Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1>O.CCO.[Fe]>[Cl:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[NH2:12]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Yield: 100 %

Procedure:
According to Scheme 3 Step 2: A suspension of iron (5.07 mmol, 283 mg), acetic acid (1.22 mmol, 70 μL) and of 2-chloro-1-(3-chlorophenoxy)-4-nitrobenzene (1.02 mmol, 288 mg) in water/EtOH (1:1, 8 mL) was stirred at 80° C. for 30 minutes. After evaporation of EtOH, the aqueous phase was basified with a saturated solution of NaHCO3 and was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 3-chloro-4-(3-chlorophenoxy)aniline (1.02 mmol, 258 mg, 100%) as a solid. The product was used without further purification.
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[F:36][C:37]1[C:38]([NH:47][C@H:48]2[CH2:52][CH2:51][CH2:50][C@@H:49]2[NH2:53])=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1.[CH3:54][C:55]1[N:59]=[C:58]([C:60]2[CH:68]=[CH:67][CH:66]=[CH:65][C:61]=2[C:62](O)=[O:63])[O:57][N:56]=1>>[F:36][C:37]1[C:38]([NH:47][C@H:48]2[CH2:52][CH2:51][CH2:50][C@@H:49]2[NH:53][C:62](=[O:63])[C:61]2[CH:65]=[CH:66][CH:67]=[CH:68][C:60]=2[C:58]2[O:57][N:56]=[C:55]([CH3:54])[N:59]=2)=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:42]=1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ncc(C(F)(F)F)cc2F)n1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34: 450 mg, 1.71 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 349 mg, 1.71 mmol) except after the reaction was complete it was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit. The organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then purified by reverse phase column chromatography (C18 silica, 0-100% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.[SH-:15].[Na+]>O>[SH:15][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: [SH-]
Reactant: COC(=O)c1nc2nccc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2nccc(S)n2n1
Reaction time: 2 h

Procedure:
The product obtained in Step 2 was added all at once at 0° C. to a solution of sodium hydrosulfide (20 g) in 450 ml of water with stirring under a nitrogen stream. The mixture was stirred at 0° C. for one hour, then for two hours at room temperature, and the resulting yellow solution was washed with 100 ml of ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid to pH 2.0, and the formed crystals were collected by filtration and washed with 200 ml of ethanol, affording 18 g of the objective compound as faint yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:28]=1[CH2:29][N:30]([C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1)[S:31]([C:34]1[CH:39]=[CH:38][C:37](F)=[C:36]([F:41])[CH:35]=1)(=[O:33])=[O:32]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:37]2[CH:38]=[CH:39][C:34]([S:31]([N:30]([CH2:29][C:28]3[CH:48]=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:27]=3[O:26][CH3:25])[C:42]3[N:43]=[CH:44][CH:45]=[CH:46][N:47]=3)(=[O:32])=[O:33])=[CH:35][C:36]=2[F:41])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH:7]=1
Reactant: O=c1[nH]c2cc(-c3cc(Cl)ccc3O)ccc2o1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2ccc(F)c(F)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3ccc4oc(=O)[nH]c4c3)c(F)c2)c(OC)c1
Temperature: 75 °C

Procedure:
To a mixture 5-(5-chloro-2-hydroxyphenyl)benzo[d]oxazol-2(3H)-one (0.068 g, 0.26 mmol) and potassium carbonate (0.054 g, 0.39 mmol) in dimethylsulfoxide (2 mL) was added N-(2,4-dimethoxybenzyl)-3,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide (0.114 g, 0.27 mmol). The reaction mixture was heated at 70-80° C. for 16 h, allowed to cool to ambient temperature and partitioned between ethyl acetate (100 mL) and water (10 mL). The organic phase was washed with brine (2 5 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-100% gradient of ethyl acetate in hexanes to give 4-(4-chloro-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-3-fluoro-N-(pyrimidin-2-yl)benzenesulfonamide as an orange solid which was carried forward without further purification: MS (ES+) m/z: 662.9 (M+1), 664.9 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCOCC5)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCOCC3)sc2C)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a mixture of ethyl (4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.43 g), tetrahydrofuran (12 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at 50° C. for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (1.5 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give [4-(4-{[2-methoxy-4-({[4-{(E)-2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)phenoxy]methyl)-5-methyl-1,3-oxazol-2-yl}phenyl]acetic acid as crystals (0.22 g, yield 53%). Recrystallization from tetrahydrofuran-hexane gave orange prism crystals. melting point: 171-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Temperature: 80 °C
Yield: 53.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888 mg, 4 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8 mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture was heated at 80° C. for 3 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography (ethyl acetate/hexane gradient) then purified again by column chromatography (methylene chloride/ethyl acetate gradient) to yield 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (738 mg, 53.5% yield): 1H NMR (CDCl3): δ 7.64 (dd, 1H), 7.22 (dd, 1H), 5.64 (br s, 2H), 4.01 (s, 3H), 3.99 (d, 3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH:5]([CH2:6][CH:7]=[CH2:8])[C:4]([OH:20])=[O:3])=[O:19])=[CH:16][CH:15]=1
Reactant: C=CCC(NC(=O)c1ccc(OC)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCC(NC(=O)c1ccc(OC)cc1)C(=O)O
Reaction time: 3 h

Procedure:
10.56 g of the above prepared 2-(4-methoxy-benzoylamino)-pent-4-enoic acid ethyl ester (38.1 mmol) was dissolved in 120 ml of THF/EtOH=1/1 and treated at 0° with 38 ml of 2N NaOH. The reaction mixture was kept at this temperature for 3 h. It was then poured onto crashed ice/HCl, extracted twice with AcOEt, washed with brine, and dried over natrium sulfate. Evaporation of the solvents, followed by crystallisation from AcOEt at −20°, yielded 8.41 g of the title acid as white crystals of m.p. 121-124°.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[CH2:8][CH2:7][NH:6]1)[CH3:4].C(N(CC)C(C)C)(C)C.[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:33][C:34]([N:6]1[CH2:7][CH2:8][C:9]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[CH:5]1[CH2:3][CH3:4])=[O:35])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCC1NCCc2nccnc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1c2nccnc2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Ethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine dihydrochloride (Intermediate 32, 26 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (DMF, 0.75 mL) containing N,N-diisopropylethylamine (0.046 mL, 34 mg, 0.26 mmol). (3R)-3-(tert-Butoxycarbonylamino)4 (2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 36 mg, 0.11 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and a portion of molecular sieve pellets (4 Å) were added, followed 10 min later by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol). After stirring for 16 h at room temperature, the mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was washed with saturated aqueous brine (10 mL) and the aqueous layers were extracted in succession with ethyl acetate (25 mL). The organic layers were dried over sodium sulfate, decanted, and evaporated. Purification by flash column chromatography (silica gel, 15-20% ethyl aceate/0.75-1.0% methanol/dichloromethane) gave the title compound as a mixture of diastereomers. Separation was accomplished by EPLC using a Chiralcel OJ column, eluting with 8% ethanol in hexanes. The first-eluting diastereomer was used in Step B to produce the more active final product. LC/MS: 501 (M+Na).
Reaction SMILES: [IH:1].CS[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1.O.[NH2:11][NH2:12]>C(O)C>[IH:1].[NH:11]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1)[NH2:12]
Reactant: NN
Reactant: CSC1=NCCCC1
Agent: I
Solvent: CCO
Solvent: O
Product: NNC1=NCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 6.43 g portion of 3,4,5,6-tetrahydro-2-(methylthio)-pyridine, hydroiodide was added to an ice-cold solution of 1.25 ml of hydrazine hydrate in 35 ml of ethanol. The suspension was stirred at ice bath temperature for 30 minutes, then the solid was collected, washed with ethanol and ether and dried, giving 3.5 g of 2-hydrazino-3,4,5,6-tetrahydropyridine, hydroiodide, which was converted to the monohydronitrate by treatment with silver nitrate in water.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]2=[O:18])[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[O:18]=[C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:3][CH2:4]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2cc(C(F)(F)F)ccc2=O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(C(F)(F)F)ccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(4-oxo-cyclohexyl)-5-trifluoromethyl-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH:1](=[C:8](/[CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])\[C:9]([OH:11])=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:25]>C(O)C>[CH:1](=[C:8](/[CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])\[C:9]([O-:11])=[O:10])/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:25]
Reactant: O=C(O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (31 mg) in ethanol (0.3 ml) was added 1N sodium hydroxide solution (0.1 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give 30 mg of sodium (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless amorphous solid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1>>[OH:1][C@H:2]([CH2:3][NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:21][CH:22]=1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
In this case, 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)dione (II) is reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-phenyl]amino}propyl)-1H-isoindole-1,3(2H)dione (V). Subsequently, (V) is converted with a phosgene equivalent into 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H-isoindole-1,3(2H)dione (VI). Elimination of the phthalimide protective group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (VII) which is finally reacted with 5-chlorothiophene-2-carbonyl chloride (IV) to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C:3]1([CH3:17])[CH3:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:16][C:3]1([CH3:17])[C:2](=[O:1])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](O)C(C)(C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC(=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of tert-butyl ((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)carbamate (2 g crude) in DCM (110 mL) was added Dess-Martin periodinane (4.24 g, 10 mmol) keeping the temperature below 5° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with DCM and washed with saturated solution of sodium bicarbonate. The separated organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography column (6% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (1.10 g, 4.56 mmol, 65% yield over two steps). MS (ESI) m/z 242.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][N:13]=[C:14]([NH:16][N+:17]([O-:19])=[O:18])[NH2:15])=[O:7])([CH3:4])[CH3:3].Cl.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)[CH3:25].C(OC1C=CC(C#N)=CC=1)C.Cl.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>[Pd].C(Cl)Cl.C(N(CC)CC)C>[NH2:15][C:14](=[N:16][N+:17]([O-:19])=[O:18])[NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:20]([NH:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:24][CH3:25])=[CH:28][CH:29]=1)=[O:22])[NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CCOc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN=C(N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: CCOc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)OC(C)(C)C)cc1
Yield: 77 %

Procedure:
Prepared analogously to Example 8a) from Boc-D-Arg-(NO2)-OH, 4-ethoxybenzenemethylamine-hydrochloride (mp.: 262°-264° C.; from 4-ethoxybenzonitrile by catalytic hydrogenation in the presence of palladium/animal charcoal and aqueous hydrochloric acid), triethylamine and TBTU in a yield of 77% of theory. IR (CH2Cl2): 1730 cm-1 (ester-C=O) 1675 cm-1 (amide C=O) 1510 cm-1 (amide II)
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>O>[C:12]1([C:9]2[C:8]3[CH:18]=[C:4]([CH2:3][C:1]4[NH:21][N:20]=[N:19][N:2]=4)[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1ccc2occ(-c3ccccc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1
Temperature: 110 °C

Procedure:
A mixture of 4.6 g. (0.02 mole) of 5-cyanomethyl-3-phenylbenzofuran, 1.5 g. of sodium azide and 1.2 g. of ammonium chloride in 15 ml. of N,N-dimethylformaide is heated at 110° C. for 20 hours. The reaction mixture is poured into 200 ml. of water and stirred. The mixture is extracted with 50 ml. of chloroform. The extracts are washed with water, then dried over magnesium sulfate. Evaporation provides a residue which is recrystallized from ethyl acetate to provide 3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[F:36][C:35]([F:37])([F:38])[C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:24][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CCCCCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
3-{4-[1-(4′-Trifluoromethyl-biphenyl-4-yloxymethyl)-heptyl]-benzoylamino}-propionic acid methyl ester (50 mg, 0.09 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) is added. The reaction may be monitored by HPLC. After 3 h the reaction is neutralized with 5N HCl (1 mL) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated to provide the title compound. MS (ES): 540.3 [M+H]−.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[N:16]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:23][O:22][C:20]([CH:19]1[CH2:18][CH2:17][N:16]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C:5]2[CH:6]=[C:7]([C:12]([F:14])([F:13])[F:15])[C:8]([CH2:10][CH3:11])=[CH:9][C:4]=2[C:3]1=[O:2])=[O:21]
Reactant: CCc1cc(C(=O)OC)c(N(CCCC(=O)OC)C(=O)OC(C)C)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCC(C(=O)OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a 0° C. cooled solution of 5-ethyl-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-4-trifluoromethyl-benzoic acid methyl ester (39.72 g, 91.64 mmol) in toluene add potassium tert-butoxide (24.68 g, 219.92 mmol). Stir the mixture at room temperature for 30 min under an atmosphere of N2. Quench the mixture with 2 N HCl (150 mL) and dilute with ethyl acetate (1.5 L). Wash with water (2×400 mL) and brine (500 mL). Dry the organic layer over anhydrous sodium sulfate and filter through Celite to provide the title compound as a yellow viscous oil (31.25 g, 85%): TLC Rf 0.63 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.0-1.40 (m, 9H), 2.31-2.55 (m, 2H), 2.88-2.94 (m, 1H), 3.75 (s, 3H), 3.89 (s, 3H), 4.89-4.93 (m, 1H), 5.11-5.12 (m, 1H), 7.43 (s, 1H), 7.91 (s, 1H).