Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].C(Cl)(Cl)Cl.[Br:8][C:9]1([C:15]2[O:16][C:17]3[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[Br:8][C:9]1([C:15]2[O:16][C:17]3[C:25]([CH2:26][C:1]#[N:2])=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [C-]#N
Reactant: O=c1cc(C2(Br)CCCCC2)oc2c(CBr)cccc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
NaCN (3.88 g, 0.075 mole) was dissolved in water (11 ml) and to the solution was added benzyltrimethylammonium chloride (13.9 g, 0.075 mole). After stirring at 50° C. for 15 minutes, chloroform (120 ml) was added and further 2 -(1-bromocyclohexyl)-8-bromomethyl-4-oxo-4H-[1]-benzopyran (12 g, 0.03 mole) was added. The mixture was stirred for 4 hours. The chloroform layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure to obtain crystals. The crude crystals were recrystallized from ethyl acetate to obtain the title compound (7.5 g) as prisms, m.p. 143°-144° C., yield 72.2%. IR and NMR spectra of this compound were identical with those of the compound obtained in Reference Example 20.
Reaction SMILES: [Br-].O=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16](O[K])(C)(C)C>O1CCCC1>[CH2:16]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)O[K]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
47.2 g of methyltoluphenylphosphonium bromide and 21.9 g of tert-butyl 4-oxo-1-piperidinecarboxylate were added to a mixture of 14.8 g tert-butoxy potassium and 300 ml tetrahydrofuran, and stirred for 40 min at room temperature. The reaction solution was evaporated, diethyl ether was added thereto, and then filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 20.8 g of tert-butyl 4-methylene-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.Br[C:18]1[C:19]2[C:20]3[CH:33]=[CH:32][S:31][C:21]=3[C:22](=[O:30])[NH:23][C:24]=2[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][C:24]2[NH:23][C:22](=[O:30])[C:21]3[S:31][CH:32]=[CH:33][C:20]=3[C:19]=2[C:18]=1[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 60.5 %

Procedure:
Following General Procedure E, tert-butyl 4-bromobenzylcarbamate (0.78 g, 2.7 mmol) was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (0.76 g, 2.5 mmol) to afford the desired product (0.66 g, 62%) as a brown solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.P(OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Agent: CCOP(OCC)OCC
Product: Clc1ccc2c(c1)[nH]c1ccccc12
Temperature: 150 °C
Yield: 69.2 %

Procedure:
A mixture of 4′-Chloro-2-nitrobiphenyl (640 mg) and triethyl phosphite (1.9 ml) was heated at 150° C. for 3 hrs. The mixture was then allowed to cool and purified by flash chromatography (5-10% ethyl acetate/hexane) to afford the sub-title compound as a white solid (382 mg): 1H NMR (400 MHz, d6-DMSO) δ 7.12-7.23 (2H, m), 2.40 (1H, m), 7.46-7.54 (2H, m), 8.12 (2H, d).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.ClCCl.C1COCC1>[O-]S([O-])(=O)=O.[Cu+2].O1CCOCC1>[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2

Procedure:
Commercially available 2-methyl-propane-2-sulfinic acid amide is reacted with commercially available 1,4-dioxa-spiro[4.5]decan-8-one in the presence of a coupling agent such as Ti(OEt)4 or CuSO4, in an organic solvent such as dichloromethane, THF or dioxane, at a temperature in the range of about 25° C. to about 80° C., to yield 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide. 2-Methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide is treated with an organometalic agent such as R1MgBr or R1Li, in an organic solvent such as ether, THF or dioxane, at a temperature in the range of about ˜78° C. to about 25° C., to yield the corresponding sulfonamide (XXVI).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A mixture of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (1 g, 3.43 mmol) and NaBH4 (0.156 g, 4.12 mmol) in ethanol (20 mL) was stirred at room temperature for 3 h. The reaction was quenched with NH4Cl saturated solution and extracted with EA. The organic layer was separated and concentrated to afford the title compound (0.9 g, 89% yield) as a white solid. LCMS: rt=3.71 min
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:52]([O:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][NH2:68])=[O:66])=[CH:63][C:62]=1[C:71]([F:74])([F:73])[F:72])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C(OCC)(=O)C.C(Cl)Cl.CN(C=O)C>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@:12]([CH3:16])([C:13]([NH:68][NH:67][C:65](=[O:66])[C:64]2[CH:69]=[CH:70][C:61]([O:60][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[C:62]([C:71]([F:72])([F:74])[F:73])[CH:63]=2)=[O:15])[CH2:11][O:10]1
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 92.1 %

Procedure:
(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid (D7) (210 mg, 0.81 mmol), HATU (372 mg, 0.98 mmol), diisopropylethyl amine (DIEA) (0.705 mL, 4.1 mmol), CH2Cl2-DMF and 4-(octyloxy)-3-(trifluoromethyl)benzohydrazide (D6) (270 mg, 0.81 mmol) were mixed together. The reaction was condensed, diluted with ethyl acetate, washed with water and brine, and condensed again. Another batch was made using this method with (D7) (0.1 mmol), HATU (46 mg, 0.12 mmol), DIEA (87 mL, 0.5 mmol), CH2Cl2-DMF and 4-(octyloxy)-3-(trifluoromethyl)benzohydrazide (D6) (>6 mg, 0.1 mmol). The batches were chromatographed and combined to provide the title product (428 mg). MS (ESI): 573.84 (MH+); 1H NMR (400 MHz, CDCl3) δ 9.43 (br, 2H), 8.06 (d, 1H, J=2.0 Hz), 7.94 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 6.96 (d, 1H, J=8.8 Hz), 4.52 (br, 1H), 4.07 (t, 2H, J=6.4 Hz), 3.76 (br, 1H), 1.82 (m, 2H), 1.67 (s, 6H), 1.57 (s, 3H), 1.51 (s, 9H), 1.51-1.43 (m, 4H), 1.38-1.24 (m, 6H), 0.88 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].C(Cl)Cl.CCO>C(OC(=O)C)(=O)C>[N+:10]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[B:7]([OH:9])[OH:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1B(O)O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of phenylboronic acid (10 g; 82 mmol) in acetic acid anhydride (100 ml) at −15° C. was added fuming HNO3 (5 ml; 120 mmol) over 30 min such that reaction temperature was kept below −10° C. The reaction mixture was allowed to warm up to rt. and left with stirring over night. The reaction mixture was poured onto ice and concentrated to 50 ml. The remanense was then re-evaporated 5 times from additional H2O (100 ml) and finally filtered to give 7.1 g crude product as a mixture of isomers. Column chromatography (CH2Cl2/EtOH=10/0.5) gave 4.8 g (35%) pure product as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH2:24][OH:25])[CH:23]=3)=[N:14][C:12]=2[N:13]=1.[P:35](=O)([OH:38])([OH:37])[OH:36]>CC#N>[P:35]([O:25][CH2:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:11]3[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]4[CH3:34])=[N:9][C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])=[N:13][C:12]=3[N:14]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH3:27])([OH:38])([OH:37])=[O:36]
Reactant: O=P(O)(O)O
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COP(=O)(O)O
Temperature: 25 °C

Procedure:
On a 50 mg scale using a 1:1.1 molar ratio of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol:Phosphoric acid. 50 mg of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol was dissolved in the minimal amount of MeCN, this solution was then added drop-wise to a vial containing the phosphoric acid which caused a yellow solid to immediately precipitate. The experiment was then left to stir over night at room temperature before filtering and isolating the precipitate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])O.[Na+]>C(O)C.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Brc1ccc2nc(-c3ccccc3)cn2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
1.99 g of 2-bromo-1-phenylethanone, 1.73 g of 2-amino-5-bromopyridine and 1 g of sodium hydrogen carbonate in a mixture of 20 ml of ethanol and 5 ml of water are placed in a round-bottomed flask. The mixture is heated at 80° C. for 4 h and left to cool and 40 ml of water are added. The mixture is stirred for 15 min and the precipitate is then recovered by filtration; it is washed with water and then with diisopropyl ether and dried in a desiccator. 1.8 g of compound are obtained. Mp=192-194° C.
Reaction SMILES: [CH2:1]([O:3][CH:4](O)[CH3:5])[CH3:2].C(Cl)Cl.N1C(C)=CC=CC=1C.[F:18][C:19]([F:32])([F:31])[S:20]([O:23]S(C(F)(F)F)(=O)=O)(=[O:22])=[O:21]>O>[O:23]([CH2:2][CH2:1][O:3][CH2:4][CH3:5])[S:20]([C:19]([F:32])([F:31])[F:18])(=[O:22])=[O:21]
Reactant: CCOC(C)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOCCOS(=O)(=O)C(F)(F)F
Temperature: -5 °C

Procedure:
25 g of ethoxyethanol was placed in a round bottom flask provided with a stirrer piece therein, which was connected to a nitrogen bubbler to replace the air in the flask by dry nitrogen. 141 ml of methylene chloride was added and 33 ml of 2,6-lutidine was further added, followed by cooling down to −10 to 0° C., dropping 57 ml of trifluoromethanesulfonic acid anhydride in one hour and continuing agitation under the cooling conditions for one hour. 100 ml of distilled water was added to the reaction solution, and an organic phase was separated, washed with 100 ml of distilled water and dried with anhydrous sodium sulfate, followed by removing the sodium sulfate by filtration and distilling off the solvent under reduced pressure. The resulting residue was distilled under a reduced pressure of 150 Pa at 30° C. to obtain 57 g of a 2-ethoxyethyl triflate fraction.
Reaction SMILES: C(OC1C(=O)N=C(CO)NC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].N(C(OCC)=O)=NC(OCC)=O>CC(N(C)C)=O>[C:42]1(=[O:43])[NH:38][C:39](=[O:48])[C:40]2=[CH:47][CH:46]=[CH:45][CH:44]=[C:41]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=c1nc(CO)[nH]cc1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-(Benzyloxy)-2-(hydroxymethyl)-4(1H)-pyrimidinone (0.696 g) (3 mmol), 0.787 g (3 mmol) of triphenylphosphine and 0.489 g (3 mmol) of N-hydroxyphthalimide are dissolved in 50 ml of dimethylacetamide. A solution of 0.640 g (3.3 mmol) of diethyl azodicarboxylate in 2 ml of dimethylacetamide is added dropwise at 20° C. The mixture is stirred at room temperature for 20 hours, the solvent is evaporated in a high vacuum and the residual yellow oil is crystallized from ethanol/ether. After recrystallization from ethanol there is obtained N-[(5-benzyloxy)-1,4-dihydro-4-oxo-2-pyrimidinyl]methoxy]phthalimide as white crystals of m.p. 157° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[NH:5][C:6](=[O:27])[N:7]([CH:26]=1)[C@@H:8]1[O:25][C@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>CN(C=O)C>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][CH2:13][C@H:12]1[O:25][C@@H:8]([N:7]2[CH:26]=[C:3]([CH2:1][CH3:2])[C:4](=[O:28])[NH:5][C:6]2=[O:27])[CH2:9][C@@H:10]1[OH:11]
Reactant: NCc1ccccc1Br
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
2.5 g of 2'-deoxy-5-ethyl-5'-O-(p-toluenesulphonyl)uridine were dissolved in 15 ml of DMF and added to 2-bromobenzylamine. The mixture was heated at 80° C. under nitrogen for 5 hours. The solvent was removed by evaporation and the residue was re-evaporated with toluene to given an oil. This was taken up in 20 ml of water/methanol (1:3) and stored in a refrigerator for 1.5 hours. A solid crystallized out and this was filtered off and washed with water/methanol (1:3) to give 0.99 g of 5'-(2-bromobenzylamino)-2',5'-dideoxy-5-ethyluridine, mp 144°-146° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([CH3:31])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:24][C:25]1[CH:26]=[C:27]([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]2=[O:23])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccccc12
Reactant: Cc1cc(C)cc(B(O)O)c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[2-(2-bromo-1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (150 mg in a mixture of 5 mL toluene and 5 mL ethanol) was added 3,5-dimethylphenyl boronic acid (85 mg) followed by 1.0 mL of 1M sodium carbonate. To the stirred solution was added lithium chloride (60 mg) followed by tetrakis(triphenylphosphine)palladium (28 mg) and the mixture heated to reflux on an oil bath. After 4 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 5:1) gave the title compound (146 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred suspension of 6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 990 mg, 5.15 mmol) in DMF (3.0 mL) is added K2CO3 (855 mg, 1.2 equiv.) followed by Mel (0.64 mL, 2.0 equiv.). The resulting solution is stirred overnight at room temperature. Water (20 mL) is then added and the reaction mixture is extracted with ethyl acetate (20 mL×2) and washed with saline (20 mL). The organic layers are collected and dried over MgSO4. Solvent is removed to yield the title compound as a yellow solid (956 mg, 90%). 1H NMR (300 MHz, DMSO) δ 8.16-7.26 (m, 3H), 3.30 (s, 3H), 3.00 (t, 2H), 2.61 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.N1C=CC=CC=1.O>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]2=[O:1])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccncc1
Product: O=c1c([N+](=O)[O-])cccn1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
(1a-1) To a solution of 2-hydroxy-3-nitropyridine (Aldrich, 3.0 mmol, 420 mg) in 1,4-dioxane (20 mL), were added 4-fluorophenyl boronic acid (Combi-block, 6.0 mmol, 840 mg), copper(II) acetate (Aldrich, 4.5 mmol, 815 mg) and pyridine (2 mL). The reaction was heated at 80° C. for 20 h. After cooling to room temperature, 30 mL of cold water was added. The solid formed was collected by filtration, washed with ammonium hydroxide and water, and dried under vacuum to give 1-(4-fluorophenyl)-3-nitropyridin-2(1H)-one (610 mg, 87% yield) as a solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:35]=[CH:34][C:7]([C:8]([NH:10][C:11](C(OCC)=O)([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20](=[O:28])[CH:19]=2)[C:12]([O:14]CC)=[O:13])=[O:9])=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20](=[O:28])[CH:19]=2)[C:12]([OH:14])=[O:13])=[O:9])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C(Cc1cc(=O)[nH]c2ccccc12)(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: O=C(NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.04 %

Procedure:
100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96%) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 3.93 g of potassium hydroxide (90%) was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 4 hours to complete the reaction. The concentrated hydrochloric acid were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with DMF and water to yield 7.17 g (92.04%) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(F)(F)F)c(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
2-amino-4-trifluoromethylpyridine (5 g, 30.8 mmol, Langfang Beixin Chemical Co., Hebei) was dissolved in 100 mL of chloroform and N-bromosuccinimide (5.92 g, 33.3 mmol) was added in batches. The mixture was stirred in darkness or away from light at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography with gradient elution (petroleum ether: ethyl acetate=10:1 and dichloromethane), so as to give 4.33 g of red solid. Yield: 58.2%. LC-MS: 240 (M+1), 242 (M+2+1).