Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10](=[O:12])[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCN1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To 1.00 g (4.33 mmol) of (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid was added 750 mg (8.66 mmol) of piperazine, 20 mL of DCM, 1.34 g (6.5 mmol) of DCC and 17.9 mL (12.99 mmol) of TEA. This was allowed to stir overnight at room temperature. The next morning, it was diluted with more DCM, and filtered. The filtrate was concentrated and purified in the ISCO using a 40 gram column and eluting with 0-10% MeOH/DCM to obtain the desired product in 79% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=[O:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCC(F)(F)F
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 3.96 g of vaniline (e-1) (26.0 mmol) in 26 ml of dry DMF was added 1.04 g of 60% NaH (26.0 mmol) slowly, and the mixture was stirred for 30 min. in a stream of nitrogen. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.64 g: 28.6 mmol) was added dropwise to the mixture and stirred overnight at room temperature. The reaction solution was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with benzene-AcOEt to give 5.98 g of the objective compound 3-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde (f-1) (Yield: 98.2%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC=C)=[O:22])[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1>C1COCC1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)OC(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(C(=O)O)c1
Reaction time: 1 h

Procedure:
To a solution of (S)-2-t-butoxycarbonylamino-3-(3-allyloxycarbonylbenzyloxy)-propionitrile (8.0 g, 22.22 mmol) in THF (100 mL) is added morpholine (19.4 mL, 222 mmol). After deoxygenation with bubbling nitrogen (2 min.), Pd(PPh3)4 (1.28 g, 1.11 mmol) is added in one portion, and the solution is stirred 1 h. Solvent is evaporated, the residue is taken up in EtOAc (250 mL), and washed with 1 N HCl (250 mL), brine (100 mL), dried (MgSO4), evaporated, and the residue chromatographed (silica, 2% methanol, CH2Cl2) to yield (S)-2-t-butoxycarbonylamino-3-(3-carboxybenzyloxy)-propionitrile, as a light yellow oil.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[CH:16][N+:17]([O-])=[O:18])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1>C(O)(=O)C.O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([C:16]([N+:1]([O-:3])=[O:2])=[N:17][OH:18])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1
Reactant: O=N[O-]
Reactant: O=[N+]([O-])C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrite, 5 g (0.072 mole), was added in portions over a period of 5 min to a solution of 20 g (0.06 mole) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine* in 100 ml of glacial acetic acid. Following the addition, the reaction mixture was stirred at room temperature for 15 min. The product, which crystallized partially during this period, was further precipitated by slow addition of 50 ml of water and collected by filtration. The crystals were washed with water, sucked dry and washed with methanol/ether to leave light yellow product. The filtrate was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated. Crystallization of the residue from methylene chloride/hexane yielded additional product. The analytical sample was recrystallized from ether to give pale yellow crystals with mp 220°-230° C. dec.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][O:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH3:32][O:31][CH2:30][CH2:29][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)c[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1cc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of tert-butyl 2-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate (400 mg, 1.39 mmol, prepared according to example 7, steps 1-2) and potassium carbonate (423 mg, 3.06 mmol) in DMF (4 mL) was stirred for 30 min at RT. After cooling to 0-5° C., 1-bromo-2-methoxyethane (157 μL, 1.67 mmol) was added. The ice bath was removed after 5 min and the reaction mixture was stirred at RT for 16 h. Another two equivalents of both potassium carbonate (618 mg, 4.45 mmol) and 1-bromo-2-methoxyethane (262 μL, 2.78 mmol) were added at RT and the reaction mixture was heated to 60° C. and stirred for 20 h. The reaction mixture was poured into ethyl acetate (50 mL) and the organic phase was washed with water (3×20 mL) and brine (25 mL). The aqueous layers were back-extracted with ethyl acetate (50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless solid (359 mg, 1.04 mmol, 74.7%). MS: M=346.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)([Cl:10])[Cl:9])[N:3]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:10])[Cl:9])[N:3]=1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: Cl
Solvent: CO
Product: Clc1cccc(C(Cl)Cl)n1

Procedure:
A mixture of 23.1 g (0.10 mole) of 2-chloro-6-(trichloromethyl)pyridine, 10.0 g of methanol, 15.0 g of concentrated hydrochloric acid and 40.0 g (0.20 mole) of ferrous chloride as the tetrahydrate was stirred while heating to reflux. The mixture was a slurry which slowly became fluid and a two-phase liquid mixture resulted after 15 minutes. The mixture was maintained under reflux conditions (80°-90° C.) for one and one-half hours and then cooled to ~45° C. The mixture was extracted with 50 ml of methylene chloride and then 20 ml of water. The extracts were combined and the organic phase separated. Further dilution of the aqueous phase with water and extraction with 20 ml of methylene chloride gave an oil which was combined with the main extract and washed once with water. The crude product mixture was recovered in a yield of 88 g and after drying over anhydrous sodium sulfate, analyzed by glc. This analysis showed the mix to contain 82 percent 2-chloro-6-(dichloromethyl)pyridine, 4 percent 2-chloro-6-(trichloromethyl)pyridine and ~14 percent unresolved impurities.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([Br:13])=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:13][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([CH3:14])[CH:16]=2)=[N:12][CH:11]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: CCOC(=O)c1cc(Br)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ncc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution ethyl 2,5-dibromoisonicotinate (1-2, 1.5 g, 4.86 mmol) in degassed dimethylformamide (24 mL) at 25° C. was added (5-methylpyridin-3-yl)boronic acid (0.665 g, 4.86 mmol), PdCl2dppf (0.355 g, 0.486 mmol), cesium carbonate (4.75 g, 14.6 mmol) and water (0.262 mL, 14.57 mmol). The reaction flask was purged with nitrogen, sealed and stirred at 50° C. overnight. The crude reaction mixture was partitioned between water and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. The solvent was removed by rotary evaporation and the crude product was purified by normal phase column chromatography (0 to 50% EtOAc in hexanes) to afford the product (1-3) as a white solid. ESI+MS[M]+C14H13BrN2O2=321.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:18])[CH2:16][Cl:17])[CH:11]=[CH:10][C:9]=2[OH:19])=[O:5])[CH3:2].[CH2:20]([NH2:23])[CH:21]=[CH2:22].Cl>CS(C)=O>[ClH:17].[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:18])[CH2:16][NH:23][CH2:20][CH:21]=[CH2:22])[CH:11]=[CH:10][C:9]=2[OH:19])=[O:5])[CH3:2]
Reactant: C=CCN
Reactant: CCOC(=O)c1cc2c(C(=O)CCl)ccc(O)c2[nH]1
Agent: Cl
Solvent: CS(C)=O
Product: C=CCNCC(=O)c1ccc(O)c2[nH]c(C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 g of 4-chloroacetyl-7-hydroxyindole-2-carboxylic acid ethyl ester is combined with 1.5 ml of allylamine and 15 ml of absolute dimethyl sulfoxide and stirred at room temperature for one hour. Then 150 ml of 2N hydrochloric acid is added to the reaction mixture, the immediately formed precipitate is vacuum-filtered, and the filtrate is allowed to stand and thus yields, in crystalline form, 1.5 g of 4-allylaminoacetyl-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride, mp 264°-265° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28]Br>CC(CC)=O>[Br:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: BrCCCBr
Reactant: O=C(c1ccccc1)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCBr)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-hydroxy-3-nitrobenzophenone (2.5 g) and 7.1 g of potassium carbonate were suspended in 15 ml methylethylketone. The suspension was stirred under heating with reflux for 30 minutes, added with 1,3-dibromopropane and then heated with reflux for 6 hours. The reaction mixture was cooled down to room temperature, and insoluble substances were removed by filtration. The filtrate was then concentrated, and the resultant precipitate was subjected to silica gel column chromatograph (hexane/ethyl acetate=3.1 (v/v)) for purification; thereby 2.08 g of an oil, 4-(3-bromopropyloxy)-3-nitrobenzophenone, was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([O:21][NH2:22])[CH3:20]>>[CH2:19]([O:21][NH:22][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:2]=[CH:7][C:6]([I:8])=[CH:5][CH:4]=1)[CH3:20]
Reactant: CCON
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: CCONC(=O)c1ccncc1Nc1ccc(I)cc1

Procedure:
N-ethoxy-3-(4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.40 mmol of O-ethyl-hydroxylamine LC/MS [9.14 min; 418 (M+1)]
Reaction SMILES: FC1C=CC(C(O)C=CC[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:14][CH2:13]2)=CC=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:27]=[C:19]1[N:18]([CH:15]2[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CC=CC(O)c2ccc(F)cc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccccc2n1C1CCNCC1
Reaction time: 1.5 h

Procedure:
A mixture of 1-[4-(p-fluorophenyl)-4-hydroxy-2-butenyl]-4-(2-keto-1-benzimidazolinyl)piperidine (0.56 g) in chloroform (12 ml) and manganese dioxide (4.4 g) was stirred for 1.5 hours under ice-cooling. Filtration of inorganic materials and concentration of the filtrate afforded 1-[4-fluorophenyl)-4-oxo-2-butenyl]-4-(2-keto-1-benzimidazolinyl)piperidine as pale yellow crystalline materials. M.P. 167 - 170° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])=[O:7].ClS([N:23]=[C:24]=[O:25])(=O)=O.C(#N)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([C:24]([NH2:23])=[O:25])[C:9]1=[O:18])=[O:7]
Reactant: O=C1Nc2cc(F)ccc2C1C(=O)c1ccco1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccc(F)cc21
Yield: 17 %

Procedure:
Following substantially the procedure of Example 19, the title was prepared in 17% yield from: 3-(2-furoyl)-6-fluoro-2-oxindole (0.30 g, 1.2 mmole), chlorosulfonyl isocyanate (0.20 g, 1.4 mmole), acetonitrile (15 ml), and water (10 ml), Yield=0,060 g; m.p.=231°-235° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>>[CH3:21][O:22][CH2:23][C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: COCC(=O)Cl
Product: CCOC(=NC(=O)COC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and methoxyacetyl chloride, there is obtained ethyl N-(methoxyacetyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: 339 (1, M+H), 309 (1), 293 (98), 194 (20), 167 (100);
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:42]([O:44][CH3:45])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1)=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:53]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:54]([C:64]([NH:66][C@H:67]([C:72]([NH:74][C@H:75]([C:80]([NH:82]N)=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:68][C:69](=[O:71])[NH2:70])=[O:65])[CH2:55][O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>>[NH:53]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:54]([C:64]([NH:66][C@H:67]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:42]([O:44][CH3:45])=[O:43])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:35][CH:36]=1)=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:68][C:69](=[O:71])[NH2:70])=[O:65])[CH2:55][O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NN
Reactant: COC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Yield: 63.8 %

Procedure:
By using 2.50 g of Boc-Ser(Bzl)-Thr(Bzl)-Tyr(CH2COOH)-OCH3 and 2.23 g of Boc-Ser(Bzl)-Asn-Leu-NHNH2 and the same procedure as in Reference Example 7 was repeated to obtain 2.49 g (yield: 63.8%) of the above-mentioned objective product.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH2:70])[CH:65]=2)(=[O:57])=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C>[N:49]1([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH:70][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:65]=2)(=[O:57])=[O:56])[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.010 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 53% yield: LCMS (ESI) m/z 507 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:25]=[C:26]([CH2:29][CH2:30][NH2:31])[S:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32].[CH3:36][S:37]([CH2:40][C:41](O)=[O:42])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:25]=[C:26]([CH2:29][CH2:30][NH:31][C:41](=[O:42])[CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[S:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32]
Reactant: NCCc1nc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)cs1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)NCCc1nc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)cs1

Procedure:
(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-(6-(2-(2-aminoethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine (0.229 mmol) was reacted with methanesulfonyl acetic acid (0.252 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.252 mmol) in DMF as outlined in procedure (I) to provide the title compound after purification by chromatography. 1H NMR (CDCl3) δ 8.82 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.14 (d, 1H), 8.02 (m, 1H), 7.92 (d, 1H), 7.81 (s, 1H), 7.62 (m, 1H), 7.55 (s, 1H), 7.36 (m, 1H), 7.21 (m, 2H), 7.02 (m, 2H), 5.18 (s, 2H), 3.95 (s, 2H), 3.91 (m, 2H), 3.36 (m, 2H), 2.88 (s, 3H). Electrospray MS m/z 625.87 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[OH:10][CH2:11][C:12]([NH:14][CH2:15][C@H:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH3:37])[CH:31]=1)=[N:22][CH:23]=[N:24]2)[CH3:17])=[O:13]>>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[CH:28][C:19]=3[O:18][C@H:16]([CH3:17])[CH2:15][NH:14][C:12](=[O:13])[CH2:11][OH:10])[N:24]=[CH:23][N:22]=2)=[CH:31][C:32]=1[CH3:37]
Reactant: Fc1cccc(CCl)c1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1cccc(F)c1
Yield: 25 %

Procedure:
The procedure described in Example 3 was repeated using 1-(chloromethyl)-3-fluorobenzene and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a light yellow solid in 25% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.25 (s, 3H), 3.42 (dt, 1H), 3.72 (dt, 1H), 3.81 (d, 2H), 4.94 (m, 1H), 5.17 (s, 2H), 5.47 (t, 1H), 6.99 (d, 1H), 7.16 (td, 1H), 7.22 (d, 1H), 7.30 (m, 3H), 7.43 (m, 1H), 7.56 (d, 1H), 7.61 (dd, 1H), 7.68 (t, 1H), 8.16 (t, 1H), 8.43 (s, 1H), 9.94 (s, 1H); Mass spectrum MH+ 491.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([N:17]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:29][C:30]([NH2:32])=[NH:31])=[N:6][CH:5]=1.[H-].[Na+].[C:35](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=NC=CC=1)([CH3:38])([CH3:37])[CH3:36]>COCCOC>[C:35]([O:20][C:19](=[O:21])[CH2:18][N:17]([S:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:4]([Cl:3])=[CH:5][N:6]=[C:7]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:12][CH:11]=1)(=[O:15])=[O:16])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccnc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3cccnc3)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(Cc1cccnc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine dihydrochloride ##STR26## Guanidine hydrochloride (317 mg, 3.32 mmol was added in one portion to a stirred suspension of NaH (62.3 mg, 80% dispersion by wt in mineral oil, 2.08 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine t-butyl ester (400 mg, 0.83 mmol) in DME (10 mL) was added and the mixture heated at 80° C. for 4 h. The solvents were evaporated in vacuo, the residue was dissolved with EtOAc (200 mL), and washed with aqueous NH4Cl (200 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using (i) pentane-EtOAc (70:30 to 50:50) and then (ii) CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 90:101) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine t-butyl ester (104 mg, 0.21 mmol) as a pale yellow solid.