Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:33]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cncc3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1cncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A microwave vial charged with 4-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (Intermediate PPPP) (0.066 g, 0.135 mmol), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (Combi-Blocks, San Diego, Calif.) (0.044 g, 0.202 mmol), potassium carbonate (0.093 g, 0.673 mmol), dioxane (0.673 ml) and water (0.224 ml) was purged with argon prior to the addition of Pd(PPh3)4 (0.016 g, 0.013 mmol). The vessel was sealed and irradiated at 100° C. for 30 min. The resulting mixture was diluted with EtOAc and extracted with water, the aqueous phase was extracted with EtOAc and the combined organics were dried under reduced pressure. To the crude brown oil was added DCM (3 ml) and TFA (1 ml) and the resulting solution stirred overnight at RT affording conversion to desired product. The mixture was dried under reduced pressure and purified with a 25 g HP spherical silica gel (Interchim, Mouintlucon, France, 15 μm) ramping EtOAc in heptane (0 to 50%, 10% DCM isocratic throughout) providing product as a film which was lyophilized from MeOH/H2O to provide 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (38 mg, 0.082 mmol, 60.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87 (d, J=4.60 Hz, 1H) 7.28 (d, J=4.60 Hz, 1H) 7.46-7.53 (m, 2H) 7.54-7.59 (m, 1H) 7.61 (d, J=8.90 Hz, 1H) 8.02 (dd, J=8.85, 1.91 Hz, 1H) 8.53 (s, 1H) 8.75 (d, J=1.56 Hz, 1H) 9.55-9.66 (m, 1H) 12.88 (br. s., 1H). m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[NH:5])C.[OH:12][CH:13](O)[C:14](=O)[CH3:15].[NH3:18]>CO>[Cl:11][C:8]1[S:7][C:6]([C:4]2[NH:5][C:14]([CH2:13][OH:12])=[CH:15][N:18]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)C(O)O
Reactant: N
Reactant: CCOC(=N)c1ccc(Cl)s1
Solvent: CO
Product: OCc1cnc(-c2ccc(Cl)s2)[nH]1
Temperature: 77 °C
Yield: 95.6 %

Procedure:
A mixture of 5-chlorothiophene-2-carboximidic acid ethyl ester (38.7 g, 0.171 mol), 15.4 g of dihydroxyacetone (0.171 mol) and 102.18 g of gaseous ammonia (6.0 mol) in 500 ml of methanol was heated at 77° C. in a high-pressure reactor. After cooling and evaporation under vacuum, ammonium chloride was filtered and washed with methanol. The filtrate was concentrated under vacuum and yielded 35.1 g of crude product, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2[CH3:26])[N:13]=[C:12]([Cl:27])[CH:11]=1>CN(C)C=O>[ClH:27].[CH3:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2[CH3:26])[N:13]=[C:12]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc(Cl)nc(N2CCc3ccccc3C2C)n1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)n1
Product: Cl
Yield: 52 %

Procedure:
After 4-fluoroaniline(0.8 ml, 8.4 mmol) was added to a mixture solution of 6-methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(1.5 g, 5.5 mmol) and dimethylformamide(10 ml), 1.1 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]1([C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]2[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:26][C:25]([C:23]1[N:22]=[CH:21][N:20]([C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=1)=[O:27]
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1cccc(C=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C=CC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1OC

Procedure:
0.149 mole of 2,3-dimethoxybenzaldehyde is added over 5 hours at room temperature to a solution of 0.149 mole of 1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-ethanone prepared in Example 2.1 in a mixture of 800 ml of ethanol and 186 ml of a 2N aqueous solution of sodium hydroxide. The reaction medium is then brought to pH 7.5 by addition of a 5N aqueous solution of hydrochloric acid. The ethanol is distilled off and a solid is formed, which precipitates. This solid is filtered off and washed with water before drying. The solid is redissolved in 2 liters of boiling 2-propanol and the insoluble salts are filtered off. Half the 2-propanol is evaporated off and the 3-(2,3-dimethoxyphenyl)-1-(1-triphenylmethyl-1H-imidazol-4-yl)-2-propen-1-one is recrystallized.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCCCOc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCOc1ccc(COc2ccc(C(=O)OCC)cc2)cc1
Yield: 84.6 %

Procedure:
In 20 ml of benzene were dissolved 2.2 g of 4-heptyloxybenzyl alcohol and 1.7 g of ethyl 4-hydroxybenzoate, 1.8 g of diethyl azodicarboxylate and 2.6 g of triphenylphosphine were added to the solution, and a reaction was carried out with stirring. The reaction liquid was concentrated and the concentrate was separated and purified by the silica gel chromatography to obtain 3.1 g of ethyl 4-(4'-heptyloxybenzyloxy)benzoate. This ester was dissolved in 20 ml of ethanol and 4.2 ml of a 2N aqueous KOH solution was added to the solution to effect the hydrolysis. The reaction mixture was treated by customary procedures to obtain 2.7 g of 4-(4'heptyloxybenzyloxy)benzoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl>[N:21]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: CCC(=O)Cl
Reactant: NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
A solution of 2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (0.5 g), propionic chloride (0.18 ml) and triethylamine (0.3 ml) in methylene chloride (20 ml) was stirred at room temperature for 2 hr. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a pale-yellow substance (0.8 g). The obtained pale-yellow substance was crystallized from hexane/ethyl acetate (1:1, 50 ml) to give the title compound (0.5 g) as pale-yellow crystals.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([C:27]([O:30]CC1C=CC=CC=1)([CH3:29])[CH3:28])[N:7]=2.CO>C1COCC1.[Pd]>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([C:27]([OH:30])([CH3:28])[CH3:29])[N:7]=2
Reactant: COc1ccc(Cn2cnc(N)c3nc(C(C)(C)OCc4ccccc4)nc2-3)cc1OC1CCCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)(C)O)nc2-3)cc1OC1CCCC1

Procedure:
A solution of 6-amino-8-(1-benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine hydrochloride (2.13 g, 4.06 mmole), in THF:methanol,1:1 (60 ml), was hydrogenated at room temperature and pressure with 10% Pd-C (0.26 g) for 12 hours. The catalyst was filtered off and the solvents removed in vacuo. The residue was suspended in hot acetone, the solid collected at 0-5° C. (1.23 g) and recrystallized from methanol-acetone to give the title compound, 0.76 g (43.2%) mp 231-232° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1ccc(C#C[Si](C)(C)C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available: 0.25 g, 0.871 mmol) in tetrahydrofuran was added bis(triphenylphosphine) palladium(II) dichloride (61.7536 mg, 0.087 mmol), copper(I) iodide (16.6 mg, 0.087 mmol), triethylamine (889 mg, 1.23 mL, 8.70 mmol) and ethynyltrimethylsilane (130 mg, 0.19 mL, 1.30 mmol). The reaction mixture was stirred at 65° C. overnight. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)-2-pyridyl]amino]butanoate (26 mg, 10% yield). 1H NMR (400 MHz, CDCl3) 8.39 (s, 1H), 8.14 (m, 2H), 7.74 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H), 0.24 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[CH3:15][S:16]([C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:24](=[O:25])[C:22]1[S:23][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)s1
Agent: CN(C)c1ccncc1
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)s1
Yield: 70 %

Procedure:
The title compound was prepared according to the procedure of Example 32. A 2.06 g (10.0 moles) sample of 5-methylsulfonyl-2-thiophenecarboxylic acid (prepared according to Cymerman-Craig, J., et al., J. Chem. Soc.:237 (1954)) reacted with 10 ml of thionyl chloride to give 2.14 g of crude acid chloride as a solid. The reaction of 1.75 g (8.33 mmoles) of 5-chloro-2-oxindole-1-carboxamide with 5-methylsulfonyl-2-thiophenecarbonyl chloride in the presence of 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine gave 3.17 g of crude product after acidic workup. A single recrystallization from acetic acid gave 2.31 g (5.80 mmoles, 70% yield) of pure 5-chloro-3-(5-methylsulfonyl-2-thenoyl)-2-oxindole-1-carboxamide as a deep-orange solid, m.p. 212°-14° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:9][C:10]([F:18])([F:17])[C:11]([F:16])([F:15])[C:12]([O-])=O.[Na+].C1(C)C(C)=CC=CC=1.CN1CCCC1=O>[Cu]I.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[F:9])=[CH:4][N:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:12]([C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[F:9])=[CH:4][N:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)c1ccc(Cl)nc1
Temperature: 160 °C

Procedure:
A mixture of 2-chloro-5-iodopyridine (20.0 g), sodium pentafluoropropionate (77.8 g), copper (I) iodide (31.8 g), xylene (84 ml) and N-methyl pyrrolidone (84 ml) was heated to 160° C., and stirred while heating under reflux 6 hours. The reaction mixture was cooled to room temperature, and water was poured thereto. Then, the mixture was extracted with methyl-tert-butyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 2-chloro-5-pentafluoroethyl pyridine 2-chloro-5-pentafluoroethyl pyridine.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.[OH2:19].Cl.C1[CH2:25][O:24]CC1>CCCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:25]([OH:24])=[O:19])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: COCOc1cccc2sccc12
Reactant: O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COCOc1cccc2sc(C(=O)O)cc12
Temperature: -78 °C

Procedure:
4-(Methoxymethyloxy)benzo(b)thiophene (83 g) was dissolved in THF (700 ml) and the mixture was cooled to −78° C. At this temperature, a solution (363 ml) of n-butyllithium in hexane was added dropwise. The temperature was raised to 0° C. and then cooled again to −35° C., and carbon dioxide was bubbled. After the completion of the reaction, the reaction mixture was poured into water, and in the presence of ice, hydrochloric acid was added to adjust its pH to 1 and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure to give the title compound (80 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 426 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.CCOCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=C[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
A solution of 0.29 g (1.19 mmol) of the resultant compound of Example 31 and 0.25 ml (1.8 mmol) of triethylamine in 7 ml of dichloromethane was cooled to 0° C. and treated with 0.12 ml (1.55 mmol) of methanesulfonyl chloride. After 45 min, the solution was diluted with ether, washed sequentially with 10% aqueous citric acid, aqueous NaHCO3 and saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 3:1 hexane:ethyl acetate provided 0.23 g (61%) of the desired compound (Rf 0.48, 3:2 hexane:ethyl acetate).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH2:6][C:7](OCC)=[O:8])([O-])=O.[H][H]>C(O)C.[Ni]>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=[C:12]1[CH:5]1[CH2:4][NH:1][C:7](=[O:8])[CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1cc2ccccc2o1
Agent: [Ni]
Solvent: CCO
Product: O=C1CC(c2cc3ccccc3o2)CN1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Ester (IV) (81.5 g; 0.297 mole) obtained in b) is dissolved in 500 ml ethanol and hydrogenated at ordinary pressure at 55° C. in the presence of 10 g Raney Nickel. The hydrogen required for the reaction (14.8 l) is taken up within 7 hours. After filtration of the catalyst and evaporation of the ethanol, the oily residue is heated at 100° C. under the vacuum of a water pump, for 2 hours. On trituration with isopropyl ether, the product crystallizes. M.P. (inst.)=142° C. Weight: 47.9 g (80%).
Reaction SMILES: [OH:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].CCOCC>CN(C=O)C.[Cl-].[Na+].O>[Si:26]([O:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 29.0 g (0.1 mol) of di-tert-butyl 2-hydroxypropane-1,3-diyldicarbamate and 17.0 g (0.25 mol) of imidazole in 200 ml DMF at 0° C., was added 18.09 g (0.12 mol) of t-butyldimethylsilylchloride (TBDSMCl) in portions. The reaction was warmed up to RT and stirred for 2 hours. To this mixture was added 400 ml ether and 400 ml brine. The layers were separated and the aqueous layer was extracted with 400 ml ether. The combined organic layer was dried and concentrated to give 35 g of di-tert-butyl 2-(tert-butyldimethylsilyloxy)propane-1,3-diyldicarbamate (86% yield).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[NH2:1][C:2]1([C:7]([O:9][CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC1(C(=O)O)CCCC1
Product: COC(=O)C1(N)CCCC1
Product: Cl
Yield: 97 %

Procedure:
1-Amino-1-cyclopentanecarboxylic acid (5.00 g, 38.8 mmol) was dissolved in methanol (100 mL) and then thionyl chloride (9.25 g, 77.7 mmol) was added dropwise with stirring. The resulting mixture was stirred overnight at room temperature and then concentrated in vacuo which left a white solid. The solid was tritruated in ethyl ether, filtered, and dried to give 6.78 g (97%) of methyl 1-amino-1-cyclopentanecarboxylate hydrochloride as a white solid. 1H NMR was consistent with product. ESMS (M+1) 144.2
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[Na+].[Na+].CI>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9](=[O:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1c(=O)oc(=O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a solution of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (200 mg, 1.10 mmol) in DMF (2 ml) was added Na2CO3 (129 mg, 1.22 mmol), followed by methyl iodide (104 μl, 1.66 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with ethyl acetate and the mixture was washed with water and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 8-fluoro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (190 mg, 88%) which was not purified due to its poor solubility but directly used in the following step without further purification. To a suspension of the residue (190 mg, 0.97 mmol) in ethanol (4 ml) was added DMAP (12 mg, 0.09 mmol) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to RT and then concentrated in vacuo to give a residue which was partitioned between ethyl acetate and 0.1M HCl solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give the desired product (132 mg, 69%) as a light yellow oil. 1H NMR (CDCl3, 300 MHz): 7.69 (aptd, J=8.0 Hz, 1H), 7.50 (brds, 1H), 7.08 (ddd, J=14.0, 8.0, 1.5 Hz, 1H), 6.51 (aptdt, J=8.0, 4.5 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.12 (m, 3H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+:9](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.N.O1CCOCC1>CN(C)C=O>[NH2:9][C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=1
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (180 mg, 0.46 mmol) was added to a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-isopropoxyphenyl)propanoic acid (100 mg, 0.3 mmol) (Example 136, step 2) in N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (110 uL, 0.62 mmol). The reaction was stirred for 10 min., and 0.5 M ammonia in 1,4-dioxane (1.2 mL, 0.62 mmol) was added. The reaction was stirred for 1 h. at r.t., and was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, (S)-tert-butyl 1-amino-3-(4-isopropoxyphenyl)-1-oxopropan-2-ylcarbamate (90 mg, 90%). Analytical LCMS (M+H-Boc)+: m/z=222.9.