Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[PH:22](=[O:24])[OH:23])([O-:3])=[O:2].[PH2](Cl)=O.O[N:29]=[C:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[PH:22]([O:23][N:29]=[C:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:24])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)=NO
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[PH](=O)O
Agent: O=[PH2]Cl
Product: CCOC(=O)C(C)=NO[PH](=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, the phosphinic acid is halogenated to the corresponding phosphinic chloride, which is then reacted with ethyl 2-hydroxyiminopropionate to yield ethyl 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][N:6]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]2=[O:20].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CS(C)=O>[CH2:23]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[C:5](=[O:20])[N:6]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:7]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1c2cc(Cl)ccc2NCN1CCN1CCOCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2cc(Cl)ccc2N(Cc2ccccc2)CN1CCN1CCOCC1
Reaction time: 0.5 h

Procedure:
3.50 Grammes (11.8 mmoles) of 6-chloro-2,3-dihydro-3-[2-(4morpholinyl)ethyl]-4(1H)-quinazolinone are dissolved in 20 ml of a mixture of toluene and dimethylsulfoxide in a ratio 5:1. The solution is dripped into a suspension containing 340 mg (14.2 mmoles) of 95% sodium hydride in 30 ml of dimethylsulfoxide and the reaction mixture is kept at 40° C. for 30 minutes. Afterwards a mixture containing 2.11 ml (17.7 mmoles) of benzylbromide and 60 ml of toluene is dripped into the solution and the suspension is kept at 40° C. for 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23].Cl[CH2:25][C:26]#[N:27].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]#[N:27])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(CC#N)C3=O)CC2)cc1C
Temperature: 70 °C

Procedure:
To a solution of (R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (6.32 mmol, 2.0 g) and chloroacetonitrile (6.32 mmol, 0.48 g) in THF (50 mL) was added sodium hydride (60%, 9.48 mmol, 0.38 g) and heated to 70° C. for 30 min. The reaction was allowed to cool to ambient temperature and dried under vacuum. Flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white residue (1.1 g, 49% yield). Calculated molecular formula=C20H25N3O3=355.4406. found MS (ESI) m/e 356.1978 (M+H+); analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.591 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1.[CH3:24][S:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1COCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:30]([C:29]2[CH:33]=[CH:34][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)=[O:31])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1ccc(F)cc1
Reactant: CSc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(SC)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
1 N Lithium bis(trimethylsilyl)amide (20 mL, 20 mmol) was added dropwise to a solution of ethyl (4-fluorophenyl)acetate prepared according to the method of Example 1A, (3.84 g, 20 mmol) in THF (20 mL) at −78° C. After 15 minutes the mixture was treated dropwise with a suspension of crude 4-(methylthio)benzoyl chloride (3.7 g, 20 mmol) in THF (50 mL), and the resulting mixture was stirred at −78° C. for 60 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH2Cl2-ethyl acetate) to provide the desired product (yield: 4.55 g; 69%). MS (DCI-NH3) m/z 333 (M+H)+, 350 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ1.25 (m, 3H), 2.50 (s, 3H), 4.20 (m, 2H), 5.53 (s, 1H), 7.03 (t, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 7.38 (m, 2H), 7.85 (d, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)[C:10]([F:13])([F:12])[F:11].[CH2:27]([O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:27]([O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[CH:19]4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cccc4cnccc34)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl -propyl)-phenol (40 mg) in N,N-dimethylacetamide (1 ml) were added ethyl-4-(bromomethyl)benzoate (18 mg) and cesium carbonate (23 mg). The mixture was stirred for 1 h at room temperature. Ice water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (28 mg) as an off-white solid. MS (m/e)=544.2 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2c(c3cc(OCc4ccccc4)ccc3n2Cc2ccccc2)C1
Temperature: 10 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A mixture of intermediate (1) (0.09 mol) in N,N-dimethylformamide (200 ml) was stirred at 10° C. under a N2 flow. Sodium hydride (60%; 0.1 mol) was added portionwise. The mixture was stirred for 1 hour at room temperature, then it was cooled to 5° C. Benzylbromide (0.1 mol) was added dropwise. Stirring was continued for 2 hours. The mixture was cooled to 10° C. and poured out into cold water (500 ml). This mixture was extracted with CH2Cl2 (2×250 ml). The separated organic layer was washed with water (100 ml), dried, filtered and the solvent was evaporated. The solid residue was washed with CH3CN (50 ml), cooled and the resulting precipitate was filtered off and dried, yielding 30.0 g (76%) of ethyl 1,3,4,5-tetrahydro-8-(phenylmethoxy)-5-(phenyl-methyl)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 2).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C[O:18][C:19](=[O:23])[CH:20](Cl)[CH3:21].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:20]([CH3:21])[C:19]([OH:23])=[O:18])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: COC(=O)C(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 127.5 parts of 4-(2',4'-dichlorophenoxy)-phenol and 69.2 parts of 2-chloropropionic acid methyl ester in 650 parts of xylene, 100 parts of 50% sodium hydroxide solution are added dropwise at about 110° C. and 500 mbar while simultaneously distilling off the azeotropic mixture of water and methanol. The addition being complete, stirring is continued for 15 minutes at 110° C. Work-up is as described in Example 1. 163.3 Parts of 2-[4'-(2",4"-dichlorophenoxy)-phenoxy]propionic acid are obtained. The content of pure final product is 99.8%, corresponding to 99.6% of theory. The residual amount of 4-(2',4'-dichlorphenoxy)-phenol is 0.15%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]2=[N:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 90 °C
Yield: 75.1 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (378 mg, 1.272 mmol), (chloromethanetriyl)tribenzene (426 mg, 1.53 mmol) and triethylamine (193 mg, 1.91 mmol) in dry DMF (20 mL) was heated to 90° C. for 16 hours. Reaction mixture was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc: petroleum ether=1:15) to afford 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (515 mg, 75%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.29 (s, 1H), 8.01 (s, 1H), 7.29-7.26 (m, 10H), 7.13-7.11 (m, 5H), 1.51 (s, 9H). LCMS: (M+H)+=539.
Reaction SMILES: [Na].[O:2]=[C:3]1[CH:10]2[CH2:11][C:6]3([O:13][C:14](=[O:22])[C:15]([F:21])([F:20])[S:16]([OH:19])(=[O:18])=[O:17])[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[Cl-].[C:24]1([S+:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C(#N)C>[O:2]=[C:3]1[CH:10]2[CH2:11][C:6]3([O:13][C:14]([C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:17])=[O:18])=[O:22])[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:37]1([S+:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)O)(C3)C2
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)[O-])(C3)C2

Procedure:
To 5.4 parts (35.6% purity) of the sodium salt of difluorosulfoacetic acid-4-oxo-1-adamantyl ester, a mixture of 16 parts of acetonitrile and 16 parts of ion-exchanged water was added. To the mixture, a solution of 1.7 parts of triphenylsulfonium chloride, 5 parts of acetonitrile, and 5 parts of ion-exchanged water was added. The resultant mixture was stirred for 15 hours, then concentrated, and extracted with 142 parts of chloroform. The organic layer was washed with ion-exchanged water, and the resulting organic layer was concentrated. The concentrate was washed with 24 parts of tert-butyl methyl ether, giving 1.7 parts of triphenylsulfonium 4-oxo-1-adamantyloxycarbonyldifluromethanesulfonate (B1) in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].CC1CCCCC1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)CCl
Reactant: OCCc1ccc(F)cc1
Solvent: CC1CCCCC1
Product: O=C(O)COCCc1ccc(F)cc1
Yield: 78.8 %

Procedure:
7.0 g of 4-fluorophenethyl alcohol were reacted with 4.73 g of chloroacetic acid in a manner analogous to that described in Example 1(a) to give 7.8 g (79%) of 2-(4-fluorophenyl)ethoxyacetic acid of melting point 82°-85° C. (from methylcyclohexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Cl:20][C:18]1[CH:17]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])[CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3,5-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (42.2 mg) with purity >90%. LCMS (pos) m/z 395.0, 397.0.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[Li]C(C)(C)C.CCCCC.[N+:24]([C:27]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=1)([O-:26])=[O:25]>C1COCC1>[CH3:38][O:37][C:29]1[C:30]([O:35][CH3:36])=[CH:31][C:32]([CH:33]([C:2]2[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=2)[OH:34])=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=1
Reactant: COc1cc(I)cc(OC)c1OC
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])cc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A flame-dried round-bottomed flask under N2 atmosphere was charged with 5-iodo-1,2,3-trimethoxybenzene (2.92 g, 9.93 mmol) and THF (31 mL) was added. The solution was cooled down to −78° C. and 1.5 M solution of t-BuLi in pentane (13.6 mL, 20.57 mmol) was added dropwise. The mixture was stirred for 1 h and transferred via canula to a precooled (−78° C.) solution of 6-nitroveratraldehyde (2.02 g, 9.57 mmol) in THF (12 mL) under N2 atmosphere. The resulting mixture was stirred for 2 h and slowly warmed up to 0° C., quenched with saturated aqueous solution of NH4Cl and allowed to warm-up to rt. Solvent was removed in vacuo and the residue was partitioned between water and DCM. Organic layer was collected and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc/DCM (9:91) affording the title compound 241 (1.46 g, 40% yield) 1H NMR (CDCl3) δ (ppm): 7.61 (s, 1H), 7.16 (s, 1H), 6.58 (s, 2H), 6.45 (s, 1H), 6.09 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H). m/z: 402.4 (MH+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(C=CC2CCC(c3ccc(C#N)cc3)CC2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CC[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1

Procedure:
7.0 g of p-[4-[2-(p-pentylphenyl)vinyl]cyclohexyl]benzonitrile were dissolved in 350 ml of toluene, treated with 1.4 g of palladium/carbon (10%) and hydrogenated at room temperature and normal pressure until the hydrogen uptake came to a standstill. The crude p-[trans-4-[2-(p-pentylphenyl)ethyl]cyclohexyl]benzonitrile obtained after filtering off the catalyst and concentrating the filtrate was recrystallized twice from ethanol. Yield 4.2 g; m.p. (C--N) 61.5° C., cl.p. (N--I) 126° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)=[CH:9][C:7]=2[CH:8]=1)(=[O:31])=[O:30]
Reactant: N#Cc1cccc(-c2ccc3oc(CCO)cc3c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 μL, 0.72 mmol) were dissolved into CH2Cl2 (3 mL) and cooled to 0° C. The solution was treated with methanesulfonyl chloride (55 μL, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 μL, 0.13 mmol) and triethylamine (10 μL, 0.072 mmol) were added. The mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na2SO4), concentrated, and used without further purification in the next step.
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H](CCCNC(=N)N)N[N+]([O-])=O)C1C=CC=CC=1.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C([O:43][C:44](=[O:67])[C@H:45]([CH2:60][CH2:61][CH2:62][NH:63][C:64](=[NH:66])[NH2:65])[N:46]([N+]([O-])=O)[C:47](=[O:56])[CH:48]([CH3:55])[CH2:49][CH2:50]C(OC)=O)C1C=CC=CC=1.COC(CCC(C)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)=O.C(CCC(C)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)(O)=O>>[C:9]([CH:61]([CH2:62][NH:63][C:64](=[NH:66])[NH2:65])[CH2:60][C@@H:45]([C:44]([OH:43])=[O:67])[NH:46][C:47](=[O:56])[CH:48]([CH3:55])[CH2:49][CH3:50])([OH:22])=[O:8]
Reactant: COC(=O)CCC(C)C(=O)N([C@@H](CCCNC(=N)N)C(=O)OCc1ccccc1)[N+](=O)[O-]
Reactant: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: CC(CCC(=O)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: COC(=O)CCC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Product: CCC(C)C(=O)N[C@@H](CC(CNC(=N)N)C(=O)O)C(=O)O

Procedure:
By substituting nitro-L-arginine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23, and then treating the product by the procedures of Examples 24 and 26, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-nitro-L-arginine benzyl ester, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-L-arginine, and Nα -(4-carboxy-2-methylbutanoyl)-L-arginine are obtained.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5](CC)[CH2:6][CH2:7][N:8]1[C:25](=[S:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:27])C.O>C(O)(C(F)(F)F)=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:27])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[C:25](=[S:26])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 70 °C
Yield: 91.9 %

Procedure:
Compound 4 (17.5 mg, 0.042 mmol) was dissolved in TFA (2 ml), to give a clear red solution. Water (0.5 ml) was added and the mixture was heated at 70° C. overnight. Additional water (2 ml) was added and the solvents of the reaction mixture reaction mixture were evaporated under reduced pressure to afford Compound 5 as a yellow-brown solid (15 mg, 90% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][C:15]=1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(-c2ccc(Cl)c(CNC(=O)OC(C)(C)C)c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Yield: 100.7 %

Procedure:
Methyl 3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-chlorophenyl)benzoate (199 mg) was dissolved in 3 ml of methanol, 100 mg of 10% palladium-carbon was added thereto, and the mixture was stirred at room temperature for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, then washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 182 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1C.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Reactant: COc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2OC)cc1
Reaction time: 23 h
Yield: 100.8 %

Procedure:
To a stirred solution of ethyl 4-amino-3-methylphenylacetate (1.32 g, 7.37 mmol) and triethylamine (205 ml, 1.47 mmol) in THF (20 ml) was added 2-methoxyphenyl isocyanate (980 ml, 7.37 mmol), and the resulting mixture was stirred for 23 h. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give precipitate, which was collected to give ethyl 4-[N′-(2-methoxyphenyl)ureido]phenylacetate (2.44 g, quant.) as a white crystalline material. mp 107-109° C.; 1H-NMR (CDCl3) δ1.26 (t, J=7.1 Hz, 3 H), 3.56 (s, 3 H), 3.79 (s, 3 H), 4.15 (q, J=7.1 Hz, 2 H), 6.82-6.85 (m, 1 H), 6.91-7.00 (m, 2 H), 7.08 (s, 1 H), 7.17 (d, J=8.5 Hz, 2 H), 7.27 (d, J=8.6 Hz, 2 H), 7.33 (s, 1 H), 8.07-8.10 (m, 1H); MS (ESI) m/z 329 (M30 +H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:10])[NH:11][CH:12]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1ncc(Cl)cc1N
Product: O=c1[nH]cnc2cc(Cl)cnc12
Temperature: 25 °C

Procedure:
A suspension of 3-amino-5-chloro-pyridine-2-carboxamide (3.43 g, 20 mmole) in triethyl orthoformate (50 ml) was refluxed for 3 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane. The title compound was obtained as a white solid (3.4 g, yield 94%) which was characterized by its mass spectrum as follows: MS (m/z): 182.1 ([M+H]+, 100).