Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:16][CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[CH2:29]([Sn+](CCCC)CCCC)[CH2:30][CH2:31]C.C(OC=CC(=C)C)(=[O:44])C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:16][CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:29][C:30](=[O:44])[CH3:31])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C=COC(C)=O
Reactant: CC(C)(C)OC(=O)N(CCc1c(Cl)cccc1Cl)Cc1cccc(I)c1
Reactant: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc(CN(CCc2c(Cl)cccc2Cl)C(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
[2-(2,6-Dichloro-phenyl)-ethyl]-(3-iodo-benzyl)-carbamic acid tert-butyl ester (Example 14, step b) (500 mg), tributyltin methoxide (350 μL), isoprenyl acetate (170 μL), tri-o-tolylphosphine (30 mg) and toluene (20 mL) were charged to a flask and the solution degassed with nitrogen for 5 minutes. Palladium acetate (10 mg) was added and the resultant mixture heated to 100° C., under nitrogen, for 3 hours. On cooling, potassium fluoride (580 mg) in water (3 mL) was added, stir at room temperature for 18 hours. The solids were filtered off, and the filter cake washed with ethyl acetate. The filtrate was evaporated and purified on silica, eluting with a gradient of iso-hexane/ethyl acetate [4:1 to 2:1], to give the subtitle product as an oil (230 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[C:16]([N+:24]([O-:26])=[O:25])[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:13]1[CH2:14][CH2:15][N:11]([CH3:10])[C:12]1=[C:16]([N+:24]([O-:26])=[O:25])[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccccc2)C1=C(Sc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.71 g of benzoyl chloride was added to 1.26 g of 1B and 0.63 g of triethylamine in 25 ml of methylene chloride at 0°-20°. After stirring overnight at room temperature, the solvent was stripped. The solid residue was triturated with ice-cold methanol and then filtered to give 2, as a yellow solid, m.p.: 175°-178°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:17]([O:19]CC)=O)[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([S:56]([NH2:59])(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1>C1COCC1.O.CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:17]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([NH2:59])(=[O:57])=[O:58])[CH:51]=2)=[O:19])[N:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1nc(C(C)(C)C)nn1Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)Nc2cccc(S(N)(=O)=O)c2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
A suspension of ethyl 5-tert-butyl-2-benzyl-2H-1,2,4-triazole-3-carboxylate (0.10 g 0.35 mmol) and LiOH.H2O (29 mg, 0.70 mmol) in THF (1 mL) and H2O (1 mL) was stirred at room temperature 2 h. The solvent was evaporated under vacuum, and to the residue was added DMF (2 mL) and HATU (0.13 g, 0.35 mmol). The reaction was stirred for 3 min, then 3-amino-benzenesulfonamide (60 mg, 0.35 mmol) was added. The reaction was stirred for 3 h, diluted with water, and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-5% MeOH-CH2Cl2) to obtain 5-tert-butyl-2-benzyl-N-(3-(aminosulfonyl)phenyl)-2H-1,2,4-triazole-3-carboxamide (16 mg, 11% yield). LC/MS: m/z 414.3 (M+H)+ at 3.46 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C:4]1=[O:5].[CH2:11]([O:18][C:19](N[C@H](C(O)=O)CCC(=O)N)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]([N:6]1[C:7](=[O:10])[CH2:8][CH2:9][CH:3]([NH2:2])[C:4]1=[O:5])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: NC1CCC(=O)N(C(=O)OCc2ccccc2)C1=O

Procedure:
α-aminoglutarimide hydrochloride is commercially unavailable internally. It is synthesized from N-benzyloxycarbony-L-glutamine, which reacts with N,N′-carbonyldiimidazole in THF refluxing to yield N-benzyloxycarbony-aminoglutarimide. After that amino protection group is removed and α-aminoglutarimide hydrochloride is yielded by hydrogenation under certain pressure catalyzed with Pd/C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl.[O:16]([NH2:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].[CH2:25](O)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][O:16][CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:25][CH3:26])=[O:12])=[CH:4][CH:3]=1
Reactant: CON
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CCC(=NOC)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 70.6 %

Procedure:
4-(4-Chlorophenyl)-4-oxobutanoic acid (2.0 g, 9.41 mmol), methoxylamine hydrochloride (0.982 g, 11.76 mmol) and sodium carbonate (0.472 ml, 11.29 mmol) in ethanol (30 ml) were stirred and heated at 80° C. for 4 hours. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated by evaporation then purified by flash silica chromatography, eluting with 15% TBME in isohexane. Pure fractions were evaporated to dryness to afford ethyl 4-(4-chlorophenyl)-4-(methoxyimino)butanoate (1.790 g, 70.6%) as a colourless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1.O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][N:15]2[CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: O=C1CCCO1
Reactant: COc1ccc2c(C)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(C)cn(CCCC(=O)O)c2c1
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Anhydrous potassium carbonate (34.5 g, 0.25 mmol) was added to a solution of 6-methoxy-3-methylindole (16.1 g, 0.1 mol) and γ-butyrolactone (43 g, 0.5 mol) in dimethylacetamide (750 mL). Under mechanical stirring and protected with a drying tube, the reaction mixture was refluxed for 18 hours, more γ-butyrolactone (21.5 g, 0.25 mol) was added, and the reflux was continued for 12 hours. A final portion of γ-butyrolactone (21.5 g, 0.25 mol) was added and the thick suspension was refluxed for another 12 hours, cooled to ~30° C., and poured into water (600 mL). Toluene (600 mL) was added and the 2 layer system was stirred for 15 minutes. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The product was extracted with toluene (3×250 mL). The combined extracts were washed with water (600 mL), dried over MgSO4, filtered, evaporated, and the dark oily residue was chromatographed on silica gel (480 g). Elution with chloroform/hexane (1:1) afforded 18.2 g (74%) of the title compound as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[O:14][CH2:19][CH2:18][Br:17])=[CH:15][CH:16]=1
Reactant: OCCBr
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Clc1ccc(C(OCCBr)c2ccc(Cl)cc2)cc1
Yield: 8380.7 %

Procedure:
A mixture of 4,4′-dichlorobenzhydrol (4.40 g, 0.17 mmol) and 2-bromoethanol (3.0 g, 24.0 mmol) in benzene (50 ml) was treated with sulfuric acid (0.25 ml) and the resulting mixture was heated under reflux for 1 h. The cooled mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and hexane (1:1) as eluent to give the title compound as a clear oil (5.13 g, 82%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:13])[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH2:51])=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:13])[C:10]([NH:51][CH2:50][C:47]2[CH:48]=[CH:49][N:44]=[CH:45][CH:46]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:22])[CH3:23])[C@H:16]1[CH3:24]
Reactant: CC(C(=O)O)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1ccncc1)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Yield: 51.7 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid (40 mg, 0.099 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.199 mmol), 1-hydroxybenzotriazole anhydride (4 mg, 0.03 mmol) and triethylamine (28 μL, 0.199 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (20 μL, 0.199 mmol) at room temperature for 17.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the desired product (25 mg, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([CH3:18])[C:3]=1[C:4]([O:6]C(=O)CC=O)=O.[CH:19]([O:26]CC)([O:23][CH2:24][CH3:25])OCC.[C:29]([O:32][C:33](=O)[CH3:34])(=O)[CH3:30]>>[F:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([CH3:18])[C:3]=1[C:4]([C:30](=[CH:29][O:32][CH2:33][CH3:34])[C:19]([O:23][CH2:24][CH3:25])=[O:26])=[O:6]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)OC(=O)CC=O
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 25 °C

Procedure:
A solution of 7.1 g (27 mmol) of ethyl (3-2 (2,4,5-trifluoro-6-methylbenzoyl)-β-oxopropanoate, 6.8 g (41 mmol) of triethyl orthoformate and 60 mL of acetic anhydride was refluxed for 3 hours, cooled to room temperature, and concentrated to give 8.4 g of the title compound. The crude material was used as is in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([CH2:18][CH3:19])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([CH2:18][CH3:19])[N:17]=1)=[O:9]
Reactant: CCc1nc(N)sc1-c1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: CCc1nc(NC(=O)c2cc(Br)ccc2O)sc1-c1ccccc1
Yield: 17.4 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.C(#N)C.C[Si](I)(C)C>C(Cl)Cl>[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([NH:16][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(S)-N-[1-(4-bromophenyl)ethyl]ornithine amide (0.50 g; 0.78 mmol; from step (c) above) was suspended in CH2Cl2 :acetonitrile (20 mL; 1:3) and was cooled to 0° C. Trimethylsilyl iodide (0.17 g, 0.86 mmol) was added at 0° C. and the reaction stirred for 2 hours at 0° C. (solids dissolving as the reaction proceeded). When the deprotection was complete, as determined by TLC analysis, the reaction was quenched with water and diluted with EtOAc. The organic layer was separated and washed with water (1×), 1 N sodium thiosulfate (1×) and brine (2×). The combined aqueous washings were extracted with CH2Cl2. The organics were combined and triethylamine (5 mL) was added. The mixture was allowed to stand for 18 hours, transferred to a separating funnel, washed with brine (3×), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a yellow solid (0.40 g). The crude product was chromatographed on silica gel eluting with MeOH:CH2Cl2 (3:7), then MeOH:CH2Cl2 (1:1), to give sub-title compound (free base) as an off-white solid (0.25 g).
Reaction SMILES: [OH-].[Li+].[C:3]1([CH2:14][C:15]([O:17]C)=[O:16])[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1COCC1.Cl>O.CO>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccc(CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A 655 mg portion of lithium hydroxide was dissolved in 32 ml of water and added to 32 ml of a mixture of 6.4 g of dimethyl 2,2′-(1,4-phenylene)diacetate, 32 ml of THF and 32 ml of methanol. After 2Hours of stirring at room temperature, the reaction solution was neutralized with 1 M hydrochloric acid and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 2.6 g of [4-(2-methoxy-2-oxoethyl)phenyl]acetic acid. EN: 207.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH:42][CH2:43][CH:44]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][C@H:20]([C:32](=[O:34])[N:42]([CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:43][CH:44]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:45]([CH3:47])[CH3:46])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(CNCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CCCP(=O)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(CN(Cc1ccccc1)C(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (466.5 mg, 1 mmol), benzyl-(3-methyl-2-phenyl-butyl)-amine (279 mg, 1.1 mmol) and N-ethyldiisopropylamine (1.37 mL, 8 mmol) in dimethylacetamide (6 mL), propylphosphonic anhydride solution (˜50% in DMF, 0.95 mL, ˜1.5 mmol) is added. The reaction mixture is stirred for 7 h at RT and evaporated in vacuo. The residue is dissolved in ethyl acetate and washed twice with an aqueous 10% K2CO3 solution. The organic layer is dried (Na2SO4) and evaporated in vacuo and the residue is purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated to afford the title compound as a white amorphous solid. MS: 702.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.87 min.
Reaction SMILES: FC1C=CC(N[C:9]([C:11]2(C(NC3C=CC(OC4C5C(=CC(OC)=C(OC)C=5)N=C(C)N=4)=CC=3)=O)CC2)=[O:10])=CC=1.[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:43]=1[NH2:52].C(OC(=O)C)(=O)C>CCCCCCC>[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:43]=1[NH:52][C:9](=[O:10])[CH3:11]
Reactant: COc1cc2nc(C)nc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O

Procedure:
′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide. Commercially available 2-amino-4,5-dimethoxy-benzoic acid methyl ester (3 g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heated in heptane at 100° C. for 3 hours. After removal of heptane in vacuo, the crude product of 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester was obtained and used without further purification. LC/MS: m/z 254 (M+H).
Reaction SMILES: [N:1]([C:4]1[C:5]([N+:17]([O-:19])=[O:18])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([OH:15])[C:8]([OH:16])=[N:7]2)=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[Cl:14][C:13]1[C:4]2[C:5](=[N+:17]([O-:19])[O:18][N:1]=2)[C:6]2[N:7]=[C:8]([OH:16])[C:9]([OH:15])=[N:10][C:11]=2[CH:12]=1
Reactant: [N-]=[N+]=Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: [O-][n+]1onc2c(Cl)cc3nc(O)c(O)nc3c21
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 1 g (3,5 mmol) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinoxaline and 15 ml xylene was refluxed for 3 h. After cooling to 25° C. the precipitate was filtered off and washed with toluene and ether to give 0,86 g (96%) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide, m.p.>300° C. NMR (DMSO-d6): 12.6 (1H, broad s), 12.0 (1H, broad s), 7.10 (1H,s).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[CH:30]=1)[NH:27][C:26](=[O:35])[CH2:25]2.NC1C=C(F)C=C2C=1NC(=O)C2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[CH:30]=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:35])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[CH:24]4[C:28](=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[CH:30]=[C:22]([F:21])[CH2:23]4)[NH:27][CH2:26]3)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Agent: Nc1cc(F)cc2c1NC(=O)C2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4c(NC(C)=O)cc(F)cc43)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3CNC4=C(NC(C)=O)C=C(F)CC34)c(C)c2C1=O
Yield: 30.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide which was prepared by the acetylation of 7-amino-5-fluoro-1,3-dihydro-indole-2-one (prepared according to U.S. Pat. No. 6,114,371, US1997-810659) as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5-fluoro dihydro-1H-indol-7-yl}-acetamide (36 mg, 30.8%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15].C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:29])=[O:30])(=[O:20])=[O:21])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15]
Reactant: CCOC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC(=O)O)Cc2ccccc2)c1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield from 3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride as prepared in step b of Example 53, in a manner analogous to Example 27. 1H-NMR (300 MHz, DMSO-d6) δ 8.19 (t, J=7.9 Hz, 2H), 7.99 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.56 (br s, 4H), 7.34 (m, 5H), 6.74 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.63 (s, 2H), 3.97 (t, J=6.2 Hz, 2H), 3.89 (t, J=6.1 Hz, 2H), 3.51 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.5 Hz, 4H), 2.22 (s, 3H), 1.99 (pentet, J=6.1 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C27H32N4O9S2: 621.2 (M+H), 643.2 (M+Na). Found: 621.0, 642.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.ClCCl.[Br:17]N1C(=O)CCC1=O>CCCCCC>[Br:17][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1nc(N2CCOCC2)ncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
4-(4-Methylpyrimidin-2-yl)morpholine (300 mg) was mixed with dichloromethane (4 ml), and N-bromosuccinimide (357 mg) was added thereto at 0° C., followed by stirring at room temperature for 1 hour. Hexane was added to the reaction mixture, followed by purification by silica gel column chromatography (EtOAc/hexane), to obtain 4-(5-bromo-4-methylpyrimidin-2-yl) morpholine (372 mg).