Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][OH:8].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:5]1[CH2:6][C@H:2]([OH:1])[C@@H:3]([CH2:7][OH:8])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@H]1CNC[C@@H]1O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,4R)-(4-Hydroxypyrrolidin-3-yl)methanol (1.18 g) was dissolved in ethanol (25 mL). To this solution, triethylamine (1.40 mL) was added and while the mixture was chilled in a salt/ice water bath, benzyl bromide (1.10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: methanol=20:1) to give (3R,4R)-(1-benzyl-4-hydroxypyrrolidin-3-yl)methanol as a milky white syrup (1.02 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12](Cl)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1Cl)[CH:2]([CH3:4])[CH3:3].[C:17]1([Mg]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1P(Cl)OCC12COP(Cl)OC2
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)CN1P(c2ccccc2)OCC12COP(c1ccccc1)OC2

Procedure:
Into a solution of 10.0 g (32.7 mmol) of 1-isobutyl-2,8-dichloro-3,7,9-trioxa-1-aza-2,8-diphosphaspiro[4.5]decane, the compound of Example 8, in 60 mL of tetrahydrofuran (THF) is added dropwise 32.7 mL (65.4 mmol) of a 2M solution of phenyl magnesium chloride in THF at ambient temperature. The title compound is isolated in a yield of 11 g as an oil and identified by mass spectrometry: m/z=389.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:20][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCCCCBr
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.6 %

Procedure:
5-(5-Methyl-2-phenyloxazol-4-yl)-1-pentanol (2.9 g) was dissolved in 62 ml of dry ether, and 8.4 g of carbon tetrabromide was added. To the mixture was added gradually 6.6 g of triphenylphosphine under ice-cooling. The mixture was then stirred for 2.5 hours at room temperature, filtrated to remove insolubles and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide 2.61 g of the objective compound as yellowish oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC(C(O)c2ncccc2CCc2ccccc2)CC1
Yield: 87.5 %

Procedure:
To a mixture of 5.0g (16.2 mmole) of (1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanone (which can be prepared in the same manner as described in Preparative Example 1, Steps A-D) in 70 mL of methanol was added portionwise 0.8 g (21.1 mmole) of sodium borohydride. The next day the solution was concentrated in vacuo to give a slurry which was dissolved in water and extracted with CHCl3. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to provide a liquid which was distilled (bp 190°-195° C. 1 mm Hg) to give 4.4 gms of the title compound as a viscous oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]=[CH:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>CO.[Pd]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2C=CNCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(C2CCNCC2)cc1
Reaction time: 18 h
Yield: 118.7 %

Procedure:
A mixture of 10 g (47 mmol) of 4-(4-fluorophenyl) tetrahydro pyridine hydrochloride (Aldrich-Saylor) and 1.18 g of 10% Pd/C in 100 mL of degassed MeOH (N2) was stirred under hydrogen at 45 psi for 18 h. The reaction mixture was then filtered though a thin pad of celite eluting with MeOH. The filtrate was concentrated and the residue was stirred in 75 mL of ether. To it at 0° C. was added 5 g of solid NaOH. The layers were separated and the aqueous layer was extracted with ether. The combined organic fractions were washed with sated NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was crystalized from cold heptane to give 10 g of the title compound.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:16]=1[CH2:17][NH:18][C:19]1[C:20]([CH2:25][NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O.O>[CH3:13][O:14][C:15]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:16]=1[CH2:17][N:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]=2[CH2:25][N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[C:1]1=[O:2]
Reactant: COc1ccc(CNc2cccnc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3ncccc32)c(OC)c1
Temperature: 150 °C

Procedure:
Carbonyldiimidazole (1.22 g, 7.53 mmol) was added to a solution of the material from Step C in dimethylformamide (20 mL) and the reaction was heated to 150° C. overnight. The reaction was diluted with water and extracted with dichloromethane, and the organic phase dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 30 to 100% ethyl acetate in methylene chloride gradient elution), which gave the title compound (0.10 g). MS 483.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17](I)[CH3:18]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:17][CH3:18])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Reactant: CCI
Product: CCOCc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (2.0 g) was alkylated with ethyl iodide analogously to the conditions of O5.043. 1.18 g of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:21]=2[CH:31]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+].O>C1COCC1.CO>[C:6]1([CH2:5][C@@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:21]=3[CH:31]=2)=[O:14])[C:3]([OH:32])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxy-carbonylamino)-propionic acid methyl ester 28(0.7 g, 1.63 mmol) in THF (15 ml) and methanol (15 ml) was added a solution of lithium hydroxide (1N) in water (2 ml, 2 mmol). The reaction mixture was heated at 50° C. for 6 hrs then left at room temperature overnight. The solvent was evaporated and water (20 ml) was added. The mixture was acidified with 1N HCl and ethyl acetate was added. The solid obtained after precipitation and evaporation of the solvent was purified by recrystallization to give about 0.35 g of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-propionic acid 29, mp. 172.8–173.5° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[Cl:1][CH2:2][CH2:3][CH:4]([O:5][S:20]([CH3:19])(=[O:22])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCCl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCCl)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (R) 3-chloro-1-phenyl-propan-1-ol (Aldrich) (0.250 g) in 40 ml dichloromethane was added triethylamine (0.272 g) at 0° C. followed by the dropwise addition of methanesulfonyl chloride (0.185 g). The reaction mixture was stirred at this temperature for 2 hours and then quenched by the addition of sodium bicarbonate solution. The phases were separated and the organic phase was evaporated to dryness to afford methanesulfonic acid 3-chloro-1-phenyl-propyl ester as an oil which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=O.[Cl-].[OH:16][NH3+:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[N:17][OH:16]
Reactant: CC(C)CC=C(C=O)c1ccccc1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CC=C(C=NO)c1ccccc1
Yield: 74.7 %

Procedure:
To a solution of 5-methyl-2-phenyl-2-hexenal (5.0 g, 27 mmol) and hydroxylammonium chloride (3.7 g, 53 mmol) in a mixture of 96% ethanol (20 ml) and water (5 ml) was carefully added a solution of sodium carbonate (11.2 g, 106 mmol) in water (30 ml). The resulting mixture was stirred for 2h, the precipitated compound was filtered off and suspended in dichloromethane (500 ml). The suspension was filtered and the solvent evaporated from the filtrate in vacuo to give 4.1 g of 5-methyl-2-phenyl-2-hexenal oxime.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:15][C:16]([F:47])([F:46])[C:17]1[CH:18]=[C:19]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:20]([N:22]([CH:24]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[CH2:25][C:26](O)=[O:27])[CH3:23])=[O:21]>ClCCl>[C:2]1([NH:1][C:26](=[O:27])[CH2:25][CH:24]([N:22]([C:20](=[O:21])[C:19]2[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=[C:17]([C:16]([F:46])([F:15])[F:47])[CH:18]=2)[CH3:23])[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)Nc1ccccc1)Cc1c[nH]c2ccccc12
Reaction time: 24 h

Procedure:
Aniline (8.3 mg, 1.2 eq) is placed in dichloromethane (0.5 ml), and triethylamine (52 μl, 5 eq) and 3-[N'-(3,5-bistrifluoromethyl-benzoyl)-N'-methyl-amino]-4-(1H-indol-3-yl)-butanoic acid [Example 7(b)] (35 mg, 0.07 mmol) are added. Propanephosphonic acid anhydride (31.6 mg, 4 eq, in 0.5 ml of ethyl acetate/dichloromethane) is added and the mixture is left to stand at room temperature for 24 hours. The mixture is washed with 1N potassium carbonate solution (0.5 ml) and the solvent is concentrated by evaporation. The resulting title compound has an Rf value (ethyl acetate) of 0.69.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][OH:12])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Nc1ccccc1C=O
Temperature: 117 °C
Yield: 90.6 %

Procedure:
Manganese dioxide (85% 182.6 g, 1.79 mol) was added to a stirred solution of 2-isopropylaminophenylmethanol (118 g, 0.71 mol) in toluene (800 mL) and the reaction mixture was heated to 117° C. for 4 h. The reaction mixture was allowed to cool to room temperature overnight and then filtered through a pad of Celite which was eluted with toluene. The filtrate was concentrated under reduced pressure to yield 2-isopropylaminobenzaldehyde (105 g, 90%) as an orange oil. 1H NMR (CDCl3; 300 MHz): 1.28 (d, 6H, CH(CH3)2), 3.76 (sept, 1H, CH(CH3)2), 6.65 (t, 1H, ArH), 6.69 (d, 1H, ArH), 7.37 (d, 1H, ArH), 7.44 (t, 1H, ArH), 9.79 (s, 1H, CHO).
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH:8]([NH2:11])([CH3:10])[CH3:9].[OH-].[Na+]>>[CH:8]([NH:11][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)([CH3:10])[CH3:9]
Reactant: CC(C)N
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)NCC1OCCO1
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (15 grams; 0.09 mole) and isopropylamine (38 ml; 0.45 mole) were charged into a Parr Shaker. The shaker was sealed and was heated with an infrared lamp to a pressure of about 50 p.s.i. Heating was stopped and the reaction mixture was shaken for a period of about 1/2 hour. After this time aqueous sodium hydroxide (12 ml; 50% concentration) was added to the reaction mixture with stirring. The organic phase was then separated from the aqueous phase, was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield the desired product N-isopropyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:31])[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:27])([F:28])[F:29])=[C:20]2[C:19]=1[OH:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(F)(F)F)ccnc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2nccc(C(F)(F)F)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-(trifluoromethyl)nicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:17](=[O:22])[NH:18][CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[C:17](=[O:22])[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:6]
Reactant: Nc1ccc[nH]c1=O
Agent: O=C(O)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc[nH]c1=O)c1cccnc1Cl
Reaction time: 8 h

Procedure:
The acid chloride of 2-chloronicotinic acid was prepared by refluxing 11 g. (0.07 mole) of 2-chloronicotinic acid in 80 ml. of thionyl chloride for 1.5 hours. After evaporating to dryness, the oily residue was dissolved in 50 ml. of ether. The ether solution was added to a stirred ice-cold solution of 7.7 g. (0.07 mole) of 3-amino-2-pyridone in 80 ml. of dry pyridine during 15 minutes. After 30 more minutes at ice temperature and 4 hours at room temperature, it was allowed to stand overnight in an open dish. The crystalline residue was extracted with water and the solid residue (12.9 g.) was collected and recrystallized from dimethyl formamide-ether to give gray crystals of 3-(2-chloronicotinoylamino)-2-pyridone, m.p. 295° C.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=[O:10])[NH:2]1.C(N(CC)CC)C.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(#N)C>[N:18]1([C:24]([N:2]2[C:3](=[O:10])[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1]2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=c1[nH]sc2ncccc12
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N1CCOCC1)n1sc2ncccc2c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a suspension of isothiazolo[5,4-b]pyridin-3-one (5.0 g, 32.86 mmol) in acetonitrile (180 ml) was added dropwise triethylamine (14 ml, 99 mmol) and afterwards 4-morpholinecarbonyl chloride (3.8 ml, 32.9 mmol) at room temperature. The reaction mixture was stirred for 3 h at 60° C. The solvent was removed under reduced pressure. To the crude oil was added water (50 ml) and ethyl acetate (50 ml), the phases separated and the aqueous phase extracted with ethyl acetate. The organic layers were combined, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by high performance liquid chromatography (RP silica gel, acetonitrile/water/trifluoroacetic acid) and lyophilization of the product fractions provided 5.0 g (57%) of the title compound as a white powder.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([CH3:23])[CH:21]=[CH2:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[Si:1]([O:18][CH2:19][C@H:20]([CH3:23])[CH:21]1[O:32][CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C1CO1
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, (S)-4-(t-butyldiphenylsilyloxy)-3-methyl-1-butene (50) (1.0 g, 3.1 mmol) was dissolved in 25 ml of dry dichloromethane, mCPBA (1.4 g, 7.4 mmol) was added to the resultant solution at 0° C., and the mixture was stirred for 15 min. Then, the mixture was further stirred overnight after the temperature was returned to room temperature. The reaction mixture was extracted with ethyl acetate after the addition of water. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated. The obtained crude product was purified by column chromatography (30 g, 2% Et2O-hexane) to obtain a colorless oily product (51). (1.1 g, quant.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[NH:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1>>[OH:26][CH:23]1[CH2:24][CH2:25][N:21]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:22]1
Reactant: OC1CCNC1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1)C(F)(F)F

Procedure:
Prepared in analogy to Example C1 from 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (CAS: 845616-82-2) and rac-3-pyrrolidinol. The crude material was crystallized with dichoromethane to provide the title compound as white solid. MS (m/e): 382.3 (M+H+, 100%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[O:19])[C:13]=1[OH:34]>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)=[O:19])[C:13]=1[OH:34])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Yield: 78 %

Procedure:
There is heated at reflux 61.2 mg of acetic anhydride and 27.6 mg of formic acid for 4 hours and 46 mg of 4-amino-3-hydroxy-N-para-phenoxyphenylpicolin-amide of Example 1 is added, dissolved in 5 mL of tetrahydrofuran. After 8 hours at reflux, the reaction mixture is concentrated and purified by chromatography to give 39 mg of a yellow solid MP 208° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([C:24]([NH2:26])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][C:11](=[O:13])[OH:12])=[O:7])[CH2:3][CH2:4][CH3:5].Cl.[NH:28]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:29]([C:40](ON1C(=O)CCC1=O)=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[NH:28]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:29]([C:40]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([C:24]([NH2:26])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][C:11](=[O:12])[OH:13])=[O:7])[CH2:3][CH2:4][CH3:5])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1
Reactant: CCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 63.3 %

Procedure:
1.50 g (3.74 mmoles) of H-Nva-Asp-D-Phg-NH2.HCl are reacted with 1.50 g (3.74 mmoles) of BOC-Trp-OSu in 30 ml of DMF in the presence of 1.05 ml (7.5 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the residue is admixed with water, and the mixture is filtered. The obtained crude product, weighing 2.36 g, is recrystallized from 300 ml of 80% ethanol. 1.54 g (66.2%) of BOC-Trp-Nva-Asp-D-Phg-NH2 are obtained; m.p.: 240° C. (decomposition), Rf5 :0.35, [α]D :-60.5° (c: 1.0, in dimethyl formamide).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:25](O)=[O:26])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH2:15][CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C@H:24]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)[C@@H:28]([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CCC(CC(=O)OC)c1ccc(Cl)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.07 mmol) of (+/−)-methyl 3-(3-amino-4-chlorophenyl)pentanoate and 668.9 mg (2.48 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 1.7 ml of pyridine and 3.3 ml of DMF, and 1.02 g (2.69 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase initially cyclohexane, then cyclohexane/ethyl acetate 50:1). This gave 675 mg of the target product (66.6% of theory).