Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=1)[C:34]([NH2:36])=[O:35]>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(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=3)[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: NC(=O)c1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)Cc2cc(-c3cncc(C(N)=O)c3)ccc21
Temperature: 150 °C

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 3a (75 mg, 0.26 mmol) in 12-dimethoxyethane (0.7 mL) was added water (0.3 mL) and ethanol (0.2 ml). The solution was then charged with sodium carbonate (27.6 mg, 0.26 mmol) and 5-bromonicotinamide (CAS#28733-43-9, 53.5 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (CAS#13965-03-2, 9.1 mg, 0.013 mmol). The reaction vessel was sealed and was heated by microwave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to room temperature, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (methanol-dichloromethane, 0 to 10%) to furnish 5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-nicotinamide; MS: (ES+) m/z 268 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 3H), 3.63 (s, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.62 (br. s., 1H), 7.69-7.75 (m, 2H), 8.22 (br. s., 1H), 8.42 (t, J=2.0 Hz, 1H), 8.94 (dd, J=18.9, 1.96 Hz, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:5]([O:4][CH2:2][CH3:3])=[O:11])=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)OC(=O)c1cc(N=C=S)ccc1Cl
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCN1C(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
1.8 g (0.01 mol) of proline ethyl ester hydrochloride and 1.0 g of triethylamine were added dropwise to 30 ml of benzene and 2.6 g (0.01 mol) of 4-chloro-3-isopropoxycarbonylphenyl isothiocyanate were added thereto. The mixture was stirred at room temperature for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by means of silica gel column chromatography to give 2.5 g (yield 63%) of the desired product as a yellow glassy substance.
Reaction SMILES: [I-:1].[NH+]1C=CC=C[CH:3]=1.[CH:8]([NH:10][C:11]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:9].CI.C(NC1C=CC=CC=1CCC1C=CC=CN=1)=O>>[I-:1].[CH:8]([NH:10][C:11]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[CH3:3])=[O:9]
Reactant: c1cc[nH+]cc1
Reactant: COc1ccc(NC=O)c(CCc2ccccn2)c1
Agent: O=CNc1ccccc1CCc1ccccn1
Agent: [I-]
Solvent: CI
Product: COc1ccc(NC=O)c(CCc2cccc[n+]2C)c1
Yield: 95 %

Procedure:
The pyridinium iodide is obtained by treating 2-(2-formamido-5-methoxyphenethyl)pyridine with methyl iodide according to the procedure described in Example 2 (c) for 2-(o-formamidophenethyl)pyridine. Analytically pure 2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide is obtained in a yield of 95% and has a melting point of 184°-186.5° C. (corr.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[OH:41][CH:38]1[CH2:39][CH2:40][N:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:22]3[CH:21]=[C:20]([O:19][C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[S:13])=[CH:43][CH:42]=4)[CH:25]=[CH:24][N:23]=3)=[O:28])[CH2:30][CH2:31]2)[CH2:36][CH2:37]1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reaction time: 4 h
Yield: 19 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (214 mg) and (+)-10-camphorsulfonic acid (105 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=100:0 to 97:3) to provide the title compound (58.6 mg, 19%) as white powder.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>COCCOC>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: NS(N)(=O)=O
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: COCCOC
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(S(N)(=O)=O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A mixture of Example 1 (42 mg, 0.0896 mmol) and sulfamide (15 mg, 0.155 mmol) in DME (1 mL) in a sealed tube was heated at 90° C. overnight. After condensation, the residue was purified by CombiFlash (eluent: 5% 7N NH3 in methanol in DCM) to give the product as a yellow oil. LC/MS: C23H32F3N5O5S: m/z 548.2 (M+H).
Reaction SMILES: Br[CH:2]([CH3:24])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)=[O:4].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([CH:2]([CH3:24])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=[CH:8]3)=[O:4])[CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C(=O)C(C)Br)ccc32)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(=O)C(C)N4CCC(O)(c5ccccc5)CC4)ccc32)cc1
Yield: 86.8 %

Procedure:
5-(2-Bromopropionyl)-1-(p-toluenesulfonyl)indole (1.67 g, 3.37 mmol, 83% purity) was dissolved in hot ethanol (100 ml) and 4-hydroxy-4-phenylpiperidine (0.6 g, 3.39 mmol) and triethylamine (0.94 ml, 6.74 mmol) were added. The mixture was refluxed overnight. The reaction was cooled and concentrated directly onto silica gel and flash chromatographed. Elution with 1:3 ethyl acetate:hexane removed 0.1 g of non-brominated ketone. Continued elution with 1:1 ethyl acetate hexane gave 1.47 g, 87% of the title product as a glassy orange solid. NMR 8.34 (s, 1H), 8.09 (d, J=9 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.33-7.29 (m, 2H), 7.24-7.21 (m, 4H), 6.72 (d, J=3.5 Hz, 1H), 4.18 (q, J=7 Hz, 1H), 2.88-2.84 (m, 2H), 2.73-2.62 (m, 2H), 2.32 (s, 3H), 2.18-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.77-1.66 (m, 1H), 1.59-1.54 (m, 1H), 1.31 (d, J=7 Hz, 3H). IR 1679, 1605, 1375, 1289, 1260, 1169, 1126, 994. FAB HRMS calcd for C29H31N2O4S (MH+): 503.2006. Observed m/e: 503.2023.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[F:22][C:23]1[CH:24]=[C:25]([C@H:30]2[O:34][C:33](=[O:35])[NH:32][C@H:31]2[CH3:36])[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:32]2[C@@H:31]([CH3:36])[C@@H:30]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[O:34][C:33]2=[O:35])[CH:6]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(F)cc(F)c1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3cc(F)cc(F)c3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4S,5R)-5-(3,5-difluoro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)O.[OH-].[Na+]>FC(F)(F)C(O)=O>[NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
After dissolving 120 mg of t-butyl 4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added and extraction was performed with ethyl acetate. The extract was washed with saline and dried over sodium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. After adding 5 ml of tetrahydrofuran, 26 mg of acetic acid, 92 mg of sodium triacetoxyborohydride and 0.5 ml of formaldehyde (37% in water) to the residue, the mixture was stirred at room temperature for 10 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with saline and then passed through a glass filter coated with NH type silica gel. The silica gel was washed thoroughly with ethyl acetate, the ethyl acetate layers were combined and subjected to distillation under reduced pressure, and the residue was solidified with ethyl acetate and hexane to obtain 80 mg of a colorless powder.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:14]1=[O:27]>C(O)C>[OH:11][CH:9]([CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][N:18]1[CH2:19][CH2:20][C:15]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:13]([CH3:12])[C:14]2=[O:27])[CH2:16][CH2:17]1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCO
Product: CN1C(=O)C2(CCN(CC(O)COc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 1.7 g of 1-phenoxy-2,3-epoxypropane, 2 g of 1-methyl-2-oxo-indoline-3-spiro-4'-piperidine and 120 ml of ethanol was refluxed for 3 hours. The resulting mixture was concentrated and crystallized from diisopropylether to give 1'-(2-hydroxy-3-phenoxypropyl)-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine
Reaction SMILES: C(=O)([O-])[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:29][CH2:30][CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[CH2:29]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[C@@H:13]([CH2:24][CH3:25])[C:14]1=[O:23])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CCCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with 1-bromobutane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1-Butyl-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−4° (c=0.0058 G/ML, DMSO); MS (ESI) m/z 407 ([M+H]+); MS (ESI) m/z 405 ([M−H]−);
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([C:24]([OH:26])=O)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([C:24]([Cl:3])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-c2cccnc2C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(-c2cccnc2C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (8 mL) and N,N-dimethylformamide (few drops) are added to a solution of 3-(3-methoxy-phenyl)-pyridine-2-carboxylic acid (11.86 g) in dichloromethane (80 mL). The mixture is heated to 40° C. and stirred at this temperature overnight. The solution is then concentrated and the residue is taken up in toluene and concentrated again to give the crude title compound that is used without further purification in the next step. Yield: 12.80 g (crude).
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=O)[C:6]=2[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.[NH2:19][NH2:20]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[O:18])[NH:20][N:19]=[C:7]3[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[NH:10][C:11]=1[C:6]=23
Reactant: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(F)c2[nH]1
Reactant: NN
Solvent: CCO
Product: O=C(O)C1=Cc2n[nH]c(=O)c3ccc(F)c(c23)N1
Temperature: 90 °C

Procedure:
To a solution of 35 (0.600 g, 2.39 mmol) in EtOH (5 mL) was added hydrazine (0.0840 g, 2.63 mmol). The resulting mixture was heated at 90° C. for 24 hand then cooled to room temperature. The resulting precipitate was filtered, washed with Et2O (25 mL), and dried in vacuum at 60° C. for 6 h to give a white solid (36, 0.484 g, 74.5%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.25-8.30 (m, 1H), 7.51-7.57 (m, 1H), 7.06 (s, 1H); Anal. Calcd for C11H6N3O3F (2H2O): C, 46.65; H 3.56; N 14.84. Found: C, 46.80; H, 3.59; N, 14.86.
Reaction SMILES: [O-]CC.[Na+].CCO[C:8]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=[O:9].Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[CH3:21][C:20]1[NH:23][C:8](=[O:9])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:22]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a freshly prepared solution of sodium ethoxide (18 g of sodium metal was dissolved in 1 L of ethanol), was added ethyl benzoyl acetate (75 g, 0.39 mol) and the mixture was stirred at room temperature for 30 min. To this was added acetamidine hydrochloride (37 g, 0.39 mol) in portions and the mixture was refluxed for 24 h under nitrogen. The reaction mixture was cooled and excess ethanol was removed under vacuum. The residue was acidified to pH=4 with 1.5N HCl and the precipitate was filtered and dried under suction to afford 15 g (21%) of the titled compound as a white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2](=[O:11])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1cnc2ccc(Br)cc2[nH]1
Reaction time: 18 h
Yield: 66.2 %

Procedure:
To a stirred solution of 1H-quinoxalin-2-one (50 g, 342.5 mmol) in glacial acetic acid (2500 mL) was added bromine (54.7 g, 342.5 mmol in 120 mL acetic acid) over a period of 1.5 h at rt. After 18 h stirring, the mixture was slowly poured into 2000 mL water and stirred for 1 h at rt. The precipitate was filtered and the residue was washed with water and dried to give 7-bromo-1H-quinoxalin-2-one as an off-white solid (51 g, 66%): 1H-NMR (300 MHz, d6-DMSO): δ=12.42 (1H, s), 8.19 (1H, s), 7.75 (1H, d), 7.44 (2H, m) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:23])[C:21]=1[NH2:22])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](ON1C(=O)CCC1=O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)(Cl)Cl>[NH2:22][C:21]1[N:20]([CH3:23])[N:19]=[CH:18][C:17]=1[NH:16][C:14](=[O:15])[C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (4.90 g) and triethylamine (1.52 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.26 g). The mixture was stirred at room temperature for 17 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[N:27]1[O:31][N:30]=[C:29]2[C:32]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:34]=[CH:35][C:28]=12.N1C=CC=CC=1>>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:36]([C:32]2[C:29]3=[N:30][O:31][N:27]=[C:28]3[CH:35]=[CH:34][CH:33]=2)(=[O:38])=[O:37])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH3:26]
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: c1ccncc1
Product: CCOc1ccc(NS(=O)(=O)c2cccc3nonc23)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
120 ml (0.34 mmol) of the compound from example 42A are reacted with 111 mg (0.509 mmol) of benzofurazane-4-sulfonyl chloride and 0.17 ml (2.10 mmol) of pyridine. Yield: 109 mg (60.1% of theory).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1[CH:65]=[CH:64][C:63]([CH2:66][CH2:67]O)=[CH:62][CH:61]=1>C(Cl)Cl>[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:67][CH2:66][C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCCc1ccncc1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCc4ccncc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Diethyl azodicarboxylate (244 mg, 1.4 mmol) was added to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(4-pyridyl)ethanol (104 mg, 0.84 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), in methylene chloride and the mixture stirred for 30 minutes at ambient temperature. The solvent was removed by evaporation. The residue was suspended in ether and the ether then decanted. The resulting crude oil was purified by column chromatography eluting with methylene chloride/methanol (90/10) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline (300 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[C:4]=2[CH:3]=1.C([Li])(C)(C)C.C(O[B:39]1[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]1)(C)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([B:39]4[O:40][C:41]([CH3:46])([CH3:47])[C:42]([CH3:44])([CH3:45])[O:43]4)=[CH:7][C:6]=3[C:5]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])=[CH:13][CH:14]=1
Reactant: BrCCCCCCC1(CCCCCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC1(C)OB(c2ccc3c(c2)C(CCCCCCBr)(CCCCCCBr)c2cc(Br)ccc2-3)OC1(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
2,7-Dibromo-9,9-bis(6-bromohexyl)fluorene (2.00 g, 3.08 mmol, 1 eq.) was dissolved in diethyl ether (25 ml). The solution was cooled to −78° C. and t-butyllithium (2.0 mL of a 1.7 mole/L solution in hexanes, 3.38 mmol, 1.1 eq.) was added drop wise with strong stirring. The resulted white suspension was allowed to warm to −10° C. and stirred for 10 min. Then the solution was cooled to −78° C. again and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.69 mL, 3.38 mmol, 1.1 eq.) was added in one time. The mixture was stirring for another 1 h at −78° C. and was allowed to warm to 25° C. and stirred for 24 h, and then the reaction was quenched by 10 mL of water. The organic layer was washed thoroughly by water and was dried by anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude oil was separated by column chromatography with hexane/chloroform=3/1 (v/v) as eluent to give 1.18 g of white powder (yield=50%). 1H NMR (500 MHz, CDCl3) δ (ppm): 7.81 (d, J=7.55 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=7.55 Hz, 1H), 7.58 (dd, J=1.90 and 6.70 Hz, 1H), 7.46 (dd, J=1.80 and 6.70 Hz), 3.27 (t, J=6.85 Hz, 4H), 2.03-1.95 (m, 2H), 1.94-1.91 (m, 2H), 1.67-1.62 (m, 4H), 1.39 (s, 12H), 1.19-1.14 (m, 4H), 1.09-1.04 (m, 4H), 0.61-0.55 (m, 4H). 13C NMR (500 MHz, CDCl3) δ (ppm): 153.19, 149.12, 142.97, 139.98, 134.06, 130.09, 128.75, 126.14, 121.64, 121.56, 119.14, 83.85, 55.35, 40.00, 33.88, 32.65, 28.97, 27.76, 24.98, 23.44.