Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][CH2:22][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:29]([NH:33][C:17]([C:14]1[CH:15]=[C:16]2[C:11]3=[C:12]([CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][CH2:22][N:10]3[CH2:9][CH2:8][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)=[O:19])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN
Reactant: O=C(O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxylic acid (14), (189 mg, 0.512 mmol) in dichloromethane (10 mL) were added butyl amine (0.027 mL, 0.512 mmol), EDCl (196 mg, 1.02 mmol), followed DMAP (4-(Dimethylamino)pyridine) (70 mg, 1.02 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 25 to 30% EtOAc:Hexane to give N-butyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxamide (481), (113 mg 52%). 1H NMR (300 MHz, CDCl3) ppm 1H NMR (300 MHz, Solvent) ppm 0.87 (t, J=6.0 Hz, 3H) 1.17-1.38 (m, 2H) 1.36-1.52 (m, 2H) 2.03-2.17 (m, 2H) 2.18-2.36 (m, 2H) 3.06-3.37 (m, 6H) 4.21 (t, J=5.27 Hz, 2H) 5.61-5.75 (m, 1H) 7.03-7.16 (m, 4H) 7.17-7.37 (m, 8H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=O.C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O.O>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([NH2:27])=[O:19]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 14 h
Yield: 66 %

Procedure:
To 100 mg of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetic acid in 5 ml of dry tetrahydrofuran were added 0.2 g of oxalyl chloride and a drop of dimethylformamide, and the mixture was stirred with ice cooling under a dry atmosphere for 3 hours. To the mixture was added 5 ml of tetrahydrofuran containing 1% ammonia, and the mixture was stirred under a dry atmosphere at room temperature for 14 hours. After the addition of water, the mixture was extracted with ethyl acetate. The extract was washed with a 1% sodium hydroxide solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was recrystallized from ethyl acetate, thereby obtaining 66 mg (yield: 66%) of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetamide as colorless crystals having a melting point of 188°-189° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:17]=[CH:16][C:15]=2[CH3:21])=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(O)ccc2C)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2cc(Oc3ccc(C(F)(F)F)cc3Br)ccc2C)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
A mixture of 3-[4-(5-hydroxy-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (Example 84, Step D) (0.46 g, 1.46 mmol), 3-bromo-4-fluorobenzotrifluoride (0.35 g, 1.45 mmol) and 325 mesh potassium carbonate (0.21 g, 1.52 mmol) in dry DMSO (10 mL) is heated to 100° C. and stirred for 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 0.633 g (81%) of the title compound. Rf=0.38 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H24O4F3Br 536, found 554 and 556 (M+NH4, 100%).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1>ClCCl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:31](=[O:37])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
In dichloromethane (30 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.55 g), followed by the addition of succinic anhydride (1.50 g). The mixture was stirred at room temperature for 2 hours. The dichloromethane was distilled off and, following the addition of 3% aqueous phosphoric acid solution (100 ml), the residue was extracted with ethyl acetate (150 ml). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride (100 ml×2), dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was treated with ether and the resultant powder was recovered by filtration, washed with ether and dried under reduced pressure over phosphorus pentoxide. The procedure provided 7β-(2-thienylacetamido)-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (4.00 g).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)([CH3:45])[CH3:44]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)NC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(=O)NC(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.4 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-isopropyl-acetamide (52 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 277 (88 mg, 0.18 mmol, 51%). LCMS: RT=2.85 min, [M+H]+=492. 1H NMR δ (ppm) (CDCl3): 8.43 (1 H, d, J=8.29 Hz), 7.59 (1 H, s), 7.01 (1 H, dd, J=8.34, 1.82 Hz), 6.97 (1 H, s), 6.89 (1 H, d, J=1.76 Hz), 5.92-5.82 (1 H, m), 4.48-4.44 (2 H, m), 4.42-4.38 (2 H, m), 4.13-4.02 (1 H, m), 3.10-2.85 (4 H, m), 2.58-2.46 (1 H, m), 2.38 (3 H, s), 2.35-2.20 (2 H, m), 1.94-1.84 (2 H, s), 1.81-1.68 (2 H, m), 1.54 (6 H, d, J=6.64 Hz), 1.16 (6 H, d, J=6.55 Hz)
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH2:40]([NH:43][C:44](=[O:51])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1)[C:41]#[CH:42]>CN(C=O)C.[Cu]I>[Cl:29][C:27]1[CH:28]=[C:23]([C:17]2([C:19]([F:22])([F:20])[F:21])[O:16][N:15]=[C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([N:1]4[CH:42]=[C:41]([CH2:40][NH:43][C:44](=[O:51])[C:45]5[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=5)[N:3]=[N:2]4)=[CH:5][CH:6]=3)[CH2:18]2)[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: C#CCNC(=O)c1ccncc1
Reactant: [N-]=[N+]=Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)nn1)c1ccncc1
Reaction time: 5 h

Procedure:
CuI (211 mg) is added to a solution of 3-(4-azido-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (500 mg), DIPEA (3.3 ml) and N-prop-2-ynyl-isonicotinamide (180 mg) in DMF (2.0 ml). After 5 hours at room temperature, the reaction is quenched with a saturated solution of NaHCO3 and extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and concentrated in mow. The crude product is purified on a semi-preparative HPLC to yield N-(1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-1H-[1,2,3]triazol-4-ylmethyl)-isonicotinamide as a colorless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=O)C.C[O-].[Na+].Cl.[NH2:16][C:17]([NH2:19])=[NH:18].Cl>CO.CN(C)C=O>[NH2:19][C:17]1[NH:18][C:7]2=[CH:8][CH:9]=[CH:10][C:6]2=[C:4]([OH:3])[N:16]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(O)c2cccc-2[nH]1
Yield: 18 %

Procedure:
A solution of 2-ethoxycarbonyl cyclopentanone (114 ml, 0.77mol) and N,N-dimethylformamide (40 ml) was added dropwise to a mixture solution of sodium methoxide(83.2 g, 0.44 mol) and N,N-dimethylformamide(80 ml), while maintaining the temperature of the reaction system below 0° C. A solution of guanidine HCl salt(81 g, 0.85 mol) and methanol(127 ml) was added to the above reaction mixture and then was heated to reflux for 14 hours. The reaction mixture was neutralized by conc. HCl and the resulting solid was filtered and dried under reduced pressure to give 20.69 g of titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[CH2:16]([N:18]1[C:30]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([N:18]1[C:30]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17]
Reactant: COc1cccc(-c2ccccc2Br)c1
Reactant: CCn1c2ccccc2c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1c2ccccc2c2ccc(-c3ccccc3-c3cccc(OC)c3)cc21
Reaction time: 5 h
Yield: 68.9 %

Procedure:
3.93 g (15.00 mmol) of 2-bromo-3′-methoxybiphenyl, 5.3 g (16.50 mmol) of 9-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)carbazole, and 0.35 g (0.30 mmol) of Pd(PPh3)4 were dissolved in 50 ml of toluene, and 4.77 g (45.00 mmol) of Na2CO3 was put into 25 ml of distilled water and then refluxed and agitated for 5 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=7:3 (v/v) to obtain 3.90 g of 9-ethyl-2-(3′-methoxybiphenyl-2-yl)carbazole (yield 69%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:7][N:6]2[CH:8]=1
Reactant: O=C1CCCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(N3CCCC3=O)ccc2n1
Yield: 51 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (135 mg, 0.34 mmol) was converted, using 2-pyrrolidone instead of benzamide, to the title compound (61 mg, 51%) which was obtained as a light brown solid. MS: m/e=359.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11](Br)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([S:26]([N:29]1[C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[NH2:41])(=[O:28])=[O:27])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:23]([S:26]([N:29]1[C:33]2[CH:34]=[C:35]([C:11]3[N:10]=[C:9]([CH3:22])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[NH2:41])(=[O:27])=[O:28])([CH3:25])[CH3:24]
Reactant: Cc1nc(Br)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
To a solution of 1-(benzyl)-4-(bromo)-5-(2,4-difluorophenyl)-2-(methyl)-imidazole (1.12 g, 3.08 mmol) in 8 mL DME, add 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (2.62 g, 9.25 mmol). Add sodium carbonate (0.98 g, 9.25 mmol) dissolved in 1 mL of water and trans-dichlorobis(triphenylphosphine) palladium (II) (0.65 g, 0.93 mmol). Heat the mixture to 100° C. with stirring under nitrogen. After 3 hours, cool the solution and filter over a pad of Celite® and sodium sulfate. Purify the residue by radial chromatography eluting with 3% methanol in CH2Cl2 with a gradient to 10% methanol. Perform a second purification by radial chromatography eluting with 4% methanol in CH2Cl2 with a gradient to 6% methanol to yield 390 mg (24%) of the title compound as a yellow solid. MS(ES+): m/z=522.0 (M+H)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([F:12])([F:11])[F:10].C([O-])(=O)C.[Na+].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29].ClCCl>C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]([C:9]([F:12])([F:11])[F:10])=[N:29]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(2-furyl)-4,4,4-trifluorobutane-1,3-dione (105 g, 0.51 mole) in glacial acetic acid (220 mL) was added sodium acetate (42 g 0.51 mole). The temperature rose to about 34° C. 2-Chlorophenylhydrazine hydrochloride (90 g, 0.5 mole) was added portionwise over a period of 10 minutes to give a creamy suspension. The mixture was warmed to about 60° C. for about 45 minutes. The bulk of the acetic acid was removed by stripping on a rotary evaporator at a bath temperature of 65° C. The remaining oily residue was added to about 800 ml of water with vigorous stirring and a heterogeneous mixture resulted. After about 15 minutes, dichloromethane (500 mL) was added and the mixture was partitioned. The aqueous phase was extracted with 300 ml of dichloromethane. The combined organic phases were washed with water and saturated sodium bicarbonate solution and then dried with MgSO4 and filtered. Volatiles were removed on a rotary evaporator. The crude product consisted of 151 g of a dark red oil, which contained approximately 89% of the desired product and 11% of the regioisomeric pyrazole (determined by NMR analysis).
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].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>C(O)(=O)C.C1COCC1>[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:62])([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=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
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
Solvent: C1CCOC1
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: 18.2 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. N-fluorobenzenesulfonimide (2.2 g, 6.813 mmole) dissolved in THF (4 mL) was added and stirring continued for an additional 18 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford only 0.93 g (7% yield) of crude flurithromycin.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]([O:25][C:26](=[O:72])[C@H:27]([CH2:67][CH2:68][CH2:69][CH2:70][NH2:71])[N:28]([CH2:48][CH2:49][N:50]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:29][CH2:30][N:31]([CH2:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[CH3:24][C:22]([O:25][C:26](=[O:72])[C@H:27]([CH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:28]([CH2:29][CH2:30][N:31]([CH2:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:48][CH2:49][N:50]([CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:56])[CH3:57])[CH2:59][C:60](=[O:61])[O:62][C:63]([CH3:64])([CH3:65])[CH3:66])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)CN(CCN(CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(=O)OC(C)(C)C)N(CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
Stearoyl chloride (5.45 g; 18 mmol) dissolved in CHCl3 (60 mL) was added dropwise in 1 h to a solution of N2,N2-bis[2-[bis[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]ethyl]-L-lysine 1,1-dimethylethyl ester (13.5 g; 18 mmol) in CHCl3 (300 mL) at 0° C. After 10 min the reaction mixture was allowed to rise to room temperature and TLC analysis showed the complete conversion of the starting materials. The solution was washed with 5% aq. NaHCO3, the organic phase was separated, dried over Na2SO4 and then evaporated under reduced pressure. The crude product was purified by flash chromatography (n-hexane/EtOAc=6/4 (v/v)) to give the desired product (11.3 g; 11.2 mmol). Yield 62%. HPLC: 95% (area %). the 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19](OCC)OCC)[CH3:17]>C(OC(=O)C)(=O)C>[CH2:16]([O:18]/[CH:19]=[C:8](\[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)/[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)C(=O)Cc1ccc(F)cc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(/C(=O)C(=O)OCC)c1ccc(F)cc1
Temperature: 25 °C
Yield: 14 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-2-oxopropanoate (4 g, 19.03 mmol, 1.00 equiv) and triethoxymethane (16 mL) in acetic anhydride (5 mL) was stirred at 130° C. overnight. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 700 mg (14%) of (E)-ethyl 4-ethoxy-3-(4-fluorophenyl)-2-oxobut-3-enoate as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.32-7.28 (m, 2H), 7.09-7.05 (m, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.16 (q, J=8.0 Hz, 2H), 1.37-1.20 (m, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CSc1nc(Cl)ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na2CO3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh3)4 (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600 mL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50° C. to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid.