Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])O.[Na+].O>CN(C)C=O>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 70 °C
Yield: 40.3 %

Procedure:
A mixture of 4-(3-indolyl)piperidine (7.47 g), N-(3-bromopropyl)phthalimide (10.0 g) and sodium hydrogen carbonate (3.45 g) in dry N, N-dimethylformamide (88 ml) was heated at 70° C. for 2 hours. After cooling, the reaction mixture was poured into water (880 ml) and extracted with a mixture of chloroform and methanol (10:1 V/V). The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (290 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether to give pale yellow crystals of 1-(3-phthalimidopropyl)-4-(3-indolyl)piperidine (5.83 g).
Reaction SMILES: C(O)(=O)C.C(C1C=CC=C(O)C=1O)CCCCCCCCCCCCCCCCCC.[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O.[BH4-].[Na+].P(Br)(Br)[Br:47]>>[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][Br:47]
Reactant: BrP(Br)Br
Reactant: COc1cccc(C=O)c1OC
Agent: CCCCCCCCCCCCCCCCCCCc1cccc(O)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(CBr)c1OC

Procedure:
The nonadecylcatechol acetate (NDC-AC) used in the tests was prepared as follows: 2, 3 dimethoxybenzaldehyde was reduced in the presence of sodium borohydride and the reduction product reacted with phosphorus tribromide to form 2, 3 dimethoxybenzylbromide. The benzylbromide reaction product was refluxed with triphenyl phosphine in xylene to form 2, 3 dimethoxybenzyl-triphenyl phosphonium bromide which was then reacted with octadecanal in the presence of butyl lithium to form 2, 3 dimethoxy-nonadecenylbenzene. Subsequent steps of reduction and reaction with boron tribromide produced 3-nonadecylcatechol which was purified by chromatography. The catechol was acetylated with acetic anhydride in pyridine to form the acetate (NDC-AC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:20])=[O:13])=[CH:7][CH:8]=1
Reactant: CO
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-butyric acid (25.1 g, 0.129 mol) in methanol (130 mL), was added sulfuric acid (concentrated, 1.0 mL) dropwise and it was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated, washed with brine (3×200 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil (26.8 g, 99%). Mass (MH+)=209.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:48][C:49]1[O:53][C:52]([CH:54]=O)=[CH:51][CH:50]=1>CCO>[CH3:22][N:7]1[C:6]2=[C:5]3[N:4]([C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:11]2[C:10](=[O:19])[N:9]([CH3:20])[C:8]1=[O:21])[CH2:3][CH2:2][O:1][CH:54]3[C:52]1[O:53][C:49]([CH3:48])=[CH:50][CH:51]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCO)cc2n(C)c1=O
Reactant: Cc1ccc(C=O)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCO
Product: Cc1ccc(C2OCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
6-(2-Hydroxyethyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Int C) (244 mg, 0.815 mmol), bismuth triflate (50.9 mg, 0.082 mmol, 10 mol %) and EtOH (2.4 mL) were treated with 5-methylfuran-2-carbaldehyde (commercially available, 0.089 mL, 0.082 mmol). The mixture was heated to 100° C. for 10 min using microwave irradiation. A further portion of 5-methylfuran-2-carbaldehyde (25 μL) was added to the reaction mixture and heating continued at 100° C. for 5 min. A solid formed on cooling, which was collected by reduced pressure filtration and washed with EtOH followed by diethyl ether, affording the title compound.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:14]([O-:17])([OH:16])=[O:15].[OH:18][S:19]([OH:22])(=[O:21])=[O:20]>>[OH:21][S:19]([OH:22])(=[O:20])=[O:18].[C:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:17])=[O:15])[N:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccnc2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccnc2c([N+](=O)[O-])cccc12
Product: O=C(O)c1ccnc2cccc([N+](=O)[O-])c12
Yield: 106 %

Procedure:
In a similar fashion using route 11 general procedure 15, 4-carboxyquinoline (1.6 g, 9.0 mmol) in conc. H2SO4 (3 ml) and fuming HNO3/conc. H2SO4 (1:1; 6 ml) to give the title compound and 4-carboxy-5-nitroquinoline (2.1 g, 106%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)(=[O:19])[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][CH2:16][CH2:17][CH3:18].[CH3:51][NH:52][CH2:53][CH2:54][OH:55].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH3:51][N:52]([CH2:27][CH2:26][NH:25][C:24]([O:23][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][O:20][C:1](=[O:19])[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][CH2:16][CH2:17][CH3:18])=[O:29])[CH2:53][CH2:54][OH:55]
Reactant: CNCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCN(C)CCO
Temperature: 80 °C
Yield: 74.7 %

Procedure:
In 10 ml of chloroform was dissolved 173 mg (0.224 mmol) of 1,3-O-dioleoyl-2-O-(2-bromoethyl)carbamoylglycerol followed by addition of 543 mg (7.228 mmol) of 2-(methylamino)ethanol and 27 mg (0.209 mmol) of diisopropylethylamine and the mixture was refluxed at 80° C. overnight. The reaction mixture was then washed with 5% sodium dihydrogen phosphate-H2O, dried, and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 128 mg (74.3%) of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[O:11].N1C=CC=CC=1.COC(Cl)Cl>C(Cl)Cl>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:13])[C:10]([CH3:12])=[O:11]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)C(=O)O
Agent: COC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
p-Tolyl pyruvate was prepared as follows. p-cresol (540 mg, 5 mmol) and pyruvic acid (440 mg, 5 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (790 mg. 1 mL, 12.4 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl and 30 mL of saturated aqueous NaHCO3. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator. The residue was purified by flash silica gel chromatography (20:1→15:1 hexanes-ethyl acetate) to give 450 mg of p-tolyl pyruvate as a clear oil. 1H NMR (400 MHZ, CDCl3) δ 7.21 (d, J=4 Hz, 2H), 7.05 (d, J=4 Hz, 2H), 2.59 (s, 3H), 2.36 (s, 2H). 13C NMR (100 MHZ, CDCl3) δ 191.3, 159.5, 148.1, 136.6, 130.4, 120.8, 27.0, 21.1. HRMS (ESI-12 Tesla FT-MS) [M+H]+ calcd. 179.0708, found 179.0709.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][N:19]=2)[CH:15]=[CH:14][N:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([F:11])[CH:17]=3)=[N:19][CH:20]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: NCc1ccc(-c2ccnc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromopicolinic acid 38-3 (309 mg, 1.53 mmol), (2′-fluoro-2,4′-bipyridin-5-yl)methanamine 38-2 (312 mg, 1.53 mmol) and HATU (582 mg, 1.53 mmol) in DMF (7 mL) was added DIEA (0.76 mL, 4.59 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol containing ˜7N ammonia in dichloromethane to give 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 as yellow solid. MS m/z 387.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH3:27])[CH2:8][CH:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][C:13]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:15]=2)[O:10]1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.CO.[OH2:34].OOS([O-])=O.[K+].[OH2:41]>>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][C:13]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:41])=[O:34])=[CH:14][CH:15]=2)[O:10]1)[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC1CC(=O)c2ccc(Sc3ccccc3)cc2O1)C(=O)OC(C)(C)C
Reactant: O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of methyl-(4-oxo-7-phenylsulfanyl-chroman-2-ylmethyl)-carbamic acid tert-butyl ester (200 mg, 0.5 mmol) in a mixture acetonitrile/methanol/water (1/1/1, 30 mL) was added oxone (922 mg, 1.5 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was then diluted with water and the solid was filtered off. The filtrate was concentrated in vacuo to give (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (186 mg, 86% yield) as yellow glass which was used without further purification for deprotection in the next step.
Reaction SMILES: CO.C[C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=1.[F:23][C:24]1[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:10]([C:9]3[CH:8]=[N:7][C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:5][CH:4]=3)=[N:31][C:26]=2[C:25]=1[CH3:32]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc(N)c1N
Agent: O=[Mn]=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(F)ccc2[nH]c(-c3cnc(NCCCC4CCN(C)CC4)nc3)nc12
Reaction time: 0.5 h

Procedure:
A mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 mg, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[N:3]=[CH:4][CH:5]=1.B.C1COCC1.CO.O>C1COCC1>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[CH:13][CH:14]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=C(O)c1cccc(-n2nccn2)c1
Agent: B
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(-n2nccn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of the major isomer 3-(2H-1,2,3-triazol-2-yl)benzoic acid (500 mg; 2.64 mmol) in anh. THF (7 ml) was treated dropwise with a BH3.THF (1.0 M in THF; 6.60 ml; 6.60 mmol), and this mixture was stirred at 0° C., under nitrogen, for 1 h, and then at rt for 1.5 h. The resulting reaction mixture was then cooled to 0° C., and treated successively with MeOH (10 ml) and water (10 ml). The organic solvents were removed under reduced pressure, and the resulting aq. layer was extracted with DCM (3×10 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(2H-1,2,3-triazol-2-yl)phenyl)methanol as a colorless oil. LC-MS (conditions A): tR=0.51 min.; no ionisation.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=[NH:10])[CH:6]=[C:5]([Cl:12])[N:4]=1.C(=O)(O)[O-:14].[Na+].[CH3:18][C:19](=[CH:24][CH2:25][CH3:26])[C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[NH:11][CH:24]([CH2:25][CH3:26])[CH:19]([C:20]([O:22][CH3:23])=[O:21])[C:18](=[O:14])[N:10]=2)[CH:6]=[C:5]([Cl:12])[N:4]=1
Reactant: O=C([O-])O
Reactant: CCC=C(C)C(=O)OC
Reactant: N=C(N)c1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To 10.6 g (46.8 mmol) of 2,6-dichloropyridine-4-carboxamidine hydrochloride in 100 mL of dimethylformamide was added 4.62 g of sodium bicarbonate followed by 10 g (46.8 mmol) of 80% methyl 2-methyl-2-pentenoate. The reaction was stirred at room temperature overnight before pouring onto 300 mL of ice water. The resultant pale yellow precipitate was collected by vacuum filtration and yields 12.15 g (36.8 mmol, 79%) of desired product with mp=188°-189° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([F:40])[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:37][C:36]1[CH:38]=[CH:39][C:33]([Br:32])=[CH:34][C:35]=1[F:40])=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1sc2cnccc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cnccc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A degassed solution of 3-(nonafluorobutane-1-sulfonyloxy)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (678 mg, 1.33 mmol), 4bromo -2-fluoroaniline (329 mg, 1.73 mmol), Pd2 dba3 (61 mg, 0.07 mmol), Xantphos (78 mg, 0.14 mmol) and DBU (509 μl, 3.35 mmol) in toluene (3 ml) was subjected to mnicrowave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (70 ml). The resultant solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 90:10 to 50:50) followed by crystallisation from ethyl acetate:pentane to provide the title compound as a white solid (353 mg, 67%). LCMS (method B): RT=4.08 min, M+H+=395/397.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1=[O:1])[CH3:16]
Reactant: O=C1COCCN1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCOCC1=O

Procedure:
A solution of 3-oxo-morpholine (6.5 g, 4 mmol) (Willey, Alan David; Kott, Kevin Lee; Miracle, Gregory Scot; Gosselink, Eugene Paul; Burckett-St. Laurent, James Charles Theophile Roger. Bleaching compositions containing bleach activators having alpha-modified lactam leaving-groups. PCT Int. Appl. (1996), WO 9622350 A1) in DMF (45 mL) was treated at rt in 3 portions with sodium hydride (3.34 g, 60% dispersion in mineral oil, 84 mmol). After 30 min a solution of ethyl bromoacetate (11.8 g, 71 mmol) in DMF (20 mL) was added dropwise. After 3 h the solvent was evaporated, the residue was taken up with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, dichloromethane:methanol=1000:0 to 995:5). The title compound was obtained as a light yellow oil (3.34 g, 28%). 1H-NMR (300 MHz, DMSO): δ=1.19 (t, J=7 Hz, 3H), 3.40 (mc, 2H), 3.85 (mc, 2H), 4.05-4.28 (m, 6H)
Reaction SMILES: [F:1][C:2]1[C:3]([F:23])=[C:4]2[O:9][CH2:8][C@H:7]([CH2:10][F:11])[N:6]3[CH:12]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14](=[O:17])[C:15]([CH:16]=1)=[C:5]23.[N+:24]([O-])([O-:26])=[O:25].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([F:23])=[C:4]2[O:9][CH2:8][C@H:7]([CH2:10][F:11])[N:6]3[CH:12]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14](=[O:17])[C:15]([C:16]=1[N+:24]([O-:26])=[O:25])=[C:5]23
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OC[C@@H]2CF
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OC[C@@H]2CF
Temperature: 0 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl (3R)-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (500 mg, 1.53 mmol) in H2SO4 (5.0 mL), was added KNO3 (216 mg, 2.14 mmol) under cooling with ice, the whole mixture was stirred under cooling with ice for 2 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were washed with water, and dried in vacuo to give ethyl (3R)-9,10-difluoro-3-fluoromethyl-2,3-dihydro-8-nitro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (453 mg, 80%) as a pale brown powder.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[CH2:24][C:23]1=O.[C:32]([O:35][C:36]1[CH:44]=[C:43]2[C:39]([CH2:40][C:41](=O)[N:42]2[CH3:45])=[CH:38][CH:37]=1)(=[O:34])[CH3:33]>C1COCC1>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[CH2:24][C:23]1=[S:2].[C:32]([O:35][C:36]1[CH:44]=[C:43]2[C:39]([CH2:40][C:41](=[S:2])[N:42]2[CH3:45])=[CH:38][CH:37]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Oc1ccc2c(c1)N(C)C(=O)C2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c(c1)N(C)C(=S)C2
Product: CN1C(=S)Cc2cccnc21
Reaction time: 18 h

Procedure:
P2S5 (3.80 g, 8.10 mmol) was added to a vigorously stirred suspension of Na2CO3 (0.88 g, 8.10 mmol) in THF (30 mL). After the mixture had become homogeneous (ca. 15 minutes), a solution of 1-methyl-7-aza-2-indolinone [VII: R1 =7-aza, R3 =Me] (1.00 g) in THF (10 mL) was added and stirring was continued for 18 hours at 20° C. Solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. Workup of the organic layer, and chromatography of the residue on silica gel (elution with EtOAc/petroleum ether (1:5)) gave 1-methyl-7-aza-2-indolinethione [IX: R1 =7-aza, R3 =Me] (0.81 g, 73%); mp (EtOAc/petroleum ether) 130°-133° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C.Cl>ClCCl>[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(O)ccc([N+](=O)[O-])c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Trifluoromethanesulfonic anhydride (1.57 mL, 8.77 mmol) was added to 2,3-dimethyl-4-nitrophenol (1.12 g, 6.70 mmol) and triethylamine (2.5 mL, 17.9 mmol) in dichloromethane (40 mL) at 0° C. under Ar atmosphere and the resulting mixture was allowed to stir overnight at r.t. 2M HCl (50 mL) was then added and the solution was extracted with dichloromethane (3×100 mL). The organic extracts were combined, washed with saturated aqueous NaHCO3 (100 mL), diluted with n-heptane (200 mL), and passed through a pad of silica gel to give 1.96 g (98%) of 195JP07 as a yellow oil.