Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[F:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([O:12][C:11]2[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=2)=[N:7][CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: N#Cc1nc(F)cnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)cnc1Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.3 %

Procedure:
In 30 mL of dimethylformamide was dissolved 3.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then, 2.6 g of hydroquinone, followed by 6.5 g of potassium carbonate, was added at an ice-cooled temperature, and the mixture thus obtained was stirred at room temperature for 15 minutes. A mixture of 30 mL of ethyl acetate and 60 ml of water was added to the reaction mixture, pH was adjusted to 5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 0.75 g of 6-fluoro-3-(4-hydroxyphenoxy)-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[C:22]([CH2:26][CH2:27][C:28](Cl)=[O:29])([O:24][CH3:25])=[O:23].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]([O:24][CH3:25])=[O:23])[CH:11]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COC(=O)c1ccc(I)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Nc1cc(I)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
To a solution of methyl 2-amino-4-iodobenzoate (17 g, 61.3 mmol) in DCM (200 mL), was added DIEA (10.6 mL, 64.4 mmol) and DMAP (37.5 mg, 0.31 mmol). To this solution was added 3-(carbomethoxy)propionyl chloride (8.3 mL, 67.4 mmol) dropwise, and the reaction mixture was allowed to stir at rt for 2 h. To the reaction mixture was then added H2O (80 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (2×100 mL). The organic solutions were combined, washed with H2O (2×100 mL) and brine (1×100 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-iodo-2-[(4-methoxy-4-oxobutanoyl)amino]benzoate (24,6 g, 99%).
Reaction SMILES: [Br:1]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH2:33][C:32]([CH2:38]O)=[CH:31]2)[CH2:23][CH2:24][CH2:25][CH3:26]>C(#N)C.CCOCC.CCCCCC>[CH2:22]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH2:33][C:32]([CH2:38][Br:1])=[CH:31]2)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCOc1ccc2c(c1)C=C(CO)CO2
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: CCCCCOc1ccc2c(c1)C=C(CBr)CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (4.7 mmol) of dibromotriphenylphosphorane are added to a solution of 1.15 g (4.6 nmnol) of the alcohol obtained in Step C in 25 ml of anhydrous acetonitrile. The medium is stirred for 1 hour at ambient temperature; the solvent is then evaporated in vacuo. The residue obtained is taken up in a mixture of ether/hexane (1/1); the solid formed is then filtered off over Celite. Evaporation of the filtrate yields the brominated compound of the title in the form of a chestnut-brown syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([Cl:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:22][C:4]1[CH:3]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:7]=[CH:6][C:5]=1[C:8](=[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Temperature: 140 °C
Yield: 59.8 %

Procedure:
A mixture of 72 (459 mg, 1.22 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 310 mg (60%) of 73. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.58 (m, 6H), 1.99 (m, 2H), 2.28 (m, 2H), 4.71 (s, 1H), 6.31 (d, J=16.0 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.17 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.9 Hz, 1.5 Hz, 1H), 7.47 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:12].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(Cl)ccc(I)c21
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.5 %

Procedure:
4-Chloro-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (6.94 g, 16.2 mmol) was dissolved in nitromethane (280 mL), and the solution was added with trifluoroacetic acid (17.7 mL, 230 mmol) and triethylsilane (7.35 mL, 46.1 mmol), followed by stirring at room temperature for 23 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using diisopropyl ether to obtain 4-chloro-7-iodoisoindolinone (4.73 g, yield 99%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[C-:33].[H-].[Na+].C1COCC1>C1COCC1>[CH2:38]([O:37][C:35]([C:34]1[N:32]=[CH:33][N:6]2[C:7]=1[CH:8]([CH3:17])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]2=1)=[O:36])[CH3:39]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1N=C(c2ccccn2)c2cc(Br)ccc2NC1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccn1)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
The 7-bromo-3-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 125 (3.3 g, 10 mmol) was suspended in dry THF (200 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12 mmol) was added into the suspension in one portion. The reaction mixture was allowed to stir and warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.31 mL, 16 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 0.56 g, 14 mmol) was suspended in dry THF (150 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.31 mL, 12 mmol) was added to the NaH/THF suspension, the solution which resulted was allowed to stir for 3 h. After 3 h, the first flask was cooled to −30° C. and the solution in the 2nd reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, and then cooled with an ice-water bath and slowly quenched with acetic acid (10 mL). Water was added to the reaction mixture after which it was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:1, 2:1, 3:1). The ester 126 was a white solid (1.40 g, 33%). mp 193-195° C.; IR (KBr, cm−1) 2962, 1719, 1260, 1021; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1 H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(OC)C=CC=1.[Mg].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: Brc1ccccn1
Agent: COc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccccn2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
That is, as shown in the reaction scheme below, (3-methoxyphenyl)magnesium bromide was synthesized from 22.4 g (120 mmol) of 3-bromoanisole with 3.4 g of magnesium in dry tetrahydrofuran (THF) in an argon stream by a conventional manner. This was slowly added to a dry THF solution of 15.8 g (100 mmol) of 2-bromopyridine and 1.8 g of (1,2-bis(diphenylphosphino)ethane)dichloronickel (II) (Ni(dppe)Cl2) and the mixture was stirred at 50° C. for 1 hour. After adding 250 ml of 5% hydrochloric acid aqueous solution to the reaction mixture, the reaction mixture was extracted with chloroform to obtain a target substance and the organic layer was distilled under reduced pressure. 17.4 g (93.9 mmol) of 2-(3-methoxyphenyl)pyridine (3-MeO-PPy) was obtained as a colorless transparent liquid. Identification was performed by CHN elementary analysis and 1H-NMR.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2F)cn1
Yield: 60.1 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 2-(2-thienyl)ethylamine (0.0196 g, 0.154 mmol) gives the title compound (0.0344 g, 60.2%): TOF MS ES+ 372.1 (M+H)+, HRMS calcd for C19H19N3O2FS 372.1182 (M+H)+, found 372.1168, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.9 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].CN1CCCC1.N1C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: NCCCO
Agent: CN1CCCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(NCCCO)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 70 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-methyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (500 mg), 3-amino-1-propanol (400 mg) and N-methylpyrrolidine (170 mg) were added to pyridine (1,500 mg), and the mixture was stirred at 70° C. for 15 hours. Since the raw material were not dissolved, N,N-dimethylformamide (1 ml) was added to the mixture, followed by stirring at 70° C. for 43 hours. The reaction mixture was concentrated under reduced pressure. A process of adding distilled water (1 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Another process of adding toluene (1.5 ml) to the resultant residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. A further process of adding ethanol (1.5 ml) to the resultant residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Ethanol (1 ml) was added to the resultant residue, and the mixture was heated under reflux for 5 minutes and allowed to cool. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (155 mg) as a colorless powder.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1.[C:28](Cl)(=O)[CH2:29][CH3:30].B(F)(F)F.CCOCC>O1CCOCC1.C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:27]=[C:28]([CH2:29][CH3:30])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: CCC(=O)Cl
Reactant: N=C(NO)c1ccc(C(=O)N2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc(-c2ccc(C(=O)N3CCC(c4nc5ccccc5[nH]4)CC3)cc2)no1
Temperature: 40 °C
Reaction time: 4 h
Yield: 3.2 %

Procedure:
To a stirred solution of 4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}-N-hydroxybenzene carboximidamide (0.15 g, 0.41 mmol) in anhydrous 1,4-dioxane (5 mL) is added dropwise propionyl chloride (34 μL, 0.39 mmol). The reaction is heated to 40° C. for 1 h before adding boron trifluoride etherate (10.5 μL, 0.083 mmol). Heating is continued at 80° C. for 4 h. The mixture is diluted with DCM and saturated aqueous NaHCO3 giving a suspension which is filtered. The organic layer is separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 5 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl][4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl]methanone.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10].[CH3:14]O>>[ClH:3].[NH2:5][C@@H:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCC[C@@H](N)C(=O)O
Reactant: CO
Product: CCCC[C@@H](N)C(=O)OC
Product: Cl
Reaction time: 16 h

Procedure:
To a solution of 13.7 g of thionyl chloride in 100 ml of methanol at -20° C. is added 5 g of D-norleucine (Nle) with stirring. The reaction mixture is allowed to stand for 16 hours at room temperature. The methanol is removed under reduced pressure and the residue is shaken with diethyl ether to give a crystalline product, methyl D-norleucinate hydrochloride which is represented by the folowing formula ##STR53## A solution of 12.4 g of Boc-L-tyrosine in 100 ml of dimethylformamide is cooled to -20° C. and converted to a mixed anhydride by the addition of 1 equivalent of N-methyl morpholine and 1 equivalent of isobutylchloroformate. The reaction mixture is cooled to -30° C. and 4.48 ml of N-methylmorpholine is added followed by 6.65 g of methyl D-norleucinate hydrochloride. The reaction mixture is stirred 3 hours at room temperature and allowed to stand an additional 16 hours. The dimethylformamide is distilled off under high vacuum at 40° C., and the residue is shaken with ethyl acetate and water. The ethyl acetate fraction is separated and washed successively with 0.5 M potassium bisulfate solution, water, and 1 M potassium bicarbonate solution, then dried over magnesium sulfate. The solvent is removed under reduced pressure and the product is crystallized from 50 ml of isopropanol and 40 ml of water to give methyl Boc-L-tyrosyl-D-norleucinate. 4.06 Grams of methyl Boc-L-tyrosyl-D-norleucinate is suspended in 40 ml of 1 M potassium hydroxide solution and the mixture is stirred for one hour at room temperature. Excess 2 M potassium bisulfate solution is added and the product is taken up in ethyl acetate. The ethyl acetate solution is washed successively with 0.5 M potassium bisulfate solution and water then dried over magnesium sulfate. The solvent is removed under reduced pressure to give Boc-L-tyrosyl-D-norleucine. A solution of 1.42 g of Boc-L-tyrosyl-D-norleucine in 15 ml of tetrahydrofuran is cooled to -20° C. and converted to the mixed anhydride by the addition of 1 equivalent of N-methylmorpholine and 1 equivalent of isobutylchloroformate. To this reaction is added 1.24 g of methyl glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate. The reaction mixture is stirred for 2 hours at room temperature then allowed to stand for 16 hours at room temperature. The reaction mixture is diluted with 200 ml of ethyl acetate and the ethyl acetate solution is washed successively with 0.5 M potassium bisulfate solution, water, and 1 M potassisum bicarbonate solution, then dried over magnesium sulfate. The solvent is removed under reduced pressure and the product is purified by low pressure chromatography on Woelm silica gel using a 100% chloroform to 5% methanol-95% chloroform gradient to give methyl Boc-L-tyrosyl-D-norleucyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C>[C:10]([C:9]1[C:8]([NH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:16]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:14][CH:13]=1)([OH:12])=[O:11]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)CNc1c(C(=O)O)cccc1[N+](=O)[O-]

Procedure:
A mixture of methyl glycinate (15.9 g, 127 mmol), 2-chloro-3-nitrobenzoic acid (6.07 g, 30.1 mmol) and Na2CO3 (22.9 g, 216 mmol) in tert-BuOH (40 mL) was heated at reflux for 18 h. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between H2O (200 mL) and EtOAc (200 mL). The aqueous layer was acidified to pH 2 and the organic layer was extracted. The aqueous layer was extracted further with EtOAc (2×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=255 (M+1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5].CC1N=CNC=1CSCCN>C(O)C>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Agent: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamine (9.0 g) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (5.0 g), prepared from 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure of Example 97, in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=O.[Li+].[OH-]>C1COCC1.O.CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:12](=[O:23])[NH:13][CH2:14]2)=[CH:17][CH:18]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1NCN(c2ccc(Cl)cc2)C12CCNCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.7 %

Procedure:
To a mixture of 1.5 g (2.97 mmol) 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(4-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one in 4.5 ml THF, 4.5 ml water and 4.5 ml methanol were added 0.85 g (35.6 mmol) powdered LiOH. The reaction mixture was stirred at ambient temperature for 48 hours. The solvent was removed in vacuo. The residue was stirred in water. The resulting solid was filtered, washed with water and dried to provide the title compound (0.55 g) as a colorless solid; MS (ISP): 266.1 MH+.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([NH:19][C:20]1([C:26]([OH:28])=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[NH2:36][C@H:37]([C:42]([NH:44][CH2:45][C:46]([NH2:48])=[O:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40]>O1CCCC1.CN(C)C=O>[CH2:9]([O:16][C:17]([NH:19][C:20]1([C:26]([NH:36][C@H:37]([C:42]([NH:44][CH2:45][C:46]([NH2:48])=[O:47])=[O:43])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)C[C@H](N)C(=O)NCC(N)=O
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1)C(=O)NCC(N)=O
Reaction time: 16 h
Yield: 59 %

Procedure:
4 ml of isobutyl chloroformate were added dropwise to 7.9 g of 1-benzyloxycarbonylaminocyclohexane-1-carboxylic acid and 4 ml of triethylamine in 75 ml of tetrahydrofuran at -10° C., while stirring, 5.6 g of L-leucyl-glycinamide in 50 ml of dimethylformamide were added to the resulting solution of the asymmetric acid anhydride after 15 minutes, and the mixture was stirred for 1 hour at -10° C. and then for 16 hours at room temperature, after which it was evaporated down under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed successively with 10% strength aqueous citric acid solution, sodium carbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. 7.5 g of 1-benzyloxycarbonylaminocyclohex-1-yl-carbonyl-L-leucyl-glycinamide were obtained.