Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([OH:21])[CH:10]=3.Cl.[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28]Cl)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([O:21][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])[CH:10]=3)[CH3:24]
Reactant: CCN(CC)CCCCl
Reactant: Oc1ccc2c(c1)-c1ccc(O)c3cccc-2c13
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCCOc1ccc2c(c1)-c1ccc(OCCCN(CC)CC)c3cccc-2c13

Procedure:
To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 27.9 g (0.15 mole) of 3-diethylaminopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-diethylaminopropoxy)-fluoranthene which is converted to the dihydrochloride salt with ethereal HCl and recrystallized from methanolbutanone, M.P. 235°-236.5°C.
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]4[O:29][CH2:28][CH2:27][O:26][C:20]=4[CH:21]=3)[N:16]=2)[CH:14]=1)=[O:9])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:17](=[CH:18][C:19]3[O:29][CH2:28][CH2:27][O:26][C:20]=3[CH:21]=2)[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)[NH:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)OCCO4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)OCCO4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
Lithium hydroxide monohydrate (28.7 mg, 0.684 mmol) and water (0.29 mL) were added to 1-(4-oxo-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (78.0 mg, 0.228 mmol) in THF (0.85 mL). The reaction mixture was stirred at room temperature for 18 h and was then concentrated and the residue re-dissolved in water (5 mL). This solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield the titled compound (54.3 mg, 75% yield). MS (ESI/Cl): mass calcd. for C14H10N4O5, 314.1; m/z found, 315.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.97 (s, 1H), 12.61 (s, 1H), 8.89 (d, J=0.6 Hz, 1H), 8.23 (s, 1H), 7.48 (s, 1H), 7.14 (s, 1H), 4.46-4.29 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:8]=[CH:7]2
Reactant: C1CNCCN1
Reactant: Clc1ccc2cccc(Br)c2n1
Product: Brc1cccc2ccc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 3 from 8-bromo-2-chloro-quinoline and piperazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:29]2[NH:28][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(N)=O)CC1

Procedure:
trans-4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide (40 mg, 0.10 mmol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (33 mg, 0.12 mmol), and sodium carbonate (33 mg, 0.31 mmol) were added to DME:Water (5:1) (2 mL) and the mixture degassed with Argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.007 mmol) was then added and the reaction mixture microwaved at 110° C. for 1 h, The mixture was concentrated in vacuo, taken up in DMSO, and purified by mass-directed preparative HPLC to afford desired product. 1H NMR (d6-DMSO, 400 MHz): 11.50 (br s, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 7.46 (dd, J=7.6, 0.4 Hz, 1H), 7.25 (br s, 1H), 7.13 (m, 1H), 7.08-7.00 (m, 2H), 6.70 (br s, 1H), 6.69 (br s, 1H), 3.16 (m, 1H), 2.20 (m, 1H), 2.10-1.80 (m, 4H) and 1.65 (m, 4H). MS (ES+): m/z 375.17 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (DMSO-d6): δ 6.90 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.49-7.61 (m, 4H), 7.66 (d, J=8.8 Hz, 2H), 8.81 (d, J=4.8 Hz, 2H), 10.26 (s, 1H). MS: M/z 456.9 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCCCCC>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)=[O:29]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccccc2-c2cc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 2-(1H-indol-2-yl)benzenamine (62 mg, 0.3 mmol) in dichloromethane (1.5 mL) at rt was added 4-tert-butylphenyl isocyanate (30 mg, 0.171 mmol). The reaction was stirred overnight at rt. Hexane (1 mL) was added to the reaction mixture and the reaction was allowed to set for ˜5 min. Example 1 was the solid formed which was collected by filtration (47.3 mg). (M+H)+=384.37.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[O:10])=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:32][C:33](=[O:35])[NH2:34].Cl>CN(C)C=O.C(N(CC)CC)C>[NH:11]([C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[C@H:12]([C:18]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:32][C:33](=[O:35])[NH2:34])=[O:20])[CH2:13][CH2:14][C:15](=[O:16])[NH2:17]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
14.5 of Z-Gln-ONP and 10.8 g of H-Asn-Phe-OCH3, hydrochloride (Ann. 688, 259 [1965]) are dissolved together in 100 ml of dimethylformamide and to the solution 4.55 ml of triethylamine are added slowly. A thick paste forms which is diluted with 50 ml of dimethylformamide. After a reaction period of 24 hours at room temperature, the batch is filtered and the residue washed with dimethylformamide. The resulting Z-Gln-Asn-Phe-OMe can be recrystallized from much hot dimethylformamide. Melting point, 261°-265°C (decomp.). [α]20D = + 11° (c = 0.94 in hexamethylphosphoric acid triamide).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:6]=1[C:21](=[O:23])[CH3:22].[CH:24](OCC)=O.Cl>O.COCCOC>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]2[C:6]([C:21](=[O:23])[CH:22]=[CH:24][NH:4]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of sodium methylate (270 mmol, 14.75 g, favorable prepared from sodium metal and methanol before use), 1,2-dimethoxyethane (122 ml) and 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (6.68 g 24 mmol) was stirred at 0° C. for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132 mmol) was added to the reaction mixture, that was allowed to come to room temperature and stirred for further 4 hours. The mixture was diluted with water (50 ml) and acidified to pH 1 by adding hydrochloric acid (1N, 185 ml). The precipitate was filtered, washed with water and dried to give 6.51 g of product [D]. Yield: 94%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:64])([F:52])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: COC(O)C(F)(F)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from Procedure 17, Step C) in THF (70 mL) was stirred at rt for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layers were washed in succession with saturated aq. brine (100 mL), dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/ethyl acetate, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which solidified upon standing. For the title compound:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[I:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O>N1C=CC=CC=1>[I:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CNC
Solvent: O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
Dimethylamine (100 mL of 2.0 M solution in tetrahydrofuran; 200 mmol) was added to a solution of 4-iodobenzenesulfonyl chloride (54.76 g; 181 mmol) in pyridine (300 mL) at 0° C. under N2, followed by the addition of 4-N,N-dimethylaminopyridine (15 mg). The reaction was allowed to warm to room temperature and was stirred under N2 for 48 hrs. The reaction solution was poured into 1.2 liter of water, and the precipitated product was collected by filtration and rinsed with water (300 mL×2). The solid was dissolved in ethyl acetate (500 mL) and washed with 5% aqueous hydrochloric acid (300 mL×3), water (300 mL×2) and brine (300 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated to give 4-iodo-N,N-dimethyl-benzenesulfonamide (49.46 g; 88%) as a white solid, which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 2.69 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.I[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>[Cu]I.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.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)N(c1ccccc1)CCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccccc2)CCC3(C)C)cc1
Temperature: 40 °C

Procedure:
To a mixture of 0.020 g (0.08 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-ethynylquinoline (Compound 8) and 0.51 g (1.8 mmol) of ethyl 4-iodobenzoate were added 1.5 g (2.0 mL, 14 mmol) of triethylamine, 6.2 mg(0.03 mmol) of copper(I)iodide, and 12 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was heated at 40° C. for 5.5 hours. The reaction was cooled, methylene chloride was added, and the reaction mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PNMR (300 MHz, CDCl3) d 1.36 (6 H, s), 1.39 (3 H, t, J=7.2 Hz), 1.86 (2 H, t, J=6.0 Hz), 3.64 (2 H, t, J=6.0 Hz), 4.36 (2 H, q, J=7.2 Hz), 6.87 (1 H, d, J=1.6 Hz), 6.91 (1 H, dd, J=7.9, 1.6 Hz), 7.14 (1 H, t, J=7.3 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.25 (2 H, d, J=7.3 Hz), 7.39 (2 H, t, J=7.3 Hz), 7.48 (2 H, d, J=8.5 Hz), 7.97 (2 H, d, J=8.5 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([NH2:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C[O:22][C:23](=O)[C:24]1[C:29]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:36]Br.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([N:20]3[C:23](=[O:22])[C:24]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH2:36]3)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OCC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)cc1OCC1CC1
Temperature: 90 °C
Yield: 3 %

Procedure:
To a solution of 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.0 g, 3.3 mmol) in DMF (18 mL), were added 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.3 mmol) and triethylamine (1.3 mL, 9.8 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulting oil was extracted with ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 mL×4) and brine (30 mL), and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting oil was purified by silica gel column to give cyclopropanecarboxylic acid {2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (50 mg, 5%): mp 224-226° C.; 1H NMR (CDCl3) δ 0.35-0.39 (m, 2H, c-CH2), 0.60-0.63 (m, 2H, c-CH2), (0.88-0.93 (m, 2H, c-CH2), 1.08-1.12 (m, 2H, c-CH2), 1.25-132 (m, 1H c-CH), 1.63-1.69 (m, 1H, c-CH), 2.95 (s, 3H, CH3), 3.69 (dd, J=5, 15 Hz, 1H, CHH), 3.82 (d, J=4 Hz, 2H, c-CH), 3.86 (s, 3H, CH3), 4.19 (dd, J=10, 17 Hz, 1H, CHH), 4.20 (d, J=17 Hz, 1H, CHHN), 4.43 (d, J=17 Hz, 1H, CHHN), 5.72 (dd, J=5, 10 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.46 (s, 1H, NHCO); 13C NMR (CDCl3) δ 3.3, 3.4, 8.3, 10.2, 16.2, 41.5, 47.9, 51.7, 55.9, 56.0, 74.3, 77.2, 111.8, 113.0, 116.7, 117.1, 117.9, 119.6, 129.4, 133.6, 138.2, 141.3, 149.1, 150.0, 170.1, 172.6. Analy. Calculated for C26H3oN2O6S: C, 62.63; H, 6.06; N, 5.62. Found: C, 62.41; H, 5.95; N, 5.43.
Reaction SMILES: COC([N:5]([C:13]1[CH:59]=[CH:58][C:16]([C:17]([NH:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25](=[O:33])[C@@H:24]2[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:57])[C:39]2[CH:44]=[CH:43][C:42]([N:45](C(OC)=O)[C:46]([NH:48][C:49]([O:51][CH3:52])=[O:50])=[NH:47])=[CH:41][CH:40]=2)=[O:22])=[O:18])=[CH:15][CH:14]=1)[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])=[NH:7])=O.[OH-].[Li+].[ClH:62]>CO.O>[ClH:62].[CH3:12][O:11][C:9]([NH:8][C:6](=[NH:7])[NH:5][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25](=[O:33])[C@@H:24]2[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:57])[C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]([NH:48][C:49]([O:51][CH3:52])=[O:50])=[NH:47])=[CH:43][CH:44]=2)=[O:22])=[O:18])=[CH:58][CH:59]=1)=[O:10]
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(N(C(=N)NC(=O)OC)C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)NC(=N)Nc1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(NC(=N)NC(=O)OC)cc2)cc1
Yield: 58 %

Procedure:
In a mixture of 1,4-dioxane (3.0 ml) and H2O (3.0 ml) was dissolved (S)-[4-[(4-guanidinobenzoylamino)acetyl]-3-[3-(4-guanidinobenzoylamino)propyl]-2-oxopiperazin-1-yl]acetic acid hydrochloride (another name: (S)-4-[(4-guanidinobenzoylamino)acetyl]-3-[3-(4-guanidinobenzoylamino)propyl]-2-oxopiperazine-1-acetic acid hydrochloride) (0.3 g, 0.51 mmol) produced in Working Example 15. To the solution were added gradually, under stirring at 0° C. while keeping the pH at 10 or below, a 2N aqueous solution of sodium hydroxide (2.60 ml, 5.10 mmol) and chlorocarbonic acid methyl ester (0.31 ml, 4.00 mmol). The reaction mixture was stirred for 10 minutes at 0° C., whose pH was adjusted to 4 with a 1N aqueous solution of hydrochloric acid, followed by shaking together with ethyl acetate for extraction. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (CHP-20, 10% CH3CNaq-15% CH3CNaq-20% CH3CNaq-25% CH3CNaq-35% CH3CNaq) to give (S)-[4-[[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]acetyl]-3-[3-(4-(1,3-dimethoxycarbonylguanidino)benzoylamino]-propyl]-2-oxopiperazin-1-yl]acetic acid (another name: (S)-4-[(4-(1,3-dimethoxycarbonylguanidino)benzoylamino]acetyl]-3-[3-[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]-propyl]-2-oxopiperazine-1-acetic acid) (0.26 g, 62%) as a colorless amorphous powdery product. This product (0.26 g, 0.31 mmol) was dissolved in a mixture of methanol (2.6 ml) and H2O (0.26 ml). To the solution was added, under ice-cooling, lithium hydroxide.1.0hydrate (42 mg, 1.00 mmol). One hour later, the reaction system was adjusted to pH 4 with a 1N aqueous solution of hydrochloric acid, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography [(CHP-20, 5% CH3CNaq-10% CH3CNaq-15% CH3CNaq-20% CH3CNaq) and (LH-20, H2O)] to afford the title compound (0.13 g, 58%) as a colorless amorphous powdery product.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:32]([OH:33])=[C:31]([C:34]([NH:36][CH3:37])=[O:35])[CH:30]=[CH:29][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]3[CH2:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[O:19][C:14]=3[C:13]=2[CH2:26][CH2:27][CH3:28])[CH2:3][CH2:2]1.S(OC)(O[CH3:42])(=O)=O.[OH-].[K+]>C1COCC1>[CH:1]1([CH2:4][C:5]2[C:32]([O:33][CH3:42])=[C:31]([C:34]([NH:36][CH3:37])=[O:35])[CH:30]=[CH:29][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]3[CH2:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[O:19][C:14]=3[C:13]=2[CH2:26][CH2:27][CH3:28])[CH2:2][CH2:3]1
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 17 (20 mg, 0.04 mmol), dimethyl sulfate (0.5 mg, 0.12 mmol), and potassium hydroxide (4.5 mg, 0.08 mmol) were added to about 5 ml of THF, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to give the product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][O:1][N:33]2[C:34](=[O:43])[C:35]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]3[C:37]2=[O:38])=[CH:4][CH:5]=1
Reactant: OCc1ccnc2ccccc12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccnc2ccccc12
Reaction time: 8 h
Yield: 88.4 %

Procedure:
4-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (2.27 g, 8.66 mmol, 1.15 equiv) and N-hydroxyphthalimide (1.42 g, 8.71 mmol, 1.15 equiv) were dissolved in 40 mL of dry THF. Diethylazodicarboxylate (1.44 mL, 9.15 mmol, 1.21 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture was then diluted with 50 mL of Et2O and filtered. The resulting solid was dissolved in dichloromethane and washed with 1N NaOH, H2O and brine. The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.03 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.