Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2[CH:15]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:9])=[N:6][CH:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ncc(Br)cn2)c1
Temperature: 100 °C
Yield: 96.2 %

Procedure:
A mixture of 5-Bromo-2-iodo-pyrimidine (9.0 g; 31.6 mmol; 1.0 eq.), 3-aminophenyl boronic acid (4.3 g; 31.6 mmol; 1.0 eq.), K2CO3 (17.5 g; 126.4 mmol; 4.0 eq.) and Pd(PPh3)4 (1.83 g; 1.58 mmol; 0.05 eq.) in water/dioxane (67:135 mL) was heated overnight at 100° C. The reaction mixture was then diluted with EtOAc and organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (7.6 g; 96%). HPLC (Condition A): Rt 1.90 min (purity 78.0%). MS (ESI+): 250.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][C:15](OCC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.B(F)(F)F.CCOCC.CC(C[AlH]CC(C)C)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=CCO
Temperature: -78 °C
Yield: 79.2 %

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stirred was charged with 14 (67 g, 0.20 mol) and DCM (400 mL). The solution was cooled to −78° C. To this solution was slowly added boron trifluoride etherate (30 mL, 0.20 mol). The reaction mixture was stirred for 30 min. DIBAL (1 M in DCM, 600 mL, 0.6 mol) was added at a moderate rate. The solution was stirred at −78° C. for 2 h and then treated with EtOAc (100 mL) over 30 min to discharge remaining reagent. The reaction mixture was allowed to warm to −5° C. The reaction mixture was CAREFULLY quenched by the dropwise addition of 1 M HCl. The reaction mixture was diluted with DCM and H2O and made acidic to dissolve aluminum salts. The layers were separated and the organic phase was washed successively with dilute aqueous HCl, water, and brine. The DCM layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 25% to 80% EtOAc/hexane) to afford 15 as a yellow oil (36 g, 79%). [TLC analysis, 1:1 hexane/EtOAc, Rf(14)=0.8; Rf(15)=0.2]. 1H NMR (CDCl3, 300 MHz) δ5.73-5.52 (m, 2H), 4.39-4.16 (m, 1H), 4.15-4.04 (m, 2H), 3.46-3.25 (m, 2H), 2.92 (br s, 1H), 2.08-1.93 (m, 1H), 1.92-1.79 (m, 2H), 1.78-1.62 (m, 1H), 1.42 (s, 9H) ppm.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[C:25]2[N:30]([OH:31])N=NC=2C=1.[CH3:32]CN(C(C)C)C(C)C.C(Cl)CCl.Cl.COCN>CN(C=O)C>[CH3:32][O:31][N:30]([CH3:25])[C:17]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[CH:21][CH:20]=1)=[O:19]
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Agent: COCN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
A solution of 4-{[(phenylmethoxy)carbonylamino]methyl}benzoic acid (3.99 g, 14.0 mmol; Groves, K.; Wilson, A. J.; Hamilton, A. D. J. Am. Chem. Soc. 2004, 126(40), 12833-12842.) and HOBt (2.57 g, 16.8 mmol) in dry DMF (70.0 mL) was successively treated with i-Pr2NEt (4.87 mL, 28.0 mmol) and EDC (3.22 g, 16.8 mmol) at 22° C. After 0.25 h, the solution was treated with methoxymethylamine hydrochloride (1.64 g, 16.8 mmol) in one portion. The resulting mixture was stirred 1 h then partitioned between EtOAc and 0.1 M citric acid (100 mL each) with transfer to a separatory funnel. The layers separated and the aqueous layer washed with EtOAc (2×50 mL). The combined EtOAc layers were successively washed with 0.1 M citric acid, 0.1 M NaOH and saturated aqueous NaCl (3×50 mL each) then dried over MgSO4, filtered and concentrated in vacuo. Purification by chromatography on silica (40×250 mm) using a gradient elution from 1:1→3:7 pentane/EtOAc (Rf=0.3 in 1:1 hexanes/EtOAc) afforded pure material as a colorless oil (3.94 g, 12.0 mmol; 85.9%). 1H NMR (CDCl3, 300 MHz): δ 7.63 (2H, AA′BB′, JAB=8.3 Hz, JAA′=1.9 Hz), 7.36-7.27 (7H, m), 5.20 (1H, brs), 5.13 (2H, s), 4.40 (2H, brd, J=6.0 Hz), 3.52 (3H, s), 3.33 (3H, s). 13C NMR (CDCl3, 75 MHz): δ 169.5, 156.4, 141.1, 136.4, 133.2, 128.6, 128.5, 128.1, 128.1, 126.9, 66.9, 61.0, 44.8, 33.7. HRMS calcd for C18H20N2O4: 329.1496. Found: 329.1497.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:12][O:13][CH2:14][C:15]3[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][CH:16]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C1(N)C=CC=CC=1N>ClCCl>[NH2:24][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:20]([C:18]1[S:19][C:15]([CH2:14][O:13][N:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of 100 mg (0.31 mmol) 5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carboxylic acid, 65 mg (0.47 mmol) 1-hydroxybenzotriazol, 92 mg (0.47 mmol) N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide and 65 μl (0.47 mmol) triethylamine in 3 ml dichloromethane was stirred for 15 minutes. After addition of 68 mg (0.63 mmol) phenylenediamine the reaction mixture was stirred overnight. The solvent was evaporated and the residue was subjected to preparative HPLC to yield 88 mg (0.21 mmol) 5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carboxylic acid (2-amino-phenyl)-amide (17); exact MW [M+H] calc'd: 410.12; MW found [M+H]: 410.2. 1H-NMR (400 MHz, (CH3)2SO): δ=9.67 (s, 1H), 8.18 (s, 1H), 7.85 (m, 1H), 7.20 (m, 1H), 7.14–7.09 (m, 3H), 6.97 (m, 1H), 6.91 (m, 1H), 6.77 (m, 1H), 6.58 (m, 1H), 5.29 (s, 2H), 4.90 (s, 2H), 4.26 (m, 4H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4c(c3)CC(=O)N4)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one (63.1 mg, 0.243 mmol), DMSO(1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 30 mg (34%). LCMS E-S (M+H)=471.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 3.40 (br. s., 2 H), 4.41 (d, J=4.6 Hz, 2 H), 5.25-5.41 (m, 1 H), 5.91 (s, 1 H), 6.97 (d, J=8.1 Hz, 1 H), 8.08-8.21 (m, 3 H), 8.34 (s, 1 H), 8.96 (br. s., 1 H), 10.64 (s, 1 H), 11.58 (br. s., 1 H).
Reaction SMILES: C(#N)C([CH2:4][C:5]#[N:6])O.[H-].[Na+].[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][N:13]([C:18]2[CH:29]=[C:22]3[C:23]([O:25][C:26](=O)[NH:27][C:21]3=[CH:20][CH:19]=2)=O)[CH2:12]1.C[N:31](C)C=O>O>[NH2:31][C:26]1[C:4]([C:5]#[N:6])=[C:23]([OH:25])[C:22]2[C:21](=[CH:20][CH:19]=[C:18]([N:13]3[CH2:14][CH:15]([CH3:17])[O:16][CH:11]([CH3:10])[CH2:12]3)[CH:29]=2)[N:27]=1
Reactant: CC1CN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC(C)O1
Reactant: N#CCC(O)C#N
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1CN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC(C)O1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4 g of malonitrile is dissolved in 50 ml of dimethylformamide. To the solution, in several portions, 2.4 g of 60% sodium hydride in oily dispersion are added. To the clear solution 8 g of 5-(2,6-dimethylmorpholin-4-yl)isatoic anhydride is added and the mixture is stirred at room temperature for 10 hours. The reaction mixture is diluted with 70 ml of water and extracted with 2×30 ml of ethyl acetate. The aqueous phase is evaporated in vacuum, the solid residue is dissolved in 20 ml of water, and the pH is set to 6. The precipitated material is filtered off, washed with water. After drying 6.5 g of the title compound is obtained. (MH+: 299)
Reaction SMILES: [CH2:1]([N:8]([CH:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:13]#[N:14])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:24]>>[CH2:1]([N:8]([CH:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:13]([NH2:14])=[O:24])[CH2:9][CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: N#CC(c1ccc(F)cc1)N(CCO)Cc1ccccc1
Product: NC(=O)C(c1ccc(F)cc1)N(CCO)Cc1ccccc1
Reaction time: 0.33 h

Procedure:
5 g of [Benzyl-(2-hydroxyethyl)-amino]-(4-fluorophenyl)-acetonitrile of Formula XI and 15 ml of dimethylsulfoxide (DMSO) were charged in a clean and dry 4 neck round bottom flask followed by stirring for about 20 minutes. 3.8 g. of potassium carbonate was charged to the above reaction solution followed by addition of 7 ml of 50% hydrogen peroxide over about 30 minutes. The resultant reaction solution was stirred for about 2 hours, after completion of the reaction, reaction was quenched by adding 50 ml of water over about 30 minutes. The reaction suspension was stirred for about 1 hour. Separated solid was filtered and the solid was washed with 10 ml of water. Wet cake obtained and 50 ml of petroleum ether were charged in a clean and dry 4neck round bottom flask followed by stirring for about 15 minutes. The solid was filtered and the solid was dried at about 30° C. for about 5 hours to yield 3.8 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[C:10]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(C([Sn])=C(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[CH:10]=[CH2:11]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(N)cc1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(O) (0.50 g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50° C. under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH2:42][C:43](=[O:44])[NH:45][C:46]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:35][CH2:36][CH3:37])[O:38][CH2:39][CH3:40])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=O)=[C:4]2[N:3]=1.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].CC[N:22](C(C)C)C(C)C.C([O-])(=O)C.[NH4+]>CCO>[NH2:22][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[C:19]3[NH:13][C:14](=[O:15])[NH:16][C:17]3=[O:18])=[C:4]2[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccn2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 70 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in EtOH was added hydantoin (38 mg, 0.380 mmol), DIEA (5 μL, 0.028 mmol), and ammonium acetate (88 mg, 1.143 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and purified by HPLC to yield 5-((5-aminopyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=245)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([Cl:23])[CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:9](=[O:10])[C:4]3=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]3[C:6]2=[O:8])=[C:18]([Cl:23])[CH:17]=1)([O-:15])=[O:14]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl

Procedure:
The starting material is prepared as follows: The mixture of 3.0 g of 4-chlorophthalic anhydride, 2.8 g of 4-nitro-2-chloroaniline and 30 ml of acetic acid is refluxed for 24 hours. It is cooled, the precipitate formed filtered off and washed with diethyl ether, to yield the N-(4-nitro-2-chlorophenyl)-4-chlorophtalimide melting at 209°-212°.
Reaction SMILES: BrC1C=C2C(=CC=1)C(=O)N([C@H](C(C)C)C(OC)=O)C2.[Br:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([CH2:31]Br)[CH:22]=1.Cl.[NH2:34][CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37]>>[Br:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:29][CH:30]=1)[C:25](=[O:27])[N:34]([C@@H:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:31]2
Reactant: COC(=O)C(N)CC(C)C
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 386 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 2-amino-4-methylpentanoate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6]/[C:13](/[CH3:15])=[CH:12]\[C:11]([O:17][CH3:18])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)cc(C)c1N
Reactant: COC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C(/C)Nc1c(C)cc(Cl)cc1C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a suspended solution of 4-chloro-2,6-dimethylaniline (24.0 g) in toluene (300 mL) were added methyl acetoacetate (17.9 g) and p-toluenesulfonic acid monohydrate (293 mg) and the mixture was heated to reflux and stirred for 4 hours. The reaction mixture was concentrated. To the obtained residue was added diisopropyl ether and the insoluble matter which was precipitated was removed. The filtrate was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography W-prep 2XY (column: main column 3L, inject column L; automatic condition setting: hexane:ethyl acetate=9:1, preparative isolation mode GR) to give the title compound (24.7 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:25])[CH:11]([C:20]1(O)[CH2:23][CH2:22][CH2:21]1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][N:9]1[C:20]2([CH2:23][CH2:22][CH2:21]2)[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C1(O)CCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1C(=O)N(OCc2ccccc2)C12CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(Benzyloxy)-N2 -(t-butoxycarbonyl)-α-(1-hydroxycyclobutyl)glycinamide (3.50 g, 10 mmole) in 200 ml of dry tetrahydrofuran at 0° C. under argon was treated with 2.4 ml (15 mmole) of diethylazodicarboxylate, then with a solution of triphenylphosphine (5.2 g, 20 mmole) in 50 ml of tetrahydrofuran over 10 minutes, and the mixture stirred at 0° C. for one hour. The yellow color persisted so an additional 0.52 g (2 mmole) of triphenylphosphine was added. After 15 minutes, evaporation in vacuo gave an oil. Trituration with 100 ml of hexane:ethyl acetate (2:1) gave a white solid which was filtered. Chromatography of the filtrate on 800 ml of LPS-1 gave product fractions [Rf=0.8 in hexane:ethyl acetate (1:1)] contaminated with a close-running impurity which was removed by trituration with isopropyl ether, giving the product as a white solid, 1.07 g, melting point 156°-157° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[OH:18])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>>[F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][OH:18])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(/C=N/O)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=C(O)C(Cl)Cl
Product: O=C(NOCCO)c1cc(CNO)c(F)c(F)c1Nc1ccc(I)cc1F
Yield: 81 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyimino-meth yl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-benzamide (28.14 mg, 81%).
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH2:7]1.[CH3:19][Si:20]([CH3:27])([CH3:26])N1C=CN=C1.[CH2:28]1COCC1>>[CH3:17][C:2]([O:1][Si:20]([CH3:27])([CH3:26])[CH3:19])([CH2:18][CH3:28])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH2:7]1
Reactant: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)n1ccnc1
Product: CCC(C)(CCCC1CCC2(CCCC(=O)C2)C1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-hydroxy-4-methylpentyl)-spiro[4.5]decan-7-one (29′) (100 mg, 0.396 mmol) in dry THF (2 mL) is added 1-(trimethylsilyl)imidazole (0.292 mL, 1.98 mmol). The reaction mixture is stirred at room temperature for 4 hours and the solvent removed in vacuo. The resulting residue is purified over silica (petroleum ether/EtOAc, 95:5) to afford the desired product which is used directly for the next reaction step.
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].Cl.CCOC(C)=O.[N:34]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][CH2:46][C@H:35]1C(ON1C(=O)CCC1=O)=O>CCN(CC)CC>[N:34]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][CH2:46][C@H:35]1[C:20]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O

Procedure:
The desired compound was prepared from 6.0 g of Boc-Arg(NO2)-Gly-NH2, 40 ml of 4 N HCl-AcOEt, 3.4 ml of Et3N and 5.1 g of Boc-Pro-OSu in the same manner as in Example 26-(4).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-:22].[K+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:22][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: [OH-]
Reactant: BrCCCCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCCCCCCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C

Procedure:
24.4 g (0.2 mol) of p-hydroxybenzaldehyde, 30 g (0.1 mol) of 1,10-dibromodecane and 11.2 g (0.2 mol) of KOH (85%) are heated under reflux in 200 ml of DMF for 30 min. The solution is then allowed to cool to room temperature and is poured into water/ice. The resulting solid is isolated by suction filtration. For purification, the product, which is still moist, is recrystallized from ethanol/water and dried at 70-80° C.