Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[N:13]([CH2:27][CH2:28][CH3:29])[CH2:12]1>C(Cl)Cl.C(N(CC)CC)C>[C:1]([NH:10][C@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[N:13]([CH2:27][CH2:28][CH3:29])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1C[C@@H](NC(=O)c2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 20 °C
Reaction time: 17.5 h

Procedure:
1.4 ml benzoylchloride in 5 ml CH2Cl2 are added drop-wise with stirring at 5°-10° C. to a suspension of 3.0 g 8α-amino-6-n-propylergoline in 100 ml CH2Cl2 and 2.0 ml triethylamine. The obtained reaction mixture is stirred for 15 to 20 hours at 20° C. and then washed thoroughly 2× with 25 ml 2N NaOH and H2O. The organic phase is dried over MgSO4, filtered and evaporated. The residue (pale brown foam) is dissolved in ethanol, and crystallised as the hydrobromide by addition of equivalent amounts of HBr in acetic acid. M.P. on recrystallisation from C2H5OH/H2O (80:2)=290° with decomposition.
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].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.74 (s, 3H), 6.77 (d, 2H, J=8.8 Hz), 7.21 (m, 2H), 7.27 (d, 1H, J=2 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.63 (m, 2H), 7.76 (d,1H, J=8.8 Hz), 8.76 (d, 2H, J=5.6 Hz), 9.88 (s, 1H). MS: m/z 403.9 (M++1).
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH2:14][CH:15]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[N:21][CH:22]=1)[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[Si:6]([O:13][CH2:14][CH:15]([C:17]1[CH:18]=[C:19]([B:24]([OH:29])[OH:25])[C:20]([F:23])=[N:21][CH:22]=1)[CH3:16])([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:8])[CH3:7]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CO[Si](C)(C)C(C)(C)C)c1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
n-Butyllithium (1.55M in hexane) (Aldrich, St. Louis, Mo.; 4.98 mL, 7.72 mmol) was added (dropwise over 5 min) to a solution of 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridine (1.89 g, 7.01 mmol) in THF (35 mL) at −78° C., and the resulting yellow solution was stirred at −78° C. for 1 h. Triisopropyl borate (Aldrich, St. Louis, Mo.; 1.935 mL, 8.42 mmol) was then added, and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was subsequently partitioned between EtOAc (250 mL) and water (90 mL) (1 N aq. HCl (12.0 mL) was added to bring the pH to about 6.5). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-ylboronic acid (2.25 g, 7.18 mmol, 102% yield) as a colorless oil, which was used directly in the subsequent step. m/z (ESI, +ve) 314.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8]([CH3:19])=[CH:7]2.[OH2:20].Cl.[C:22](Cl)(=[O:26])C(Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[C:8]([CH3:19])=[C:7]2[C:22]([OH:26])=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc2cccc(Cl)c2n1CCCNS(C)(=O)=O
Reactant: O
Agent: Cl
Product: Cc1c(C(=O)O)c2cccc(Cl)c2n1CCCNS(C)(=O)=O
Temperature: 120 °C

Procedure:
Under nitrogen, 2 g of 7-chloro-2-methyl-1-[3-(methylsulfonylamino)propyl]indole are dissolved in 16 ml of TCE at AT and 0.645 ml of oxalyl chloride in 7 ml of TCE is added. The mixture is heated at 120° C. for 16 hours and then cooled to AT. The reaction medium is diluted by adding 20 ml of water and is then poured onto 50 ml of a 10% HCl solution. The mixture is separated by settling out and the aqueous phase is then washed with DCM. The organic phases are combined and then washed with a saturated NaCl solution. Drying over Na2SO4 followed by concentration to dryness are performed and the product is purified by chromatography on silica, elution being carried out with CH2Cl2-MeOH (95/5; v/v). 1.33 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-3-(3-nitrophenyl)propanoic acid (20.00 g; 95.15 mmol; 1.00 eq.) in MeOH (300 mL) was added thionyl chloride (50.00 ml; 761.22 mmol; 8.00 eq.) at 0° C. slowly. Then the mixture was warmed to room temperature and stirred overnight. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel (MeOH: DCM=15:85) to obtain 20 g of the title compound. LCMS [225 (M+1)].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)cc2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.248 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (52.2 mg, 0.248 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of ice cold THF yielding 33% (48 mg, 0.083 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[CH:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C.[CH3:27]CCCCCC.CCOC(C)=O>>[CH3:27][C:4]1[CH:3]=[C:2]([C:1]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:7]=[CH:6][N:5]=1
Reactant: C#CCCCCCC
Reactant: CCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCC#Cc1cc(C)ncn1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and 1-octyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (37.6 mg, 40%); 1H NMR δ (CDCl3): 9.01 (s, 1H), 7.21 (s, 1H), 2.52 (s, 3H), 2.48 (t, J=7.23 Hz, 2H), 1.63 (p, J=7.17 Hz, 2H), 1.50-1.30 (m, 6H), 0.91 (t, J=7.25 Hz, 3H); LCMS m/z: 188.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:49]([O:51][CH3:52])=[O:50].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:29])([F:30])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)[C:49]([O:51][CH3:52])=[O:50])[C@H:14]2[CH3:45])[CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CNc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](CN(C(=O)OC)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}methyl)cyclohexyl]acetate (Step A; 50 mg; 0.73 mmol) in CH2Cl2 (3 mL) was added methyl chloroformate (50 μL) followed by diisopropylethylamine (102 μL; 0.585 mmol). The reaction stirred at 40° C. for 24 h. The reaction was diluted with EtOAc (25 mL) and washed successively with sat. NaHCO3, brine, 1N HCl and brine (15 mL each), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) and chiral HPLC (4% IPA/heptane; AD column) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](methoxycarbonyl)amino]methyl}cyclohexyl)acetate as a clear glass. LCMS=743.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.90-7.85 (m, 1 H), 7.78 (s, 1 H), 7.75 (s, 1 H), 7.27-7.17 (m, 3 H), 5.71 (d, J=8.0 Hz, 1 H), 5.00-4.54 (m, 1 H), 4.12 (q, J=7.1 Hz, 2 H), 4.10-4.02 (m, 1 H), 3.98-3.82 (m, 2 H), 3.80-3.58 (m, 3 H), 3.14-3.00 (m, 1 H), 2.17 (d, J=6.9 Hz, 2 H), 1.87-1.66 (m, 4 H), 1.52-1.41 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H), 1.13-0.94 (m, 4 H), 0.69 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:6]([N+:20]([O-:22])=[O:21])[C:7]=1[OH:8]
Reactant: O=c1n(CCCF)nnn1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])O
Product: O=c1n(CCCF)nnn1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(4-Chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-tetrazolinone (2.91 g) was gradually added into an ice-cooled nitric acid (20 ml) and stirred for 30 minutes. Crushed ice was added followed by extraction with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate, concentrated, and filtered through a silica gel SPE column (2 g) to give the title compound as a yellow solid (3.4 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][CH2:53][C:54]1[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=1[CH3:60]>ClCCl>[OH:62][C:55]1[C:54]([CH2:53][NH:52][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH:3]([O:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:2]([CH3:1])[CH3:20])=[CH:19][CH:18]=2)=[C:59]([CH3:60])[CH:58]=[C:57]([CH3:61])[N:56]=1
Reactant: CC(C)C(Oc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(Oc3ccccc3)C(C)C)cc2)c(O)n1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A mixture of 4-(2-methyl-1-phenoxypropyl)benzoic acid (208 mg, 0.77 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-te-tramethyluroniumhexafluorophosphate (439 mg, 1.2 mmol), triethylamine (0.32 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (30 mL). The organic phase was separated, dried over sodium, filtered, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methyl-1-phenoxypropyl)benzamide (Compound I-43) as a white solid (100 mg, 32%). LRMS (M+H+) m/z: calcd 404.21. found 404. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.33 (t, J=5.1 Hz, 1H), 7.47 (s, 1H), 7.34 (m, 3H), 7.20 (m, 3H), 6.88 (m, 2H), 5.84 (s, 1H), 5.54 (d, J=6.6 Hz, 1H), 4.25 (d, J=4.5 Hz, 2H), 2.35-2.30 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: [OH:1]S(O)(=O)=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[CH3:20][C:21]#[N:22]>>[CH3:15][C:14]([NH:22][C:21](=[O:1])[CH3:20])([C:11]1[CH:12]=[CH:13][C:8]([C:7]([F:19])([F:18])[F:6])=[CH:9][CH:10]=1)[CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Reactant: CC#N
Product: CC(=O)NC(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a cold (0° C.) solution H2SO4 (2.68 g, 27.3 mmol) in CH3CN (91 mL) was added dropwise a solution of 2-(4-(trifluoromethyl)-phenyl)-2-propanol (1.86 g, 9.1 mmol) in CH3CN (9.1 mL). The resulting reaction mixture was stirred at 0° C. for 1 h then at rt for 23 h. The solvent was evaporated under vacuo and H2O was added (20 mL). The mixture was extracted with Et2O (2×50 mL) and the combined organic layers were washed with H2O (2×20 mL), an aqueous solution of NaOH (1N) (2×20 mL), dried over MgSO4, filtered and evaporated to give the title compound as white solid (2.00 g, 90%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (d, J=8.3 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H), 2.10 (s, 3H), 1.79 (s, 6H). HPLC (Condition A), Rt: 3.18 min (HPLC purity: 97.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[C:13](=[O:29])[NH:14][C:15](=[O:28])[C:16]=1[C:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=2[O:19][CH:18]=1.[H-].[Na+].[CH3:32]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[C:13](=[O:29])[N:14]([CH3:32])[C:15](=[O:28])[C:16]=1[C:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=2[O:19][CH:18]=1
Reactant: Cn1cc(C2=C(c3coc4cc(CO)ccc34)C(=O)NC2=O)c2cc(F)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(c2coc3cc(CO)ccc23)=C(c2cn(C)c3ccc(F)cc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 3-(5-fluoro-1-methyl-1H-indol-3-yl)-4-(6-hydroxymethyl-benzofuran-3-yl)-pyrrole-2,5-dione (0.035 g, 0.090 mmol) in dry THF was added sodium hydride (0.005 g, 0.011 mmol, 55% in mineral oil) and methyliodide (0.006 mL, 0.090 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with ice water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by preparative TLC (methanol:dichloromethane; 5:95) to afford the product (0.012 g, 34%) as an orange solid. 1H NMR (CDCl3, 400 MHz) 3.19 (s, 3H), 3.86 (s, 3H), 4.71 (s, 2H), 6.62 (dd, J=2.3, 10.0 Hz, 1H), 6.83-6.90 (m, 3H), 7.21 (dd, J=4.3, 8.9 Hz, 1H), 7.51 (s, 1H), 7.81 (s, 1H), 8.11 (s, 1H), 13C NMR (CDCl3, 100 MHz) 23.9, 33.4, 64.8, 104.7, 106.5, 106.8, 109.6, 110.0, 110.1, 110.6, 110.8, 111.3, 121.4, 121.7, 122.1, 124.5, 126.1, 126.2, 130.8, 133.2, 134.4, 137.8, 147.0, 154.8, 156.6, 158.9, 170.9, 171.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.C(Cl)[Cl:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:25])=[O:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: ClCCl
Reactant: O=C(Cc1ccc(Br)cc1)N1CCOCC1
Solvent: CCN(CC)CC
Product: C1COCCN1
Product: O=C(Cl)Cc1ccc(Br)cc1

Procedure:
The compound shown on the left above, 2-(4-bromo-phenyl)-1-morpholin-4-yl-ethanone, is obtained by reaction of the corresponding acid chloride (A), (4-bromo-phenyl)-acetyl chloride, with morpholine and Et3N in DCM at rt. The product is obtained in high yield. The intermediate acid chloride (A) is obtained by reaction of (4-bromo-phenyl)-acetic acid (B) and oxalyl chloride (C) in DCM at rt and using DMF as reaction initiator. The intermediate (A) is obtained in good yield.
Reaction SMILES: C(O[C:4](=[O:17])/[C:5](/[C:15]#[N:16])=[CH:6]\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)C.C(OC(=O)/C(/C#N)=C/NC1C=CC(I)=CC=1)C.CCOCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[I:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]([C:15]#[N:16])[C:4]2=[O:17]
Reactant: CCOC(=O)/C(C#N)=C\Nc1ccc(I)cc1
Agent: CCOC(=O)/C(C#N)=C/Nc1ccc(I)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c[nH]c2ccc(I)cc2c1=O
Temperature: 260 °C
Yield: 85 %

Procedure:
A mixture of (Z)-2-cyano-3-(4-iodo-phenylamino)-acrylic acid ethyl ester and (E)-2-cyano-3-(4-iodo-phenylamino)-acrylic acid ethyl ester (example 14a, 150 g, 0.44 mol) in diphenylether (1500 mL) was refluxed at 260° C. for 12 h. After cooling, ether was added. The solid was collected by filtration, washed with ether and dried to obtain 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (110.5 g, 85%) as a black solid. LC-MS m/e 297 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([CH:12]([NH2:19])[C:13]3[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].O.O.Cl.CN(C)C=O>O>[CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(N)C3=CCC=CC3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)C3=CCC=CC3)[C@H]2SC1
Temperature: 25 °C

Procedure:
50 g of commercially available cephradine hydrate were suspended in a mixture of water and conc. hydrochloric acid (180/7) at 5° to 10° C. with stirring. The pH was brought to 1.6 to 2.0 with hydrochloric acid in order to form a complete solution and 16 g of dimethylformamide were added. The solution was filtered and the residue was washed with 35 ml of water. The combined filtrate was warmed to 35° to 40° and the pH brought to 2.8 with aqueous triethylamine. Stirring was continued for several minutes and the pH was finally adjusted to about 4.9 with aqueous triethylamine. The resulting slurry was cooled to room temperature and filtered. The residue was washed with 80% (v/v) acetone and dried to obtain the heading compound, m.p. 190° to 200° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3F)c2c1O
Product: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and phenylboronic acid: MS (m/z) 395.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[N:26]1[C:30]([NH2:31])=[CH:29][C:28]([CH3:32])=[N:27]1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:31][C:30]2[N:26]([C:21]3[C:20]4[C:25](=[C:16]([F:15])[CH:17]=[CH:18][CH:19]=4)[N:24]=[CH:23][CH:22]=3)[N:27]=[C:28]([CH3:32])[CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)n(-c2ccnc3c(F)cccc23)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2ccnc3c(F)cccc23)n1
Temperature: 80 °C
Yield: 2 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.13 g, 0.55 mmol) and crude 1-(8-fluoroquinolin-4-yl)-3-methyl-1H-pyrazol-5-amine (0.14 g, 0.55 mmol) in pyridine (1 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.005 g, 0.011 mmol, 2%). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=4.8 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.47-7.41 (m, 5H), 7.13 (d, J=4.8 Hz, 1H), 6.20 (s, 1H), 2.35 (s, 3H), 1.35 (s, 9H); MS: (ES) m/z calculated for C23H24FN4O2S [M+H]+ 439.5. found 439.3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].CCCCCC>C1(C)C=CC=CC=1>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:31][CH2:30][C@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[O:32][C:6]=2[C:5]=1[CH3:9]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 93 %

Procedure:
Suspended in 1 ml of toluene were 200 mg (1.316 mmol) of trimethylhydroquinone (TMH) and 100 mg of Sc-Bent, followed by heating under reflux for 10 minutes under an argon gas stream. After a solution of 430 mg (1.45 mmol) of isophytol in 1 ml of toluene was added dropwise over 5 minutes under heating and reflux, TMH and isophytol were further reacted each other for 1 hour. The reaction liquid was cooled, to which 20 ml of n-hexane were added. The resulting mixture was filtered and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: n-hexane-ether system), whereby 527 mg of the title compound were obtained in the form of a brown oil. (Yield: 93%, GLC purity: 99%)