Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=O)=C(F)C(F)=C(F)C=1F.[CH3:37][NH:38][CH3:39].N1C=CC=CC=1>C(#N)C.C(O)C>[CH3:37][N:38]([CH3:39])[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=1)=[O:8]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: CNC
Solvent: c1ccncc1
Solvent: CCO
Solvent: CC#N
Product: CN(C)C(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Reaction time: 8 h
Yield: 53 %

Procedure:
To 100 mg (0.190 mmol) 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester in 5 mL acetonitrile was added 50 μL (5.6 M in ethanol, 0.28 mmol) of a solution of dimethylamine and 20 μL (0.25 mmol) of pyridine, and the reaction was stirred overnight. The solution was concentrated, and the resulting solid was triturated with EtOAc to give the title compound as a yellow solid (39 mg, 53%): mp>230° C.; 1H NMR (DMSO-d6): δ 12.71 (s, 1H), 11.22 (s, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.60 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.31 (dd, J=1.7, 8.1 Hz, 1H), 7.23 (s, 2H), 6.93 (d, J=8.0 Hz, 1H), 2.95 (s, 6H); APCI-MS: m/z 386 (m-H). Anal. Calcd for C17H17N5O5S-1/2H2O: C, 51.51; H, 4.58; N, 17.67. Found: C, 51.69; H, 4.25; N, 17.63.
Reaction SMILES: Cl.C([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([C:11]([OH:13])=[O:12])[CH2:5]1)C.C(N([CH2:19][CH3:20])CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:4]2[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH2:5]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN1CCC(=O)C(C(=O)O)C1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc(C)cc2)CCC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
0.200 g (0.97 mmol) of 1-ethyl-4-oxopiperidine-3-carboxylate hydrochloride (commercially available, ABCR) were dissolved in 4 mL of dichloromethane with 0.135 mL (0.97 mmol) of triethylamine. The solution was cooled down to 0° C. and 0.185 g (0.97 mmol) of para-toluenesulfonyl chloride were added followed by 0.135 mL (0.97 mmol) of triethylamine. The reaction was stirred for 20 minutes at 0° C. and overnight at room temperature. Then, the reaction was further diluted with dichloromethane (50 mL) and washed with brine (20 mL×2). The organic layer was dried over Na2SO4 and solvent evaporation gave 300 mg of a white solid (95% yield) which was used for the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=[C:37]2[C@@H:33]([NH:32][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:31])[CH3:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
A mixture of (R)-3-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (2.25 g, 7.72 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (1.9 g, 8.49 mmol), HOAt (1.16 g, 8.49 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.63 g, 8.49 mmol) and 4-methylmorpholine (1.87 mL, 16.98 mmol) in anhydrous DCM (50 mL) was stirred at RT for 1.5 h. The reaction mixture was diluted with DCM (200 mL) and washed with a 10% citric acid solution, followed by a saturated solution of NaHCO3 and then brine. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 20 h and then at 80° C. for 2 h. After cooling to RT, volatiles were then removed in vacuo and the residue was dissolved in EtOAc (200 mL) and washed with a saturated solution of NaHCO3 (100 mL×2). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (R)-3-[2-((S)-1-Benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a white foam (2.75 g, 74%). LCMS: RT 3.16 min [M+H]+ 479.1.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].C(OCC)(=[O:34])C.CCCCCC>>[C:1]([O:19][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=[CH2:21])(=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCCCCCCCCO
Reactant: CCOC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: CCCCCC
Product: C=CCCCCCCCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Yield: 97.5 %

Procedure:
Compound F was prepared from Oleoyl chloride and 9-decen-1-ol following the general procedure already discussed and shown in FIG. 11. Pure compound F was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:22][C:23]1[CH:28]=[C:27]([C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: O=S(=O)(OC1=C(c2ccc(F)cc2)CCCC1)C(F)(F)F
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(C2=C(c3ccnc(Cl)c3)CCCC2)cc1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Trifluoro-methanesulfonic acid 2-(4-fluoro-phenyl)-cyclohex-1-enyl ester (200 mg, 0.62 mmol), 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (162 mg, 0.68 mmol), Bis(triphenylphosphine)Palladium (II) dichloride (43 mg, 0.062 mmol), Sodium Carbonate solution (2.0 M, 1.54 mL, 3.1 mmol) and DMF (3 mL) are mixed in a 5 mL microwave tube with a stir bar and the mixture is heated to 100° C. in microwave reactor for 30 min. The mixture is poured to water (10 mL) and extracted with EtOAc (10 mL×3). The organic extracts are washed with water (20 mL×1), brine (20 mL×1) and dried over anhydrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 20%) to give 104 mg of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][S:13]([CH2:16][CH:17]([O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH3:20])(=[O:15])=[O:14])(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:22]([O:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][S:13]([NH2:12])(=[O:15])=[O:14])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC(CS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CS(N)(=O)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 84.3 %

Procedure:
Trifluoroacetic acid (200 ml) was added to N-t-butyl-2-benzoyloxy-1-pentanesulfonamide (132.8 g). After stirring for 32 hours at room temperature, the solution was concentrated under reduced pressure. After further adding trifluoroacetic acid (100 ml) and stirring for 16 hours at room temperature, the solution was concentrated under reduced pressure to obtain an oily substance (165 g). This substance was dissolved in ethyl acetate and, after adding a saturated aqueous solution of sodium hydrogencarbonate, the solution was stirred for 15 minutes at room temperature. The organic layer was washed with 5% brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2-benzoyloxy-1-pentanesulfonamide (92.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][C:14]2[C:15]([C:18]#[N:19])=[N:16][CH:17]=[C:12]([S:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: Cc1ncccc1O
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 2 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
To 600 ml of DMF in a 4 neck 3000 mL round bottom flask equipped with an overhead stir mechanism under nitrogen was added 2-methylpyridin-3-ol (71.8 g, 658 mmol) and the reaction was cooled to 2° C. Sodium hydride (60%, 26.3 g, 658 mmol) was added over a period of 30 minutes at a rate such that the internal temperature did not exceed 10° C. The reaction was stirred while warming to ambient temperature for 1 hour. 5-Bromo-3-nitropicolinonitrile (150 g, 658 mmol) in a solution of 400 mL of DMF was added in two portions and the reaction held at ambient temperature for 1.5 hour. To the reaction at ambient temperature was added pyridine-2-thiol (73.1 g, 658 mmol) as a solid in portions and the reaction was stirred for 15 minutes to dissolve the material. The reaction was cooled to 3° C. and sodium hydride (26.3 g, 658 mmol) again was added in portions over 35 minutes such that the internal temperature did not go above 10° C. The reaction was removed from the ice bath and warmed to ambient temperature while stirring for 12 hours. The reaction was diluted with 4 volumes (8 L) of brine and stirred for 30 minutes, at which point solid formed. The solid was filtered off and the filtrate was extracted with MTBE (10 L total). The MTBE phase was concentrated in vacuo. The solid was combined with concentrated material and dissolved in ethyl acetate (3 L). The EtOAc was washed with brine (4×1 L), dried over MgSO4, filtered and concentrated in vacuo. The solid that formed was ground into a powder and dried in vacuo for 4 hours. The material was taken up in 30 mL of MTBE/10 g of product and the reaction was stirred for 30 minutes. The solid was filtered and dried in vacuo (2 hours). The mother liquor was concentrated and triturated with MTBE (same dilution rate). The solids were combined and dried for 3 hours in vacuo to yield 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g, 85%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:13][CH:9]1[CH2:8][CH2:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:11]([O:12][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[CH2:10]1
Reactant: CCOC(=O)C1CCC(C)CC1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-methyl-2-cyclohexanone-1-carboxylate (50 g, 0.27 mol) in dichloromethane (500 ml) at −10° C. was added N,N-diisopropylethylamine (52 ml, 0.3 mol) followed by dropwise addition of trifluoromethanesulphonyl chloride (57 ml, 0.3 mol) keeping the temperature between −5 and −100° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. TLC showed 80% reaction, it was cooled to −5° C. and more N,N-diisopropylethylamine (14 ml, 0.1 mol) was added followed by trifluoromethanesulphonyl chloride (15.5 ml, 0.1 mol) and the reaction mixture was stirred for 15 hours at room temperature. The mixture was washed with cold water (2×200 ml), cold saturated sodium bicarbonate (2×200 ml) and brine (1×200 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the required product (85 g) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.04 (3H, d, J=6.5 Hz), 1.43 (3H, m), 1.73-2.09 (4H, m), 2.39-2.63 (3H, m), 4.25 (2H, m).
Reaction SMILES: [CH3:1][N:2]([S:27]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(=[O:29])=[O:28])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]3([CH2:21][CH2:20][N:19]([CH2:22]C(OC)=O)[CH2:18][CH2:17]3)[CH2:15][N:16]=1)=[CH:8]2.[CH3:35][Li].C([O:39][CH2:40][CH3:41])C.[Cl-].[NH4+]>O1CCCC1>[OH:39][C:40]([CH3:41])([CH3:35])[CH2:22][N:19]1[CH2:20][CH2:21][C:14]2([S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[N:2]([CH3:1])[S:27]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)(=[O:29])=[O:28])=[N:16][CH2:15]2)[CH2:17][CH2:18]1
Reactant: COC(=O)CN1CCC2(CC1)CN=C(c1cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Reactant: [Li]C
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC4(CCN(CC(C)(C)O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of methyl (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1-thia-3,8-diazaspiro[4.5]dec-2-en-8-yl)acetate (211 mg) in tetrahydrofuran (3 mL) was added 1.5M methyllithium-diethyl ether solution (2 mL) at room temperature, and the mixture was stirred for 30 min. Saturated aqueous ammonium chloride solution 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 residue was subjected to silica gel column chromatography to give the title compound (92 mg, yield 44%) as white crystals from a fraction eluted with ethyl acetate:hexane=1:3. melting point 191° C.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Na+:6].[Na+].[Na+].[O:9]=[P:10]12[O:21]P3(O[P:12]([O:14]P(O3)([O:17]1)=O)(=[O:13])[O:11]2)=O>>[O-:2][P:1]([O:5][P:12]([O:11][P:10]([O-:21])([O-:17])=[O:9])([O-:14])=[O:13])([O-:4])=[O:3].[Na+:6].[Na+:6].[Na+:6].[Na+:6].[Na+:6]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]

Procedure:
The loaded organic extract fed to stripping column 20 was treated with water countercurrently to extract P2O5 values and yielded a purified acid stream containing the equivalent of 8,978 pounds per hour of P2O5 and 5.6 pounds per hour of fluoride ion. This purified acid was passed through line 22 into make up reactor 24 along with enough sodium carbonate to yield 7,497 pounds per hour of sodium ion. The resulting reaction yielded an ortho liquor containing a sodium orthophosphate solution having a Na:P of about 1.67, a P2O5 content of 9,127 pounds per hour and fluoride ion in amounts of 9.2 pounds per hour. The ortho liquor was removed from reactor 24 through line 28 and introduced into a spray dryer 30. The ortho liquor was heated by downwardly directed burners to yield 8,829 pounds per hour of sodium tripolyphosphate containing not more than about 1 pound per hour of fluoride ion. The sodium tripolyphosphate product was removed through line 34 and contained about 100 ppm of fluoride, which is considered acceptable for all but food grade purposes.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl>[CH2:1]([C:8]1[N:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:23])[C:18]([OH:21])=[CH:19][CH:20]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3-Benzyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl-]-[1,2,4]oxadiazole (compound of Example 4, Method A, Step 1; 0.180 g, 0.55 mmol) was dissolved in dichloromethane (7 mL) and cooled to −78° C. A solution of boron tribromide (0.41 mL, 4.40 mmol) in dichloromethane (4 mL), which was cooled to 0° C., was added slowly over a period of 15 min. After 3 h, the reaction mixture was warmed to room temperature and stirred for 3 h. After completion of the reaction, the mixture was quenched by dropwise addition of methanol (15 mL) at 0° C. and stirred for 20 min at room temperature. The solvent was evaporated and the residue obtained was redissolved in 10% methanol in chloroform at 0° C., followed by stirring with solid sodium carbonate to maintain pH ˜8. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)on2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(-c3ccc(Cl)cc3)on2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of methyl 4-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate (1.35 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (20 ml) and methanol (10 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (10 ml) was added. The crystals were collected by filtration, and recrystallized from tetrahydrofuran-hexane to give 4-[5-(4-chlorophenyl)-3-isoxazolyl]benzoic acid (1.19 g, yield 92%) as colorless crystals. melting point: >300° C.
Reaction SMILES: C([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([CH:28]([OH:56])[C@@H:29]([NH:37][C:38](=[O:55])[C@H:39]([CH:52]([CH3:54])[CH3:53])[NH:40][C:41](=[O:51])[CH2:42][NH:43]C(OC(C)(C)C)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])(OC(C)(C)C)=O.CO>ClCCl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([CH:28]([OH:56])[C@@H:29]([NH:37][C:38](=[O:55])[C@H:39]([CH:52]([CH3:54])[CH3:53])[NH:40][C:41](=[O:51])[CH2:42][NH2:43])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H](NC(=O)CN)C(=O)N[C@@H](Cc1ccccc1)C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CN)C(C)C
Yield: 91 %

Procedure:
Using the procedure of Example 6F but replacing the resultant compound of Example 6E with the resultant compound of Example 140 provided, after silica gel chromatography using 10% methanol in dichloromethane, 48.7 mg (91%) of the desired compound as a white solid. 1H NMR (DMSO-d6) δ0.70-0.8-3 (four d, 12H), 1.78 (m, 1H), 1.96 (m, 1H), 2.62 (m, 2H), 2.74 (br d, 2H), 2.97 (m, 1H), 3,4 6-3.87 (m, 5H), 4.02 (m, 2H), 4.21 (m, 1H), 5.33 (br d, 1H), 7.08-7.26 (m, 10It), 7.57 (br d, 2H), 7.67 (br d, 1H), 7.86 (br d, 1H). Mass spectrum: (M+H)+ =583.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16]/[C:17](/[CH3:25])=[C:18](/[F:24])\[C:19](OCC)=[O:20]>C(OCC)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:19](=[O:20])[C:18]([F:24])=[C:17]([CH3:25])[NH:16][C:13]2=[O:14])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(F)=C(/C)N
Solvent: CCOCC
Product: Cc1[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c1F
Reaction time: 16 h

Procedure:
A solution of 6.00 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in 100 ml of absolute diethyl ether is added dropwise while stirring at room temperature during 1 hour to a solution of 4.00 g of ethyl 3-amino-2-fluorocrotonate and the reaction mixture is stirred for 16 hours. The mixture is then evaporated to dryness under reduced pressure, the residue is dissolved in 50 ml of absolute dimethylformamide and the solution is added while stirring at room temperature to a solution of 1.31 g of a 55% sodium hydride dispersion in 50 ml of dimethylformamide and 100 ml of isopropyl alcohol. The mixture is subsequently stirred at room temperature for 4 hours, adjusted to pH ~4 with concentrated acetic acid and concentrated under reduced pressure. The residue is poured into 1 l of water and extracted twice with 200 ml of ethyl acetate each time, and the organic phases are washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane as the eluent and subsequently recrystallized from ethyl acetate/diethyl ether. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -fluoro-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 162°-164° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 70.1 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at 10°-15° C. Successively 9.2 g (0.11 mole) of sodium acetate was added over 30 minutes at the same temperature. The reaction was carried out for 3 hours with stirring at the same temperature. Thereafter 75.3 g of water was added and cooled to 0°-5° C. Precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 30.0 g (70.1% yield on L-phenylalanine methyl ester hydrochloride).