 2 h. water and diethylether were added. The aqueous phase was further extracted (2×EtOAc). Combined organic phases were dried over MgSO4, concentrated in vacuo to afford the title compound as a white solid (333 mg; 1.05 mmol; 88%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]#[N:14])=[CH:7][N:6]=1)#[N:2]>N.CO.[H][H].[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][N:6]=1
Reactant: [H][H]
Reactant: N#CCCc1ccc(CCC#N)nc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCc1ccc(CCCN)nc1
Yield: 89.5 %

Procedure:
A solution of 2,5-di(2-cyanoethyl)pyridine from Step C (3.16 g) was dissolved in 7N ammonia in methanol solution (45 mL) and hydrogenated under 40 psi of hydrogen gas pressure at 50° C. in the presence of Raney nickel (1.6 g) for 20 h. The catalyst was filtered through solka floc® and washed with methanol. The filtrate and wash were combined and concentrated under reduced pressure to give 2,5-di(3-aminopropyl)pyridine (I)(2.95 g).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13](=[O:32])[N:12]1[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]1)[C:7](=[O:46])[NH:6]2)=[O:4].C1COCC1.CO.[OH-].[Li+]>CCOC(C)=O.O>[C:28]([O:27][C:25]([NH:24][CH:14]1[C:13](=[O:32])[N:12]2[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]2)[C:7](=[O:46])[NH:6][C:5]2([C:3]([OH:4])=[O:2])[CH:22]([CH2:23]2)[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(=O)N3Cc4cccc(F)c4C3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To 14-tert-Butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid methyl ester (916 mg, 1.43 mmol) in a 1:1:1 mixture of THF:MeOH:H2O (12 mL) was added lithium hydroxide (299 mg, 41.96 mmol). The resulting slurry was stirred at room temperature overnight then diluted with EtOAc and washed with 1 N HCl and brine. The resulting organic layer was dried over sodium sulfate and concentrated to provide the crude 14-tert-Butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (910 mg, 100% yield). LCMS found 628.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.Cl>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(OCc2ccccc2)c1

Procedure:
A stirred mixture of 3-benzyloxybenzoic acid (22.0 g; 0.096 mol) and dry dimethylformamide (2 drops) in dry dichloromethane (100 cm3) was treated with oxalyl chloride (19 g; 0.15 mol) which was added in 4 approximately equal portions over ˜30 minutes. The mixture was stirred at room temperature until evolution of hydrogen chloride had ceased (˜6 hrs). The resulting colourless solution was evaporated in vacuo at 40° to constant weight to give a very pale tan oil that solidified rapidly to give the title compound as off-white needles.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-:25].[Na+].OO.C(Cl)(Cl)Cl>O1CCCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH:8]([O:25][C:1](=[O:11])[CH3:2])[CH3:9])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC(C)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 163.9 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-acetoxy-1-heptenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.5 g (yield 81%) of (+)-5-decyloxy-2-{4-(6-acetoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =+0.9 (c=1.0, CHCl3).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C#N)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Next, 0.95 g (1.82 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[(4-cyanophenyl)(methyl)phosphono]butanoate and 1.18 g (10.9 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.73 g (5.46 mmol) of aluminum trichloride at room temperature. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of an ether three times and a water layer was separated, and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 45% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[(4-cyanophenyl)(methyl)phosphono]butanoic acid (0.38 g, yield 70%) as a colorless solid.
Reaction SMILES: [CH2:1]([S:8]([CH2:11][CH:12]([CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=O)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH2:1]([S:8]([CH2:11][CH:12]([CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC(CS(=O)(=O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(CCC(CS(=O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a cooled solution (−78° C.) of dibenzyl 2-[(benzylsulfonyl)methyl]pentanedioate (8.2 g, 18.3 mmol) in dichloromethane (100 mL), was added 3-chloroperbenzoic acid (85%, 8.2 g, 40.3 mmol) with stirring. The reaction mixture was allowed to warm to room temperature. White solids precipitated from the reaction mixture. After 2 hours at room temperature, the reaction mixture was filtered and the white solids washed with dichloromethane. The filtrate was washed twice with a saturated aqueous solution of sodium bicarbonate and the dichloromethane removed under reduced pressure. The resulting oil was purified by column chromatography to yield 7.5 g (85%) of clear oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:14](=[O:16])[C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol), N,O-dimethylhydroxylamine hydrochloride (3.4 kg, 36.2 mol) and THF (32 L) are charged to a clean flask under nitrogen. The mixture is cooled to 0-10° C. and then DIPEA (12.4 L) is slowly added at a temperature less than 20° C. EDC-HCl (7 Kg, 36.2 mol) is then added slowly with slight cooling at 15-25° C. The slurry is aged overnight at 20-25° C. The mixture is then cooled to 0-10° C. and 3 N HCl (13 L) is added slowly. Then IPAC (45.5 L) is added and the layers are separated. The organic layer is washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L). The organic layer is then concentrated under vacuum to <20 L at 50° C. The clear solution is cooled slowly to room temperature, allowing the product to crystallize. Heptane (˜70 L) is then added slowly. The slurry is filtered, washed with heptane (18 L), and dried at room temperature on the filter pot. Product is obtained with >99.9% ee measured by chiral HPLC.
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]([CH:23]=[CH:24][CH:25]=3)[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C(#N)C.CCOC(C)=O>[CH:20]([N:19]([CH2:18][C:17]1[CH:23]=[CH:24][CH:25]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([CH3:22])[CH3:21]
Reactant: COCc1cc(-c2nc(-c3cccc(CNC(C)C)c3)no2)ccc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3cccc(CN(CC(=O)OC(C)(C)C)C(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
N-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)propan-2-amine (64 mg, 0.15 mmol) was dissolved in ACN (2 mL). K2CO3 (83 mg, 0.60 mmol) and tert-butyl bromoacetate (48 μl, 0.32 mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, and then dried over MgSO4. After concentration under vacuum, the crude product was purified by flash chromatography (silica, cHex/EtOAc) to give the title compound as a colorless oil (58 mg, 72%). HPLC (Method A) Rt 5.54 min (Purity: 97.7%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]C=O.C(=O)([O-])[O-].[K+].[K+].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][O:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[NH:14][C:8]=2[CH:9]=1
Reactant: O=CNc1cc(Cl)ccc1OCOc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1ccc2c(c1)Nc1ccccc1OCO2
Reaction time: 8 h

Procedure:
A suspension of 1.4 g. (0.004 moles) of (2-bromophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.: 98° to 100° C.), 0.6 g. (0.0042 moles) of potassium carbonate, 0.2 g. of copper powder and 12 ml. of Dowtherm(®) is heated up to 180° C. and is vigorously stirred at this temperature for 8 hours. The reaction mixture is filtered while hot, then the solvent is evaporated in vacuo. The remaining dark tar is hydrolyzed by boiling in a mixture of 20 ml. of ethanol and 2 ml. of a 20% aqueous sodium hydroxide solution for one hour. The reaction mixture is cooled and neutralized with a 37% aqueous hydrogen chloride solution. The solvent is evaporated and the brown solid residue is extracted with 10 ml. of hot benzene. Thereafter the solvent is eliminated and the residue is crystallized from benzine.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH:10]=1)([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.CN(C1C=CC=CN=1)C.C(Cl)(=O)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([NH:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(N)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: CN(C)c1ccccn1
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide acetic acid salt (as prepared in the previous step, 50.0 mg, 0.122 mmol) and DIEA (85.0 μL, 0.488 mmol) in 2 mL of CHCl3 was stirred at RT for 5 min before dimethylaminopyridine (DMAP) (4.1 mg, 0.037 mmol) was added. The mixture was cooled to 0° C. and a solution of acetyl chloride (10 μL, 0.15 mmol) in 2 mL of CHCl3 was added dropwise. The reaction was warmed to RT and stirred for 18 h under Ar. The mixture was treated with EtOAc (40 mL), washed with saturated aqueous NaHCO3 (5 mL), brine (10 mL) and dried over Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% MeOH/DCM) gave 7.6 mg (16%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.17 (s, 1H), 8.10 (d, 1H, J=8.6 Hz), 7.99 (s, 1H), 7.27 (dd, 1H, J=8.6, 2.3 Hz), 7.16 (d, 1H, J=2.3 Hz), 5.80 (m, 1H), 2.20-2.32 (m, 4H), 1.94 (s, 3H), 1.74-1.88 (m, 4H), 1.62 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H25N5O2, 392.2 (M+H). found 391.8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(O)cc2)c2cccc(Cl)c2C)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
300 mg of N2-(3-chloro-2-methylphenyl)-N-(4-hydroxybenzyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 2.00 mL of DMF, and 110 mg of potassium carbonate and 133 mg of ethyl bromoacetate were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40 to 30:70) to obtain 370 mg of ethyl 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]phenoxyacetate.