Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=[C:7]2[CH:6]=[N:5]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[C:9]3[CH:15]=[CH:14][N:13]([S:22]([C:19]4[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=4)(=[O:24])=[O:23])[C:10]3=[N:11][CH:12]=[C:7]2[CH:6]=[N:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ncc2cnc3[nH]ccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnn(C)c23)cc1
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 0.209 g, 5.23 mmol) in DMF (10 mL) at about 0° C. was added a solution of 1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.60 g, 3.5 mmol) in DMF (5 mL). The cooling bath was removed and after about 20 min, p-toluenesulfonyl chloride (0.996 g, 5.23 mmol) was added. After about 2 h at room temperature, water was added (15 mL) and the mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-45% EtOAc in heptane to give 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.50 g, 44%): LC/MS (Table 2, Method d) Rt=2.20 min; MS m/z: 327 (M+H)+.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11]>C(O)C>[CH2:10]([P:1](=[O:2])([O-:5])[O-:8])[CH3:11].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH3:11].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH3:11]
Reactant: CCOCCCN
Reactant: CCOP([O-])OCC
Solvent: CCO
Solvent: O
Product: CCOCCC[NH3+]
Product: CCP(=O)([O-])[O-]
Yield: 99.9 %

Procedure:
A mixture of 13.81 g. (0.1 moles) of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 10.31 g. (0.1 moles) of 3-ethoxypropyl amine and 30 ml. of ethanol as described in Example 1. 21.3 g. (99.9%) of 3-ethoxypropyl-ammoniumethyl phosphonate are obtained.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([NH:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[N:11][N:12]=1)[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([NH:7][CH:5]([CH3:6])[C:4]([OH:28])=[O:3])=[N:12][N:11]=1
Reactant: CCOC(=O)C(C)Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 2-{5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-propionic acid ethyl ester (45 mg, 0.09 mmol, 1.0 eq) and LiOH (5 mg, 0.18 mmol, 2 eq) in THF-H2O (1:1) (0.5 mL) was stirred at RT for 2 hr. The pH was adjusted to pH 5 with 1N HCl and the mixture was diluted with EtOAc, washed with brine, and dried over anhydrous MgSO4. Filtration and solvent removal resulted in a residue that was washed with ether to give rise to the desired product (41 mg). LC/MS (Method A) [5.04 min; 470(M+1)]
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[CH3:30])C.[NH2:32][NH2:33].O>C(O)C>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[C:7]1[CH3:30]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2-c2ccccc2)c2ccc(OC)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1-c1ccccc1

Procedure:
A mixture of 1.18 g (2.86 mmol) of 1-([1,1-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester and 3 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 16 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.02 g of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide. A mixture of 576 mg (1.44 mmol) of this material and 300 mg of Raney Ni in 20 mL of ethanol was heated to maintain reflux for 3 hours. After cooling the solvent was decanted and the Raney Ni washed twice with methylene chloride. The combined organic solvents were concentrated at reduced pressure and the residue chromatographed on silica gel and eluted with ethyl acetate to give 369 mg (67% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:21])=[O:20]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCCCC1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Piperidine (338 μl, 3.41 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 2-fluoro-1-nitrobenzene (219 mg, 1.55 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=20/1). Thus, 1-(2-nitrophenyl)piperidine (315 mg, 98.8%) was yielded as a colorless oily material.
Reaction SMILES: [CH2:1]([C:8]1[C:9](I)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:24](=[O:28])[CH:25]([CH3:27])[CH3:26].C(OCC)(=O)C>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH:24]([OH:28])[CH:25]([CH3:27])[CH3:26])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1nc2ccccc2cc1Cc1ccccc1
Reactant: CC(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(O)c1nc2ccccc2cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-benzyl-2-iodoquinoline 11 (1 eq., 1.45 g) in dry tetrahydrofuran (20 ml) at −78° C., was added isopropyl magnesium chloride (3 eq., 6.3 ml). The color of the solution was changed from green to orange in 1 h. Isobutyraldehyde 12 (3 eq., 1.15 ml) was added and the reaction mixture was allowed to warm up to room temperature and stirred for another hour. Ethyl acetate was added. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography to yield 150 mg of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-ol 13.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:16][CH3:17])[C:13](O)=[O:14])=[CH:8][CH:9]=2)[C:4]([CH3:19])([CH3:18])[CH2:3]1.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:16][CH3:17])[C:13]([Cl:23])=[O:14])=[CH:8][CH:9]=2)[C:4]([CH3:19])([CH3:18])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CCC(Oc1ccc2c(c1)C(C)(C)CC2(C)C)C(=O)O
Product: CCC(Oc1ccc2c(c1)C(C)(C)CC2(C)C)C(=O)Cl

Procedure:
A mixture of 100.5 g (0.364 mole) of 2-(1,1,3,3-tetramethyl-5-indanoxy)-butyric acid and 67 ml of thionyl chloride were refluxed for 2 hours. The excess thionyl chloride was evaporated.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:14][C:13]=2[F:29])[CH:8]=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].Cl>CO.CN(C)C=O>[CH2:22]([O:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=2)=[C:13]([F:29])[CH:14]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
4-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester (10.7 g) was dissolved in methanol (450 ml) and N,N-dimethylformamide (150 ml), and water (75 ml) and lithium hydroxide (1.36 g) were added thereto, followed by stirring at room temperature for 1 hr. 1N hydrochloric acid (100 ml) was added thereto, then the reaction mixture was concentrated under reduced pressure and liquid-liquid separation was carried out after addition of ethyl acetate (500 ml), and the precipitated solid was collected by filtration. The resultant solid was washed with water and hexane, and dried under aeration. The organic layer of the filtrate obtained above was washed with water (100 ml×2) and brine (200 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant solid was washed with water and hexane and dried under aeration. This solid was combined with the solid obtained above, and dried at 60° C. overnight to provide the titled compound as white powder (9.53 g, 92.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O)[C:6](=O)[CH3:7])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:7])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1)C(C)=O
Reactant: Nc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)c1C

Procedure:
The title compound was prepared from 2-[2-(4-chloro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester (from Example 35(a)) and aniline under conditions analogous to Example 35(b). MS-(+)-ion: M+1=340.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11](NC)[O:10][N:9]=2)=[CH:4][C:3]=1[F:15].[CH2:16]([N:18]([CH2:21]C)CC)[CH3:17].ClCCl.C(Cl)(=[O:28])C>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:21][NH:18][C:16](=[O:28])[CH3:17])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: CNC1CC(c2ccc(Br)c(F)c2)=NO1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
[3-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-isoxazol-5-yl]-methylamine (9 g, 33.8 mmol) and triethylamine (7 ml, 50.8 mmol) were added to anhydrous dichloromethane (100 ml) and cooled to 0° C. Acetyl chloride (2.8 ml, 40.6 mmol) was then added dropwise and the reaction was stirred for 3 hours followed by addition of ethyl acetate (200 ml). The precipitate was collected and washed with water (2×50 ml) to give the desired product (5 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[C:35]1([C@@H:41]([NH2:43])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:35]1([C@@H:41]([NH:43][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: C[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (15.5 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (30 μL) was added followed by (S)-1-phenylethylamine (17 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (32.7 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 17 h then purified directly by silica gel column (60:40 hexanes:acetone) then on one 250 μm silica gel plate (90:10 CH2Cl2:MeOH) to yield 6.9 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.48 (br s, 1H); 8.37 (d, J=5.5 Hz, 1H); 7.95 (s, 1H); 7.82 (d, J=7.5 Hz, 1H); 7.64 (d, J=7.8 Hz, 1H); 7.59 (d, J=7.5 Hz, 1H); 6.79 (d, J=5.5 Hz, 1H); 6.33 (d, J=7.8 Hz, 1H); 5.80 (br s, 1H); 5.36 (m, 1H); 5.24 (br s, 1H); 1.65 (d, J=6.9 Hz, 3H); 1.61 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 463.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl.C(OCC)(=O)C>[C:43]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][C:6]3[CH:7]=[C:2]([F:1])[C:3]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[N:4][CH:5]=3)=[O:23])=[CH:12][N:13]=2)[CH2:18][CH2:19]1)(=[O:45])[CH3:44]
Reactant: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of N-((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-6-(piperazin-1-yl)nicotinamide 46-3 (35 mg, 0.076 mmol) and DIEA (27 μL, 0.155 mmol) in DCM (1.0 mL) was added acetyl chloride 46-4 (7 μL, 0.095 mmol). After 20 minutes stirring, the mixture was diluted with ethyl acetate, washed with water, and dried over Na2SO4. After evaporation of the solvents followed by preparative reverse phase HPLC separation gave 6-(4-acetylpiperazin-1-yl)-N-((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)nicotinamide as a solid 46. MS m/z 503.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.76 (d, 1H), 8.58 (d, 1H), 8.54-8.50 (m, 1H), 8.29 (bs, 1H), 8.07 (d, 1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 6.62 (d, 1H), 4.63 (s, 2H), 3.72-3.65 (m, 4H), 3.61-3.55 (m, 4H), 2.10 (s, 3H).
Reaction SMILES: C(P([CH2:8][C:9]([O-:11])=[O:10])(CC)CC)C.[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[H-].[Na+].[CH:20]1(C=O)CCC[CH2:21]1>C1COCC1>[CH2:20]([O:11][C:9](=[O:10])/[CH:8]=[CH:12]/[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:21]
Reactant: O=CC1CCCC1
Reactant: CCCCCC
Reactant: CC[PH](CC)(CC)CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1CCCC1

Procedure:
Following the method of example 54a, reaction of triethylphosphinoacetate (196 g, 870 mmol) with hexane-washed sodium hydride (60% in mineral oil, 35 g, 870 mmol) in THF (1200 ml) and cyclopentanecarbaldehyde (86 g, 870 mmol) in THF (300 ml) gives the title product as an oil (59.1 g). MS (m/e): 169.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
2,4-Difluorobenzoic acid 10 (45.0 g, 285 mmol) was dissolved in concentrated sulfuric acid (360 mL) at 0° C. and N-iodosuccinimide (NIS, 64 g, 284 mmol) was added in portions at 0° C. The mixture was allowed to warm to room temperature (rt) and stirred 4 hours (h). The mixture was poured into ice water (approximately 1000 mL) and 10% aqueous sodium carbonate solution (80 mL) was added. After the mixture was stirred for 0.5 h, the precipitate was filtered, washed with water (approximately 2000 mL), then dried at 50° C. in a convection oven for 2 days to provide 76.3 g (94%) of 11 as a gray solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].Cl.N(CC)(CC)CC>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCCc1ccccc1

Procedure:
5-Phenylvaleric acid (2.67 g, 15 mmol) in distilled THF was reacted with CDI (15 mmol) followed by glycine ethyl ester·HCl (15 mmol) and (C2H5)3N (15 mmol) as described in Example 56 Part A. The crude material (3.25 g, 82%) was used without purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 376.02 g/mol.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:21][C:22]([OH:24])=[O:23]>C(O)(=O)C>[N+:8]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH2:12][CH:13]([CH2:21][C:22]([OH:24])=[O:23])[CH2:14]2)([O-:11])=[O:9]
Reactant: O=C(O)CC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.2 %

Procedure:
Acetic anhydride (3.5 mL) was added slowly to a stirred solution of nitric acid (2.1 g, S.G.1.42) in glacial acetic acid (4.2 mL) cooled in an ice-water bath. This nitrating solution was then added dropwise over 5 minutes to a rapidly stirred solution of indan-2-acetic acid (1.65 g) in a mixture of glacial acetic acid (4.2 mL) and acetic anhydride (3.5 mL), whilst keeping the reaction temperature below 5° C. After stirring for a further 20 minutes at room temperature the reaction mixture was poured onto ice-water (60 mL). This mixture was extracted three times with dichloromethane. The combined extracts were washed twice with a little water, then dried over magnesium sulfate and then evaporated to give the title compound (2.22 g) as a red oil which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][CH2:13][CH2:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:2]=1
Reactant: OCCCc1ccncc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCOCCCc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
Triton B (40% methanol solution, 0.5 ml) was concentrated under reduced pressure, and 4-pyridinepropanol (10.2 g, 74.5 mmol) was added thereto. After 15 minutes, tert-butyl acrylate (9.59 g, 74.8 mmol) was added to the mixture, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) to give the titled compound (17.1 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2cc(F)ccc2c1Cl

Procedure:
Prepared as in Example 1b from ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate (Example 9c) and POCl3 as an off white solid (96%). MS 254, 256 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1C=CC=C[CH:18]=1.S(Cl)(Cl)=O>CN(C=O)C.C(O)C>[CH2:17]([O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:18]
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccccc1Oc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 2-phenoxybenzoic acid (7.71 g; 0.036 mol) dry benzene (80 ml), thionyl chloride (4.76 g; 0.04 mol) and DMF (2 drops) were added, and the resultant mixture was stirred under reflux for 2 hours. The reaction mixture was dropwise added to dry ethanol (100 ml) under ice-cooling in 30 minutes, followed by allowing to stand overnight. The reaction mixture was concentrated under reduced pressure and, after addition of a 4% aqueous sodium hydrogen carbonate solution (150 ml) thereto, extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl-2-phenoxybenzoate (8.72 g, yield, 100%) as a colorless oil.
Reaction SMILES: [CH2:1](N(CC)CC)C.Cl[C:9]([O:11]C)=[O:10].[F:13][C:14]1[CH:15]=[C:16]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:23][NH:22][CH2:21]1>C(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:23][N:22]([CH2:1][C:9]([OH:11])=[O:10])[CH2:21]1
Reactant: COC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(CC(=O)O)C3)c(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
Triethylamine (150 μL, 1.08 mmol) and methyl chloroformate (65 μL, 0.84 mmol) were added to a chloroform (5 mL) suspension of (S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 82, 153 mg, 0.50 mmol) and stirred overnight. Additional chloroform (25 mL) was added and the solution washed with water (15 mL) and brine (15 mL). Drying over magnesium sulfate, filtration, and evaporation gave a foam. Chromatography over silica gel (50 g, 40-60 μm) eluting with 1-3% methanol-chloroform gave the title compound as a white solid. FAB-HRMS: theory 366.1465 (M+1); meas. 366.1468.