Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.C([N:35](CC)CC)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N1C=CC=CC=1>C1COCC1>[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[CH:16][CH:15]=1)#[N:35]
Reactant: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cccc(-c2ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(3′-methylbiphenyl-4-yl)propanoic acid (1.37 g, 3.85 mmol) in THF (25 mL) were added ethyl chloroformate (0.407 mL, 4.24 mmol) and triethylamine (0.591 mL, 4.24 mmol) at room temperature. After being stirred for 0.5 hours, the resultant precipitate was removed by filtration. The filtrate was treated with ammonium hydroxide (10 mL) and stirred for 1.5 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in THF (25 mL). TFAA (0.817 mL, 5.81 mmoL) and pyridine (0.935 mL, 11.56 mmol) were added at −10° C. and stirred for 2 hours. The reaction was quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (EtOAc/heptane) to give (S)-tert-butyl 1-cyano-2-(3′-methylbiphenyl-4-yl)ethylcarbamate. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.42 (s, 3.04-3.19 (m, 2H), 4.68-4.94 (m, 2H), 7.17 (d, J=7.58 Hz, 1H), 7.31-7.41 (m, 5H), 7.59 (d, J=8.08 Hz, 2H); MS: m/z (MH+) 337; Retention time=1.60 min. (condition A).
Reaction SMILES: [C:1](OC)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH3:20])=[CH:14][CH:13]=1.C[O-].[Na+].[NH:25]([CH2:27][CH2:28][OH:29])[NH2:26]>C1COCC1.CCO.CC(O)=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[N:25]([CH2:27][CH2:28][OH:29])[N:26]=[C:1]([C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[CH:20]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: NNCCO
Reactant: COC(=O)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCCn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 75 °C

Procedure:
To a solution of methyl isonicotinate (2 g, 14.58 mmol) in THF (50 mL) was added 4-fluorophenylacetone (2.54 mL, 18.9 mmol) and sodium methoxide powder (1.6 g, 29.17 mmol) was added in one portion with stirring. The resulting suspension was heated to 75° C. for 2 hours under nitrogen, then cooled to ambient and AcOH added (3 mL) followed by EtOH (60 mL) forming a dark orange solution. 2-hydrazinoethanol (3.5 mL, excess) was then added and the mix stirred for 16 hours at room temperature. The volatiles were removed in vacuo and the residue diluted with EtOAc (250 mL) and washed with water (3×50 mL), brine (50 mL), dried over MgSO4, filtered and stripped to a red oil. TLC revealed a mixture of regioisomers that were purified by Biotage flash chromatography, eluting with 2-6% MeOH/DCM, then separated by chiral SF chromatography to afford pure isomers that were characterized by NOE NMR. The title compound was isolated as a white solid, 1.0 g, 23%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.48-8.62 (2 H, m), 7.52-7.65 (2 H, m), 7.14 (2 H, dd, J=8.59, 5.31 Hz), 6.94-7.08 (2 H, m), 6.38 (1 H, s), 4.05-4.14 (2 H, m), 3.94-4.05 (4 H, m), 3.42-3.60 (1 H, m); m/z (APCI+) for C17H16N3FO 297.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:22])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(SC)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCn1ncc2c(Cl)c3cc(SC)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-(methylthio) anthranilic acid (4.5 g) and POCl3 (20 ml) is refluxed overnight. The reaction mixture is poured into water, then ice is added. The mixture is extracted with CH2Cl2 and then the CH2Cl2 layer is evaporated. The residue is purified by column chromatography on silica gel eluting with 50% ethyl acetate/hexane to afford 2.4 g of 1-ethyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-b]quinoline, m.p. 120°-121° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: OCCC1CCNCC1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: OCCC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2,6-dichlorobenzothiazole (3.00 g; 14.7 mmol), 4-piperidine ethanol (2.09 g; 16.2 mmol), potassium carbonate (2.33 g; 16.2 mmol) and anhydrous N,N-dimethylformamide (15 ml) was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with diisopropyl ether to give 6-chloro-2-[4-(2-hydroxyethyl)piperidine-1-yl]benzothiazole as green crystal (2.92 g; 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:18][NH2:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
100 g piperidine-1,4-dicarboxylic acid 1-tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine monohydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/MeOH=20/1)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1.[OH-].[K+]>[C:4]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH2:13][N:2]([CH3:3])[CH3:1])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CN(C)C[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.2 %

Procedure:
Dimethylamine (11.2 g, 249.3 mmol, 30.0 equiv) was added portionwise to a stirred solution of toluene-4-sulfonic acid(S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentyl ester (3.2 g, 8.31 mmol, 1.0 equiv.) in pyridine (9.6 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for an additional 20 hours at the same temperature. The reaction mixture was diluted with the addition of an aqueous solution of 10% potassium hydroxide (w/v; 30 mL) and was extracted with dichloromethane (3×150 mL). The collected organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude mass. This was purified by purified by silica gel column chromatography (100-200 mesh) using a gradient of 2-5% methanol/dichloromethane to give ((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (1.4 g, 65%).
Reaction SMILES: ClC(Cl)OC.[CH3:6][C:7]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[CH3:28])[N:8]=1.[CH:29]1([CH2:32]O)[CH2:31][CH2:30]1>>[CH3:6][C:7]1[C:11]([CH2:12][C:13]([O:15][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[O:14])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[CH3:28])[N:8]=1
Reactant: Cc1ccncc1-n1nc(C)c(CC(=O)O)c1-c1ccccc1
Reactant: OCC1CC1
Agent: COC(Cl)Cl
Product: Cc1ccncc1-n1nc(C)c(CC(=O)OCC2CC2)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
0.296 g (2.575 mmol) of dichloro(methoxy)methane was added to 0.175 g (0.569 mmol) [3-methyl-1-(4-methylpyridin-3-yl)-5-phenyl-1H-pyrazol-4-yl]acetic acid, and the mixture was stirred at 60° C. for 2 h. Excess dichloro(methoxy)methane was removed under reduced pressure, 0.660 g (9.153 mmol) of cyclopropylmethanol was added to the residue and the mixture was stirred at 20° C. for 0.5 h. The solvent was removed under reduced pressure, a mixture of 10 ml of dichloromethane, 1.5 ml of diisopropylethylamine and 10 ml of water was added to the residue and the aqueous phase was extracted with 15 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.123 g (59% of theory) of a colorless solid of m.p. 87° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=1>CCOC(C)=O>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:36][C:37]4[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CC(=O)O)cc3)c2)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 [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added (4-Amino-phenyl)-acetic acid (41.4 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. EtOAc (3 mL) was added to the mixture and was washed with 5% HCl(aq) (2 mL) and H2O (2×2 mL). The organic layers were combined dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The solid was then recrystallized from EtOAc/Hexanes affording 51% (0.068 g, 0.127 mmol) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1cccc(I)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-3-trifluoromethyl-benzene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:14]=O.[C:23](#[N:27])[CH2:24][C:25]#[N:26].C1N2CCN(CC2)C1>C(O)C.O>[NH2:27][C:23]1[O:1][C:2]2[N:3]=[C:4]([CH3:9])[N:5]=[C:6]([CH3:8])[C:7]=2[CH:14]([C:13]2[CH:16]=[C:17]([O:21][CH3:22])[C:18]([O:19][CH3:20])=[C:11]([Br:10])[CH:12]=2)[C:24]=1[C:25]#[N:26]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Reactant: Cc1cc(O)nc(C)n1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3nc(C)nc(C)c32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
4-Hydroxy-2,6-dimethylpyrimidine (546 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 2 ml ethanol at room temperature, charged with DABCO (48.4 μl, 1.46 mmol) and then stirred at 80° C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.52 g, 3.64 mmol, 82.8%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[CH:17][N:16]([Si](C(C)C)(C(C)C)C(C)C)[C:13]3=[N:14][CH:15]=2)[C:6](=[O:29])[CH2:5]1)[CH2:2][CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.O>C1COCC1>[CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[C:6](=[O:29])[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CC(=O)N(Cc2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cc2cnc3[nH]ccc3c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256 (0.7 g, 1.7 mmol) is dissolved in absolute THF (7 ml). A 1 M solution of tetrabutylammonium fluoride in THF (1.7 M, 1 eq) is added. The obtained solution is stirred for 10 min at room temperature and poured into a mixture of ether (100 ml) and water (20 ml). The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is purified by chromatography on silicagel (dichloromethane/isopropanol) to yield 0.43 g of 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one 241.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH2:11]([C:15]1[CH:20]=[C:19](Cl)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14].O>CN(C=O)C>[CH2:11]([C:15]1[CH:20]=[C:19]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCc1cc(Cl)n2nccc2n1
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
60% sodium hydride, 0.55 g, was added to a 10 ml-solution of 1.6 g of 4-(hydroxymethyl)pyridine in DMF while being ice-cooled. After the mixture was stirred at 0° C. for 30 minutes, a DMF solution (2.5 ml) containing 2.6 g of 5-(3-butenyl)-7-chloropyrazolo[1,5-a]pyrimidine was added dropwise while being ice-cooled. The mixture was stirred at the same temperature for another 1 hour. After completion of the reaction, water was added to the reaction mixture. The crystals precipitated were collected by filtration and washed with water and then with diethyl ether. The crude crystals obtained were recrystallized from ethyl acetate-n-hexane to provide 1.5 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[CH:7]=[C:6]([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2cc(Cl)ccc12
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nc2cc(Cl)ccc12
Temperature: 0 °C
Yield: 72 %

Procedure:
A solution of quinolone 13 (10 g; 51.6mmol) in 90 ml of POCl3 was refluxed for 2 hours. After cooling, the mixture was poured into 300 g ice-water and neutralized with NH4OH. The resultant precipitate was filtered off and washed with cold H2O. The crude product was recrystallized from 95% ethanol to obtain 8.95 g (72%) of 14. 1H NMR (CDCl3): δ2.71 (s, 3H); 7.28 (d, 1H); 7.55 (d, 1H); 7.92 (d, 1H); 8.08 (d, 1H).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[F:5][C:6]([F:15])([F:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:1](=[O:4])[CH3:2])=[CH:9][CH:8]=1
Reactant: CC(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Acetic acid (1.321 g, 22.000 mmol) was dissolved in DMF (10 ml), 1-[4-(trifluoromethyl)phenyl]methanamine (3.468 g, 19.800 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (7.770 g, 24.200 mmol) and N-ethyl-N,N-diisopropylamine (5.971 g, 46.200 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation and gave 3.085 g of N-[4-(trifluoromethyl)benzyl]acetamide (yield 64.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](Cl)Cl>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: ClCCl
Product: COC(=O)Cc1cccc(Br)c1

Procedure:
To a solution of 3-bromophenylacetic acid (10 g, 46 mmol) in CH2Cl2 (20 mL) was added CH2N2 (Et2O) until yellow coloration persisted. The resulting reaction mixture was quenched with AcOH, and diluted with a NaHCO3 solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated to provided the (3-Bromo-phenyl)-acetic acid methyl ester compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)=O.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25].N1CCCC1>C(O)CC>[C:24]([O:28]/[N:29]=[C:7](\[C:9]1[C:14]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)/[C:6]1[CH:20]=[C:2]([Cl:1])[C:3]([F:22])=[CH:4][C:5]=1[OH:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(c1cc(Cl)c(F)cc1O)c1ncccc1C1OCCO1
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: C1CCNC1
Solvent: CCCO
Product: CC(C)(C)O/N=C(/c1cc(Cl)c(F)cc1O)c1ncccc1C1OCCO1
Yield: 30.5 %

Procedure:
A solution of 2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (1.45 g), O-t-butylhydroxylamine hydrochloride (1.69 g) and pyrrolidine (9.56 g) in n-propanol (20 ml) was heated for 1.5 hour under reflux. The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give a mixture (540 mg) of (Z)-2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine O-t-butyloxime and (Z)-2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-yl)benzoyl]-3-(1,3-dioxolan-2-yl)pyridine O-t-butyloxime (about 2:1). A mixture of this mixture (470 mg), p-toluenesulfonic acid monohydrate (162 mg), acetone (9.0 ml) and water (3.5 ml) was heated for 14 hours under reflux. The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated to leave an oily substance. This oily substance was dissolved in chloroform (2.0 ml), to which was added, at room temperature, 50% m-chloroperbenzoic acid (75 mg). The mixture was stirred for 8 minutes at the same temperature, which was then poured into an aqueous solution of sodium sulfite, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-formylpyridine O-t-butyloxime (230 mg) (Compound 155).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](OC)=[O:18]>C1COCC1.C(O)(=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(F)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COP(=O)(CC(=O)c1cccc(F)c1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (10.1 g, 81.2 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.58N, 51.4 ml, 81.2 mmol) at -78° C. under argon atmosphere. After 30 minutes, methyl m-fluorobenzoate (5.0 g, 32 mmol) was further added dropwise and the mixture was stirred for 30 minutes. The reaction solution was allowed to warm to 0° C., diluted with 4.9 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give an oil of dimethyl 2-m-fluorophenyl-2-oxo-ethylphosphonate (6.6 g, 26.8 mmol, yield 83.8%, b.p. 132°-134° C./0.17 mmHg), which was assigned the structure by the following data: