Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:32]=[C:33]([OH:45])[CH:34]=[C:35]2[C:39]=1[NH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36]2>CC(N(C)C)=O>[NH3:3].[Cl:30][C:31]1[CH:32]=[C:33]([O:45][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:34]=[C:35]2[C:39]=1[NH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: CCOC(=O)c1cc2cc(O)cc(Cl)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2cc(Oc3ncnc4cc(OCCCN5CCCCC5)c(OC)cc34)cc(Cl)c2[nH]1
Product: N
Temperature: 100 °C
Reaction time: 2 h
Yield: 2 %
Yield: 120.6 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (84 mg, 0.24 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (162 mg, 1.18 mmol) and ethyl 7-chloro-5-hydroxyindole-2-carboxylate (62 mg, 0.26 mmol) in DMA (2.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated. The residue was purified by silica column chromatography using gradient elution dichloromethane with 2.5%, 5%, 10% methanol, then dichloromethane with 2% ammonia) to give 4-(7-chloro-2-(ethoxycarbonyl)indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (78 mg, 63%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:22][CH:21]=[N:20][CH:19]=2)=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:22]1[C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH2:7])=[CH:9][CH:10]=2)=[CH:19][N:20]=[CH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnco2)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnco2)c2ccccc12
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Compound 503C (1,34 g, 4.3 mmol) was dissolved in trifluoroacetic acid (10 mL) and the resulting mixture was allowed to stand for 1 h at room temperature. After removing the volatiles in vacuo, the residue was co-evaporated from ethyl acetate/heptane (2×50 mL) to remove traces of trifluoroacetic acid. After partitioning the residue between ethyl acetate (100 mL) and 1N NaOH (75 mL), the organic layer was washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 900 mg (99%) of compound 503D as a yellow crystalline solid. HPLC conditions: 95% at 0.92 min (retention time) (Phenomenex 5 micron ODS column, 4.6×30 mm, 10%–90% aqueous methanol over 2 min gradient with 0.1% TFA, monitoring at 254 nm.). MS (ES): m/z 211.22 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2SC.[CH3:24][S:25]([O-:27])=[O:26].[Na+].CN(C)CCN.CS(C)=[O:37]>>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([OH:37])[C:6]2[C:11](=[C:2]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CS(=O)[O-]
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Reactant: CS(C)=O
Agent: CN(C)CCN
Agent: [Na+]
Product: CS(=O)(=O)c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 120 °C
Yield: 27 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (400 mg, 1 mmol), copper(I) trifluoromethanesulfonate benzene complex (503 mg, 1 mmol), sodium methanesulfinate (752 mg, 6.26 mmol) and N,N-dimethylethylenediamine (0.039 mL, 0.36 mmol) was added DMSO (15 mL). The reaction vessel was evacuated and flushed with argon (2×), and the mixture was heated in a microwave synthesizer at 120° C. for 10 min. The mixture was filtered and the filtrate was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(methylsulfonyl)quinazolin-4-ol (100 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.22 (s, 3H) 7.81 (t, J=7.82 Hz, 1H) 8.00-8.11 (m, 2H) 8.38 (dd, J=7.54, 1.32 Hz, 1H) 8.45-8.51 (m, 1H) 8.71 (d, J=2.07 Hz, 1H) 13.64-13.78 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].Cl.Cl.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:28]([OH:31])=[CH:29][CH:30]=1>>[CH2:34]([N:33]([CH2:32][C:27]1[CH:26]=[C:25]([NH:24][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:30]=[CH:29][C:28]=1[OH:31])[CH2:36][CH3:37])[CH3:35]
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Reactant: CCN(CC)Cc1cc(N)ccc1O
Agent: Cl
Product: CCN(CC)Cc1cc(NC(=O)C(=C2C(=O)Nc3ccccc32)c2[nH]c(C)cc2C)ccc1O
Yield: 17.1 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 4-amino-alpha-diethylamino-o-cresol dihydrochloride (110 mg) using method B to give 25 mg (17%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH:24]=[C:25]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:26][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2sccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of benzothiophene (3 g, 22.4 mmol) in anhydrous tetrahydrofuran (50 ml) at -10° C. under nitrogen was added n-butyllithium (9.83 ml of a 2.5M solution in toluene), the mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was cooled to -40° C. and 1-benzyl-4-piperidone (4.23 g, 22.4 mmol) added, allowed to warm to room temperature and stirred for 14 hr. The reaction mixture was concentrated in vacuo and trifluoroacetic acid (10 ml) added. This mixture was stirred at room temperature for 14 hr and then concentrated in vacuo. The product was extracted into dichloromethane (3×100 ml) from aqueous potassium carbonate. The organic layer was washed with water (1×50 ml), brine (1×50 ml) and dried (MgSO4). After concentration of the extracts the crude product was purified using silica gel column chromatography to yield the title compound (4.2 g, 68%) as a colourless oil; δH (CDCl3) 2.64 (2H, m, tetrahydropyridinyl CH2), 2.74 (2H, m, tetrahydropyridinyl CH2), 3.18 (2H, m, tetrahydropyridinyl CH2), 3.65 (2H, s, PhCH2N), 6.18 (1H, m, CH=CR), 7.11 (1H, s, 3'-H), and 7.24-7.73 (9H, m, Ar--H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][N:20]([CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[CH3:31][N:20]([CH3:19])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: CN(C)c1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-[4-(dimethylamino)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (dd, J=7.9, 1.0, 1H), 8.04 (d, J=7.5, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.47 (d, J=8.7, 2H), 7.37 (d, J=8.6, 2H), 3.85-3.80 (m, 4H), 3.69 (s, 2H), 3.11 (s, 6H), 3.11-3.06 (m, 4H); MS (ESI−) M/Z 406 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:13]Cl.[C:15]([O-:18])(=[O:17])[CH3:16].[K+].CN(C=O)C>O>[C:15]([O:18][CH2:13][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:17])[CH3:16]
Reactant: O=c1c(Br)c(CCl)nc2ccccn12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc2ccccn2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4.53 g, 15.76 mmol), potassium acetate (1.5 equiv.) and DMF (60 mL) was stirred at 40° C. for 3.5 h, at this point the reaction was completed by LCMS. The mixture was cond under reduced pressure. To the residue was added water (100 mL) and the resulting precipitate was collected by filtration, washed with water (100 mL) and dried to give the (3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid, which was carried forward without further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.96-8.98 (dd,1H), 8.03-8.08 (m,1H), 7.74-7.76 (dd,1H), 7.43-7.48 (m,1H), 5.2 (s,2H), 2.1 (s,3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+].Cl>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCCCOCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCCCCCOCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 8-benzyloxyoctanoate was dissolved in 15 ml of THF. 15 ml (30 mmol) of phenylmagnesium bromide (2 M THF solution) was added dropwise to the obtained solution in ice bath. After stirring at room temperature for 4 hours, a saturated aqueous ammonium chloride solution and then 1 N hydrochloric acid were added to the reaction mixture to terminate the reaction. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under educed pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CC(C)=O>[C:29]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4])(=[O:31])[CH3:30]
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of (2S4R)1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (0.05 g, 0.17 mmol) and triethylamine (Aldrich) (0.19 mL, 1.37 mmol, 8 equivalents) in acetone (3 mL) was slowly added acetic anhydride (0.13 mL, 1.37 mmol, 8 equivalents) with stirring at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hours while monitored by LCMS. Upon completion, the volatiles were removed in vacuo and the residue was purified by preparative HPLC (column: Xterra MSC18 50×250 mm, 10 u) using 40/60 to 90/10 methanol/water gradient (0.1% formic acid in methanol and 0.1 formic acid in water) to afford 0.020 g (35% yield) of the desired product as white solid with limited solubility in organic solvents.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].C(N(C(C)C)C(C)C)C.[C:21]([NH:38][CH2:39][C:40](Cl)=[O:41])([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>C1COCC1.C(Cl)Cl.C1COCC1>[CH:27]1[C:26]2[CH:25]([CH2:24][O:23][C:21]([NH:38][CH2:39][C:40]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=3[Cl:11])=[O:41])=[O:22])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 4-amino-3-chlorobenzoic acid (1.5 g; 8.75 mmol) and N-ethyldiisopropylamine (1.46 mL 8.75 mmol) in THF (50 mL) was added dropwise to a solution of Fmoc-glycylchloride (2.76 g; 8.75 mmol) in CH2Cl2/THF 1:1 (30 mL) and stirred at room temperature under N2. After 3 h the solvent was evaporated under vacuum. The residue was taken up with 0.5N HCl (50 mL), filtered and dried. The white solid was suspended in MeOH (30 mL) and stirred for 1 h, then was filtered and dried to give 4-[[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetyl]amino-3-chlorobenzoic acid (2.95 g; 6.5 mmol). Yield 75%.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:22](=[O:36])[CH2:23][N:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.Cl.[CH3:54][O:55][C:56](=[O:59])[CH2:57][NH2:58]>CN(C)C=O.O1CCCC1.C(N(CC)CC)C>[CH3:54][O:55][C:56](=[O:59])[CH2:57][NH:58][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[C:13]([C:22](=[O:36])[CH2:23][N:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([CH3:26])([CH3:27])[CH3:28])[CH:12]=[CH:11][C:10]=2[O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:21]
Reactant: CC(C)(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
1.00 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid hydrochloride is combined with 4 ml of absolute dimethylformamide and 8 ml of absolute tetrahydrofuran, cooled to -10° C., and combined with 0.52 ml of N-ethylmorpholine and, 5 minutes later, with 0.28 ml of isobutyl chloroformate. The mixture is allowed to stand at -5° C. for 30 minutes, 376 mg of aminoacetic acid methyl ester hydrochloride, 0.39 ml of triethylamine--dissolved in 4 ml of absolute dimethylformamide and 6 ml of absolute tetrahydrofuran--are added thereto, the mixture is stirred for 16 hours at room temperature, concentrated, the residue is taken up in ethyl acetate/water, and the aqueous phase is acidified with 1N hydrochloric acid and once again extracted with ethyl acetate. The combined organic phases are dried, concentrated, and chromatographed over an aluminum oxide column (activity stage II; eluent: methanol/chloroform 1+4), thus obtaining 600 mg of N-[7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolylcarbonyl]aminoacetic acid methyl ester, mp 151.5°-152.5° C. (from methanol/diisopropyl ether).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)[O:41]CC.NC1C=CC(O)=CC=1>C(O)(=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:12][N:7]([C:1]3[CH:6]=[CH:5][C:4]([OH:41])=[CH:3][CH:2]=3)[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Nc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1-c1ccc(O)cc1
Yield: 49 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (500 mg, 1.99 mmol), triethyl orthoformate (5 ml), 4-aminophenol (412 mg, 3.78 mmol), and acetic acid (0.5 ml) were used to give 328 mg (0.97 mmol, 49% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]2[CH2:13][O:12]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:14].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH:21]([OH:24])([CH3:23])[CH3:22]>C(=O)=O>[N:15]1([CH2:22][CH:21]([C:23]2[CH:9]=[CH:8][C:7]3[C:6](=[O:14])[O:5][CH2:4][C:3]=3[C:2]=2[F:1])[OH:24])[CH2:20][CH2:19][N:18]([CH2:13][CH:11]([C:10]2[CH:9]=[CH:8][C:7]3[C:6](=[O:14])[O:5][CH2:4][C:3]=3[C:2]=2[F:1])[OH:12])[CH2:17][CH2:16]1
Reactant: O=C1OCc2c1ccc(C1CO1)c2F
Reactant: C1CNCCN1
Reactant: CC(C)O
Agent: O=C=O
Product: O=C1OCc2c1ccc(C(O)CN1CCN(CC(O)c3ccc4c(c3F)COC4=O)CC1)c2F

Procedure:
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-fluoro-2-benzofuran-1(3H)-one) was prepared in a similar fashion to that described for the synthesis of EXAMPLE 2 starting from 4-fluoro-5-oxiranyl-3H-isobenzofuran-1-one and piperazine. The isomers of the product were obtained via SFC resolution (Column Chiralcel OJ-H 100*4.6 mm I.D., Sum; Mobile phase: 40% iso-propanol (0.05% DEA) in CO2; Flow rate: 4.5 mL/min; Wavelength: 220 nm).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Br:3])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccnc(Br)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
NaH (761 mg, 19.83 mmol) was added portion wise to 2-bromo-4-hydroxypyridine (3 g, 17.24 mmol) in DMF (50 mL) at 0° C. under Ar(g). Then the reaction mixture was stirred at it for 10 min after which it was again cooled down at 0° C. and benzyl bromide (2.15 mL, 18.10 mmol) was added. The reaction was stirred at it for 4 h, after which it was poured onto brine (200 mL) and EtOAc (200 mL) was added. The phases were separated and the organic phase was dried over MgSO4, filtered and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 80:20) to furnish I as a white solid (2.331 g, 51%).
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH2:17][P:18]([O:21]CC)([CH3:20])=[O:19])[C:14](=[O:24])[O:13]C1)=O)C1C=CC=CC=1.[ClH:25]>>[ClH:25].[NH2:11][C@H:15]([C:14]([OH:24])=[O:13])[CH2:16][CH2:17][P:18]([CH3:20])(=[O:19])[OH:21]
Reactant: CCOP(C)(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Agent: Cl
Product: CP(=O)(O)CC[C@H](N)C(=O)O
Yield: 82.1 %

Procedure:
0.50 g (1.4 mmol) of (4S)-3-benzyloxycarbonyl-4-{2-[ethoxy(methyl)phosphinyl]ethyl}-1,3-oxazolidin-5-one (from Example 12) are, as described in DE-A-3,817,956, hydrolyzed by heating in 6N hydrochloric acid. 0.25 g (82.1% of theory) of L-homoalanin-4-yl(methyl)phosphinic acid hydrochloride are obtained as a white solid having a melting point of Mp 202° C. (decomposition).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(OCCN2CCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere a solution of 12.8 g (44.5 mmol) 1-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-pyrrolidine in 200 mL THF is combined with 15.5 g (49.0 mmol) TBAF and stirred for 3 h at RT. The solvent is distilled off i.vac., the residue taken up in EtOAc, the organic phase is washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the product is further reacted without any purification.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@H:9]2[C@@H:14]([N:15]([CH3:17])[CH3:16])[CH2:13][C@H:12]([O:18][C@@H:19]3[C:24]4[C:25]([OH:40])=[C:26]5[C:33](=[O:34])[C:32]6[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=6[C:29](=[O:30])[C:27]5=[CH:28][C:23]=4[C@@H:22]([C:41]([O:43][CH3:44])=[O:42])[C@@:21]([OH:46])([CH3:45])[CH2:20]3)[O:11][C@H:10]2[CH3:47])C[C@@H]2O[C@@H]3[C@H](O[C@H]12)O[C@@H](C)C(=O)C3.C[C@@H]1O[C@@H]([O:65][C@H:66]2[C@@H:71]([N:72]([CH3:74])[CH3:73])[CH2:70][C@H:69]([O:75][C@@H:76]3[C:81]4[C:82]([OH:97])=[C:83]5[C:90](=[O:91])[C:89]6[C:92]([OH:96])=[CH:93][CH:94]=[CH:95][C:88]=6[C:86](=[O:87])[C:84]5=[CH:85][C:80]=4[C@@H:79]([C:98]([O:100][CH3:101])=[O:99])[C@@:78]([OH:106])([CH2:102][C:103]([CH3:105])=[O:104])[CH2:77]3)[O:68][C@H:67]2[CH3:107])C[C@@H]2O[C@@H]3[C@H](O[C@H]12)O[C@@H](C)C(=O)C3>>[CH3:47][CH:10]1[O:11][CH:12]([O:18][CH:19]2[C:24]3[C:25]([OH:40])=[C:26]4[C:33](=[O:34])[C:32]5[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=5[C:29](=[O:30])[C:27]4=[CH:28][C:23]=3[CH:22]([C:41]([O:43][CH3:44])=[O:42])[C:21]([OH:46])([CH3:45])[CH2:20]2)[CH2:13][CH:14]([N:15]([CH3:17])[CH3:16])[CH:9]1[OH:8].[CH3:107][C@@H:67]1[O:68][C@@H:69]([O:75][C@@H:76]2[C:81]3[C:82]([OH:97])=[C:83]4[C:90](=[O:91])[C:89]5[C:92]([OH:96])=[CH:93][CH:94]=[CH:95][C:88]=5[C:86](=[O:87])[C:84]4=[CH:85][C:80]=3[C@@H:79]([C:98]([O:100][CH3:101])=[O:99])[C@@:78]([OH:106])([CH2:102][C:103]([CH3:105])=[O:104])[CH2:77]2)[CH2:70][C@H:71]([N:72]([CH3:74])[CH3:73])[C@@H:66]1[OH:65]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@@H]5O[C@H]6CC(=O)[C@H](C)O[C@H]6O[C@@H]5[C@H](C)O4)[C@H](C)O2)C[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@@H]5O[C@H]6CC(=O)[C@H](C)O[C@H]6O[C@@H]5[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Product: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O)[C@H](C)O2)C[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O

Procedure:
In a manner analogous to that described in Example 22, using a mixture of 200 mg of auramycin B and sulfurmycin B, there were obtained 25 mg of auramycin D and 35 mg of sulfurmycin D.