Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1)[C:6]([NH:19][NH2:20])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-c1cnc(C)o1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (115 g) was added to a suspension of 3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzoic acid (83.0 g) in THF (1 L) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was cooled to −10° C., hydrazine monohydrate (173 mL) was added, and the mixture was stirred at room temperature for 16 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and water was added to the residue. The resultant solid was collected by filtration, washed with water, dried under reduced pressure, and washed with IPE to give the title compound (85.8 g). 1H NMR (300 MHz, DMSO-d6) δ 2.48 (3H, s), 3.97 (3H, s), 4.53 (2H, brs), 7.44-7.58 (3H, m), 7.68 (1H, d, J=8.0 Hz), 9.85 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][C:10](=S)[S:11]C)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:17][NH2:18]>C(O)C>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][C:10](=[S:11])[NH:17][NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CSC(=S)NCc1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=S)NCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 187 g (772 mmole) of methyl N-(4-nitrobenzyl)dithiocarbamate and 450 ml of hydrazine hydrate in 1400 ml of absolute ethanol was stirred mechanically and heated to reflux. Precipitation began by the time the internal temperature reached about 40° C. After 2 hours at reflux, the mixture was cooled and allowed to stand at room temperature. The solid was collected on a filter, washed with ethanol, and dried to give 105 g (60%) of light yellow crystals, mp 196°-198° C. satisfactory purity by TLC in 95:5:0.5 CH2Cl2 --MeOH-concd NH4OH; mass spectrum (FAB) m/e 227 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].O[C@@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: O[C@@H]1CCOC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2[C@H]1CCOC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (R)-3-hydroxytetrahydrofuran in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.47-2.52 (2H, m), 3.95-4.00 (1H, m), 4.12-4.19 (2H, m), 4.19-4.28 (1H, m), 5.24-5.30 (1H, m), 7.12 (1H, dd, J=2.0, 8.4 Hz), 7.21 (1H, td, J=1.6, 8.8 Hz), 7.45 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:28][C:25]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:23])[O:21]2)=[CH:16][CH:15]=1>CN(C=O)C.O>[CH3:26][C:25]1([CH3:27])[C:22]([CH3:23])([CH3:24])[O:21][B:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4]3)=[CH:19][CH:18]=2)[O:28]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2ccc(Cn3ccc4ccccc43)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
To NaH (78 mg, 1.94 mmol) in anhydrous DMF (4 mL) under N2, at 0° C. was added indole (227 mg, 1.94 mmol) in anhydrous DMF (5 mL). The reaxtion mixture was maintained at this temperature for 10 min. 4-bromomethylphenylboronic acid pinacol ester (523 mg, 1.76 mmol) in anhydrous DMF (8 mL) was added and the reaction stirred at RT for 18 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2 (×2). The organic phases were combined, washed with brine, dried (phase separation cartridge) and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with isohexane and increasing the polarity to 5% EtOAc/isohexane. The compound was further purified by reverse phase preparative HPLC-MS to afford 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indole as an off-white solid (120 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6](C(C3C=CC(N(C)C)=CC=3)=C[N:10]=2)[N:7]=1.[OH-].[NH4+].[CH2:22](O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:10])=[CH:4][C:3]=1[CH3:22]
Reactant: CN(C)c1ccc(-c2cnc3ccc(Cl)nn23)cc1
Reactant: CCO
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(N)nnc1Cl
Temperature: 100 °C
Yield: 72.7 %

Procedure:
3,6-dichloro-4-methylpyridazine 6 (1 g) was dissolved in 5 mL of ethanol and was added ammonium hydroxide (10 mL). The resulting reaction mixture was sealed in a pressure bottle and heated to 100° C. for 48 hours. The reaction mixture is cooled and the solvents were evaporated and purified by CombiFlash Companion using Hexane/DCM 40:60 solvent system (4 g normal phase RediSep Flash column with run time min at flow 18 mL/min) gave 0.640 g (72.7%) of 7 as yellow solid).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([CH:8]=[C:9]([C:18]([OH:20])=[O:19])[CH:10]([C:14]([F:17])([F:16])[F:15])[O:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Cl:21]Cl>CC(O)=O.[Zn]>[Cl:21][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[CH:1]1[CH2:2][CH2:3]1)[O:11][CH:10]([C:14]([F:15])([F:17])[F:16])[C:9]([C:18]([OH:20])=[O:19])=[CH:8]2
Reactant: ClCl
Reactant: O=C(O)C1=Cc2ccc(C3CC3)cc2OC1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)C1=Cc2cc(Cl)c(C3CC3)cc2OC1C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a solution of the product of Example 146 Step 2 (0.28 g, 1.0 mmol) in 5 mL HOAc was added Cl2 in HOAc (3.0 mL, −1.5 mmol). After 0.75 h, the reaction was treated with Zn dust for 1.5 h. The reaction mixture was decanted from the Zn and concentrated under vacuum. The resulting residue was triturated with H2O, filtered, and washed with H2O. The yield of 6-chloro-7-cyclopropyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid was 0.26 g (82%) after drying overnight in a vacuum oven at 50° C.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[N:16]=CC=C[N:12]=1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Cl:10][C:11]1[NH:16][C:5](=[O:6])[C:4]2[C:3](=[CH:2][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Clc1ncccn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(Cl)nc2ccccc12
Temperature: 105 °C
Yield: 54.8 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (2.00 g, 16.38 mmol), 2-chloropyrimidine (1.88 g, 16.38 mmol) and iPr2NEt (5.71 mL, 32.75 mmol), under N2 atmosphere was heated at 105° C. for 24 h. The reaction mixture was allowed to cool to room temperature. The crude was subjected to column chromatography (silica gel, 20% EtOAc in hexanes) to furnish 1.62 g of the desired aryl ether (1) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:3]1
Reactant: Cn1nnc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc(-c2cccc(CCOCCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(3-(2-methyl-2H-tetrazol-5-yl)phenethoxy)propanoate [Example 7, Step iii)] (500 mg), DCM (4 mL) and TFA (4 mL) was stirred at 25° C. for 30 min and concentrated under vacuum to give the subtitled compound as a gum (612 mg). 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (dt, J=7.8, 1.4 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.31 (dt, J=1.4 and 7.7 Hz, 1H), 4.42 (s, 3H), 3.78 (t, J=5.9 Hz, 2H), 3.77 (t, J=6.3 Hz, 2H), 2.97 (t, J=6.3 Hz, 2H), 2.64 (t, J=6.1 Hz, 2H).
Reaction SMILES: C([O:8][C:9]1[C:15]([F:16])=[C:14]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1.O1CCCC1>[Pd].CO>[NH2:11][C:10]1[C:9]([OH:8])=[C:15]([F:16])[C:14]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2F)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(O)c2F)cn1
Reaction time: 20 h
Yield: 99.4 %

Procedure:
A mixture of 2-(benzyloxy)-3-fluoro-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}aniline (5.5 g), 10% palladium on carbon (containing 50% water, 1.6 g), tetrahydrofuran (100 mL) and methanol (80 mL) was hydrogenated at room temperature for 20 h under balloon pressure. The catalyst was removed by filtration and washed with tetrahydrofuran-methanol. The combined filtrate and washings were concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was concentrated in vacuo to give the title compound (4.2 g, 100%) as a light brown amorphous solid. MS 299 (MH+).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[N+:6]([O-])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([OH:15])(=[O:14])[CH3:13]>N1C=CC=CC=1.[Fe]>[C:12]([OH:15])(=[O:14])[CH3:13].[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:14])=[CH:3][CH:2]=1
Reactant: [O-][n+]1cccc2ncccc21
Agent: [Fe]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Oc1ccnc2cccnc12
Reaction time: 2 h

Procedure:
To a solution of 1,5-naphthyridin-5-oxide 4-01 (D-5) (330 mg, 2.0 mmol, 1.0 eq) in acetic acid (12 mL) and pyridine (2.5 mL) at RT, iron powder (456 mg, 8.15 mmol, 4.0 eq) is added in portions (over 10 min) and the resulting mixture is stirred for 2 h. The mixture is filtered and the solid is rinsed with acetic acid. The filtrate is concentrated in vacuo. The residue is triturated with acetone and then filtered. The filter cake is rinsed with acetone and dried in vacuo to afford the product, 1,5-naphthyridin-4-ol acetic acid salt (D-6).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:13](=[O:23])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:11]([CH3:34])=[C:10]2[C:35](N2C=CN=C2)=[O:36])=[CH:5][CH:4]=1)#[N:2].[OH:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][N:14]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]([C:35]([O:42][CH2:43][CH2:44][N:45]2[CH2:49][CH2:48][CH2:47][C:46]2=[O:50])=[O:36])=[C:11]([CH3:34])[N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[C:13]1=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C1CCCN1CCO
Product: CC1=C(C(=O)OCCN2CCCC2=O)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 74 %

Procedure:
The title compound is synthesized in analogy to Example 64 from Example 15A using N-(2-hydroxyethyl)-2-pyrrolidone instead of tert.-butyl-N-hydroxyethyl carbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:18]=3)[O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:42][O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)=[O:27])[CH:18]=3)[O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
TEA (0.271 ml, 1.95 mmol) was added to solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (484 mg, 1.29 mmol) in DCM (10 ml). The mixture was cooled down to 0° C., and EDC (372 mg, 1.95 mmol) and HOBt (263 mg, 1.95 mmol) were added. The mixture was stirred at 0° C. for 3 h, then NH2OTHP (182 mg, 1.56 mmol) was added and the mixture was stirred at RT overnight. The solution was washed with aqueous 5% NaHCO3 solution and brine. The organic layer was then dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (499 mg) as a light yellow solid.
Reaction SMILES: Br.[N:2]1([C:8](=[NH:10])[NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:10]=1
Reactant: N=C(N)N1CCCCC1
Reactant: SC(Cl)(Cl)Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCCCC2)ns1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of piperidine-1-carboximidamide hydrobromide (2.00 g, 9.61 mmol) and perchloromethyl mercaptan (1.04 ml, 9.61 mmol) in methylene chloride (10 ml) was added dropwise a solution of sodium hydroxide (1.54 g, 38.4 mmol) in water (4 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The reaction mixture was poured to water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give 500 mg (25.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:22])=O>ClCCl>[C:1]([Cl:22])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCC/C=C\CCCCCCCC(=O)Cl
Reaction time: 16 h

Procedure:
Synthesis of MC810 (FIG. 7). To a solution of palmitoleic acid (cis-9-hexadecanoic acid, 2.00 g, 7.87 mmol, Aldrich Chemical Company) in dichloromethane (75 mL), was added oxalyl chloride (1.72 mL, 19.7 mmol, Aldrich Chemical Company) dropwise under nitrogen. After 16 hrs, the solution was concentrated under reduced pressure (aspirator) and then placed under high vacuum to afford palmitoleoyl chloride.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].B([F:60])(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].N1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:60])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: [O-]B([O-])OB([O-])F
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: F[n+]1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 11 %

Procedure:
Erythromycin A (0.5 g, 0.681 mmole) was dissolved in glacial acetic acid (4 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 1.2 mL) while the temperature was maintained below 20° C. N-fluoropyridinium pyridine heptafluorodiborate (0.25 g, 0.75 mmole) was added and stirring continued for an additional 2 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford an 11% yield of crude flurithromycin. Although the yield was only 11%, this example demonstrates operation of the invention with N-F fluorinating agents derived from pyridine since with a co-solvent no flurithromycin is formed. (See Comparative Example 4).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2)([O-:23])=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:28]2)([O-:23])=[O:22]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 33.4 %

Procedure:
159 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(O)=O)[CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:22]([Cl:24])=[O:23]>ClCCl.CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:20])([C:22]([Cl:24])=[O:23])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)c2cc(C(=O)O)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C(=O)Cl)NN(Cc2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 1-benzyl-3-methyl-indazole-6-carboxylic acid in dichloromethane (20 ml) was treated with dimethylformamide (2 drops) then with oxalyl chloride (1.69 ml). After stirring for 2 hours the reaction mixture was evaporated and the residue was dried under high vacuum to give the title compound (0.16 g) which was used without further purification.
Reaction SMILES: [C:1]([NH:8]C1C=CC(C(F)(F)F)=CC=1C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[C:1]([NH:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:29]=[CH:30][CH:31]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-Boc 2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, et al., Synlett 1992, 360) was transformed into its methyl ester as described in procedure (80a). A solution of this ester (125 mg, 0.39 mmol) in DMF (6 mL) was charged with K2CO3 (216 mg, 1.6 mmol) and para-chlorobenzyl bromide (160 mg, 0.78 mmol). After 1.5 h, the solution was diluted with EtOAc and was washed with brine solution followed by 1N HCl solution. The organic layer was then washed with Na2CO3 solution, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue provided the desired N-Boc benzylamine (69 mg), which was dissolved in THF (0.9 mL). The solution was charged with 1N LiOH (0.3 mL) and MeOH (0.3 mL). After stirring for 18 h, the THF was removed and the solution was made acidic (pH=5) with 1N HCl. This solution was extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to give N-Boc 2-(para-chlorobenzyl)amino-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[C:15]2NC1C(Cl)=CN=CC=1Cl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[CH:15]2
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCBr
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2ccc(=O)[nH]c2c1OCCCCN(C)C
Reaction time: 2.5 h

Procedure:
A solution of dimethylamine (1.5 mL, 2M tetrahydrofuran, 3 mmol) was added to a solution of 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5 h, the reaction was poured into 10% K2CO3 (30 mL) and extracted with dichloromethane (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silical gel chromatography (1:0→4:1; dichloromethane:methanol w/1% conc. NH4OH solution) and then reverse-phase HPLC (1:9→1:1; acetonitrile:water) to give 443,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>>[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])=[CH:10][CH:9]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(O)cc1
Product: COC(=O)CNCc1ccc(O)cc1
Yield: 40 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 4-hydroxybenzaldehyde. Yield 40%. MS M+H calculated 196.1. Found 196.1
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=C[C:44]([O:47][CH2:48]CCN(C)C)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:43][CH2:44][O:47][CH3:48])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H) 8.19 (s, 1 H) 8.14 (m, 1 H) 8.06 (m, 1 H) 7.91 (m, 1 H) 7.81 (m, 1 H) 7.28 (d, J=8.32 Hz, 1 H) 7.22 (d, J=8.32 Hz, 1 H) 4.44 (m, 2 H) 3.95 (m, 2 H) 3.58 (s, 3 H) 3.23 (q, J=7.32 Hz, 2 H) 2.49 (s, 3 H) 1.37 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C23H25N2O4S, 425; found, 425.