Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([F:36])[CH:35]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:37]=[C:31]4[C:30]([F:29])=[CH:35][C:34]([F:36])=[CH:33][N:32]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(F)cc(F)cn4c3-c3ccccc3)cc2)CCC1
Yield: 10.3 %

Procedure:
1 g (2.25 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 292.8 mg (2.25 mmol) 3,5-difluoro-pyridin-2-yl-amine and 900 mg molecular sieves (3A, dried over night at 120° C. in a drying oven) in 20 mL ethanol were heated at reflux in a pressure pipe for 20 hours. The reaction mixture was sucked off via a glass fibre filter and evaporated to dryness. The residue was redissolved in dichloromethane, washed with hydrochloric acid (1 M), saturated sodium bicarbonate and brine and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 109.9 mg (9.8%) of the pure title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[NH2:17][C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].C(N(CC)CC)C>CN(C=O)C>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:17]([C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:5]2=[O:7])([O-:15])=[O:14]
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a stirred mixture of 18 (0.25 g, 0.912 mmol) and 4 (0.337 g, 0.912 mmol) in DMF (3.0 mL) was added triethylamine (0.320 mL, 2.28 mmol) and resulting mixture was stirred at 114° C. to 130° C. After 18 h, the mixture was cooled and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 19 (0.27 g, 60%) as a light brown fluffy solid. 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.45 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.80 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.44-7.19 (m, 5H), 5.17-4.84 (m, 4H), 3.05-2.96 (m, 2H), 2.69-2.52 (m, 3H), 2.20-1.94 (m, 3H), 1.35 (m, 4H). MS (ESI) m/z calcd for C25H27N4O7 [M+H]+ 495.5, found 495.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29]([NH:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH2:44][C:45](O)=[O:46])[C:37]2=[O:48])(=[O:31])=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:45](=[O:46])[CH2:44][N:38]1[C:37](=[O:48])[C:36]2[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH:35]=2)[C:39]1=[O:43]
Reactant: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.229 g, 0.544 mmol), 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetic acid (0.170 g, 0.544 mmol), EDC (0.313 g, 1.633 mmol) and DMAP (0.133 g, 1.089 mmol) were dissolved in DCM (20 ml), and the solution was stirred at room temperature for 20 hours. The mixture was diluted with DCM and washed with 0.5N HCl, aqueous 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, and the solvent removed under vacuum. The crude was purified by preparative HPLC (Method 1) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(methylsulfonamido methyl)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (0.120 g, 0.168 mmol, 30.9% yield, MS/ESI+ 714.06 [MH]+, [aD]=−27.89, c=0.9, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.88-7.94 (m, 2H), 7.85 (dd, 1H), 7.77 (t, 1H), 7.19 (d, 1H), 7.08 (s, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.42 (s, 2H), 4.23-4.56 (m, 2H), 3.83-4.00 (m, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 2.95 (s, 3H), 1.10-1.34 (m, 1H), 0.49-0.67 (m, 2H), 0.30-0.46 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:14](=[O:13])[C:15]([F:18])([F:17])[F:16])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(F)(F)F
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1

Procedure:
In the step 2, the p-Methyl acetophenone was condensed with Ethyltrifluoroacetate under alkaline conditions to give the 1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione intermediate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH2:11](O)[CH2:12][OH:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][CH:6]1[C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: OCCO
Reactant: N#Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C2OCCO2)c1
Yield: 100 %

Procedure:
A mixture of 3-cyanobenzaldehyde (9.81 g), ethylene glycol (9.31 g), p-toluenesulfonic acid monohydrate (0.07 g) and toluene (200 ml) was heated under reflux for 15 hrs., while removing generated water with a Dean-Stark trap. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-(1,3-dioxolan-2-yl)benzonitrile (13.1 g, yield 100%) as a colorless oil. NMR (CDCl3) δ: 4.01–4.17 (4H, m), 5.83 (1H, s), 4.50 (1H, t, J=7.6 Hz), 7.63–7.74 (2H, m), 7.80 (1H, t, J=1.6 Hz).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>C(OCC)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A solution of 25.82 g (100 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3 mL (20 mmol, 0.2 equiv) DBU was added to the reaction flask then the mixture was stirred at 0° C. for ten min. Slowly 15 mL (150 mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0° C. for 2 hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (<35° C.) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3″×10″ pad) in two batches eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a pale yellow oil. 1H-NMR (CDCl3): δ: 1.74 (3 H, d, J=6.5 Hz), 6.07 (1 H, q, J=6.5 Hz), 7.82 (1 H, s), 7.86 (2 H, s), 8.40 (1 H, br. s) ppm.
Reaction SMILES: II.[Br-:3].COC(=O)[C@@H]1CCCN1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:3][C:13]1[CH:18]=[CH:17][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Reactant: [Br-]
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of I2 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.), for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2H), 1.76-1.88 (m, 1H), 1.94-2.08 (m, 1H), 2.40 (dd, J=16.6, 9.0 Hz, 1H), 2.92-3.00 (m, 1H), 3.10 (d, J=12.7 Hz, 1H), 3.38 (d, J=12.5 Hz, 1H), 4.06 (dd, J=9.3, 4.6 Hz, 1H), 5.04 (s, 1H), 7.04-7.60 (m, 14H), 7.68 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc(N)cn1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2)cn1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (211 mg, 0.90 mmol) was dissolved in methylene chloride (2.7 mL) then treated with triethylamine (0.19 mL, 1.35 mmol) followed by benzoyl chloride (0.13 mL, 1.12 mmol). The reaction mixture was stirred for 3 hours at 22° C. then saturated aqueous NaHCO3 was added and the mixture was stirred for another hour. The organic layer was separated and washed 2× with 6% aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The product was recovered as a white solid. MS (m/z): 338/340 (M+H)+ ; C19H15N2O2Cl requires 338.8.
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C:17]2[C:4](=[C:5]([OH:24])[C:6]3[C:7](=[O:23])[C:8]4[C:13]([C:14](=[O:21])[C:15]=3[C:16]=2[OH:20])=[C:12]([OH:22])[CH:11]=[CH:10][CH:9]=4)[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>CS(C)=O>[OH:20][C:16]1[C:15]2[C:14](=[O:21])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:22])[C:7](=[O:23])[C:6]=2[C:5]([OH:24])=[C:4]2[C:17]=1[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]2
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)c3c(c(O)c21)CC(O)CC3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O

Procedure:
The alcohol of Example 20 (35 mg) was treated with 130 mg of dicyclohexylcarbodiimide and 0.4 ml of trifluoroacetic acid and 3 ml of dimethyl sulfoxide for 3 hours and then extracted several times with benzene. Evaporation of the benzene layers produced brown-red 5,7,12-trihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene (formula 18), m.p. above 300° C., infrared maximum 1730 cm-1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CO[C:22](OC)([N:24](C)C)[CH3:23].N1C=CC=CC=1.NOS(O)(=O)=O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([N:24]=[C:22]([CH3:23])[N:8]=2)[CH:7]=1
Reactant: COC(C)(OC)N(C)C
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Agent: NOS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Temperature: 130 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
To a stirred solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 1.0 g, 3.02 mmol) in DMF (5 mL) was added dimethylacetamide dimethyl acetal (1.33 mL, 9.06 mmol) and the reaction mixture was heated at 130° C. for 3 hrs. The reaction mixture was cooled then concentrated in vacuo. The resultant residue was dissolved in MeOH (10 mL) and pyridine (486 μL, 6.04 mmol) was added before the mixture was cooled to 0° C. and hydroxylamine-O-sulfonic acid (512 mg, 4.53 mmol) was added. The reaction mixture was allowed to warm to RT and stirred at this temperature for 20 hrs. The resultant precipitate was collected by filtration, then washed with MeOH to afford the title compound as a grey solid (323 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O:18]O)(C)(C)C>ClCCl.O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12]
Reactant: CC1(C)CCCc2ccc(Br)cc21
Reactant: CC(C)(C)OO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound 15, 1.1 g, 4.62 mmol) in 10 mL of dichloromethane was added chromium (VI) oxide (72 mg, 0.46 mmol) and 5 mL of tert-butyl hydroperoxide solution (TBHP). After stirring at room temperature for 8 h, the mixture was diluted with water (20 mL), extracted with diethyl ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (90:10 hexane/ethyl acetate) yielded the title compound (920 mg, 79% yield) as a white solid:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccnc(F)c2)cnc1F

Procedure:
By carrying out the operation analogously to example 177, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=65%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30].C(OCC)(=O)C>O1CCCC1>[O:12]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,3-diphenylpyrrolidin-2-one (2.00 g, 8.43 mmol; Example 1A) in tetrahydrofuran (10 mL) was added potassium 2-methylpropan-2-olate (9.27 mL, 9.27 mmol). After stirring for 30 minutes, the reaction was a suspension so the reaction was heated to 40° C. The reaction was cooled to ambient temperature, and then tert-butyl 4-bromobutanoate (2.068 g, 9.27 mmol) as a solution in tetrahydrofuran (3 mL) was added. The reaction was stirred for 3 hours, then poured into ethyl acetate/1 N HCl (1:1, 300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes. The product was dissolved in 5 mL of dichloromethane then 5 mL of trifluoroacetic acid was added. After stirring for 3 hours, the reaction was concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 10H), 3.45 (m, 4H), 2.79 (t, J=6.5, 2H), 2.31 (t, J=7.1, 2H), 1.89 (p, J=7.0, 2H); MS (ESI+) m/z 324.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].Cl.[O:15]([NH2:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:17][O:15][CH3:16])([O-:3])=[O:2]
Reactant: CON
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CONc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 53 %

Procedure:
2,4-Dinitrochlorobenzene (4.05 g (20.0 mmol)) and methoxylamine hydrochloride (2.00 g (23.9 mmol)) were dissolved in 15 ml of acetonitrile. To this mixture, under ice cooling and with stirring, triethylamine (7.00 ml (50.2 mmol)) was added. After being stirred for 24 hours at room temperature, the resulting black solution was concentrated under reduced pressure.Water and dilute hydrochloric acid were added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent, to give 2.26 g (53%) of N-(2,4-dinitrophenyl)-O-methylhydroxylamine as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:30][OH:31])=[C:4]([CH3:28])[CH:3]=1
Reactant: CCOc1ccc([C@H](CC(=O)c2ccnc(C)c2)c2ccc(Cl)cc2C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ccc([C@H](CC(=NO)c2ccnc(C)c2)c2ccc(Cl)cc2C)cc1

Procedure:
In analogy to example 132, step 6, from (S)-3-(4-chloro-2-methyl-phenyl)-3-(4-ethoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white foam, MS (ESI+): m/z=409.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.OS(O)(=O)=O.[OH-].[Na+]>OCC(CO)O>[F:9][C:8]1[C:2]([F:1])=[C:3]2[C:5]([CH:19]=[CH:14][CH:15]=[N:4]2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(F)c1F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: Fc1ccc2cccnc2c1F
Temperature: 135 °C

Procedure:
To a mixture of 2,3-difluoroaniline (commercially available, 3.57 g), glycerol (5.55 g) and m-nitrobenzene sulfonic acid sodium salt (10.12 g) was added dropwise 70% H2SO4 (20 mL). The reaction was heated at 135° C. for 3.5 hours and then cooled to room temperature. It was poured over ice, made basic with 50% aqueous NaOH and extracted with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator to give 4.13 g of the desired product as a light brown solid; MS (ES) m/z (relative intensity); 166 (M+H)+ (100).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.O>[Cl:1][CH2:2][C:3]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)N1CCCCC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Add chloroacetyl chloride (1.242 g, 11.0 mmol) to a mixture of potassium carbonate (2.073 g, 15 mmol) and piperidine (852 mg, 10 mmol) in THF (50 mL) at 0° C. Stir the reaction for 12 h and gradually raise to room temperature. Dilute with water, extract with EtOAc three times. Combine the organic extracts and wash sequentially with saturated aqueous NaHCO3, 0.1N aqueous HCl and brine. Dry over Na2SO4, filter and concentrate to give the title compound (1.65 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: Clc1ccc2cc[nH]c2c1
Product: Fc1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-fluoro-4-iodobenzene: ESMS m/e: 245.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].N12CCCN=C1CCCCC2.[NH:31]1[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:31]3[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: OCCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNCCO)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 0.50 g (1.84 mmole) of 1-ethyl-6,7,8-trifluoro-4-oxo-quinoline-3-carboxylic acid, 5 ml acetonitrile, 0.28 g (1.84 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.28 g (1.94 mmole) of 2-[(3-pyrrolidinylmethyl)amino]ethanol was refluxed one hour and then stirred at room temperature overnight. The reaction was filtered and the precipitate washed with ether until dry to give 0.58 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-4-oxo-3-quinoline carboxylic acid, mp 215°-216° C.