Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:15]=[CH:14]2.ClC1C=CC=C(Cl)C=1[CH2:33][O:34]C1C=C2C(=CC=1)N(C(C)CC#N)C=C2.[OH-].[Na+]>CN(C=O)C>[Cl:6][C:7]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:15]=[C:14]2[CH:33]=[O:34]
Reactant: CC(CC#N)n1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: N#CCCCn1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCCCn1cc(C=O)c2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 70 %

Procedure:
A flame dried flask under argon was charged with DMF (0.43 mL, 5.57 mmol) and cooled to 0° C. Phosphorus oxychloride (0.16 mL, 1.67 mmol) was slowly added to the cooled DMF. The solution was stirred at 0° C. for 1 min and to this was added a DMF (1.5 mL) solution of a mixture of 4-[5-(2,6-dichlorobenzyloxy)indol-1-yl]butyronitrile (85%) and 3-[5-(2,6-dichlorobenzyloxy)indol-1-yl]butyronitrile (15%) (0.5 g, 1.4 mmol). The reaction mixture was stirred at room temprature for 1 h and heated at 50° C. for 4 h. The reaction solution was poured into ice water. A light yellow colored sticky solid precipated immediately. The mixture was neutralized by adding 1N NaOH until a pH of 7 was obtained. The product was extracted into ethyl acetate (3×) and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting crude yellow oil was purified by flash column chromatography (silica gel, ethyl acetate/hexane) to yield the desired aldehyde as a white solid (0.38 g, 70%) and the undesired aldehyde (0.099 g, 18%).MS(ES) m/e 387.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[O:31][C:14]4=[C:15]([NH2:30])[N:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][N:22]([CH:24]6[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]6)[CH:23]=5)=[C:13]4[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:30][C:15]1[N:16]=[CH:17][C:18]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:28][CH2:29]3)[CH:23]=2)=[C:13]2[CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:31][C:14]=12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4cnccc34)oc12
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)CC1
Yield: 59.2 %

Procedure:
A solution of 2-isoquinolin-5-yl-4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-furo[2,3-c]pyridin-7-ylamine (30 mg, 0.07 mmol), methoxyacetyl chloride (8.02 μL, 0.0877 mmol), and DIPEA (28.0 μL, 0.161 mmol) in DCM (0.94 mL) stirred overnight at RT. The reaction was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (10% 7 N NH3/MeOH:EtOAc) afforded 20 mg (60%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.97-2.21 (m, 4 H) 2.31 (br s, 2 H) 2.81-2.94 (m, 1 H) 3.17-3.32 (m, 1 H) 3.41-3.51 (m, 3 H) 4.06-4.25 (m, 3 H) 4.46 (tt, J=11.34, 4.07 Hz, 1 H) 4.76 (d, J=12.88 Hz, 1 H) 5.01 (br s, 2 H) 7.22 (s, 1 H) 7.69-7.80 (m, 2 H) 7.84-7.91 (m, 1 H) 8.03 (s, 1 H) 8.08-8.18 (m, 2 H) 8.22 (d, J=6.06 Hz, 1 H) 8.61-8.70 (m, 1 H) 9.37 (s, 1 H); MS (ESI): 483.11 [M+H]+; HPLC tR=0.89 min (TOF, polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]([CH3:15])[C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.O1CCCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]([CH3:15])[C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH2:18])[CH:3]=1
Reactant: CN(C(=O)c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN(C(=O)c1ccccc1)c1ccc(Br)cc1N
Yield: 91.3 %

Procedure:
Dissolving 9.5 g (28 mmol) of 4′-bromo-N-methyl-2′-nitro-benzanilide obtained in the above step (2) into 100 milliliter of tetrahydrofuran, and during agitation under the atmosphere of argon gas and at room temperature, a solution provided by mixing 25 g (0.14 mmol) of sodium hydrosulfite into 90 milliliter of water was added. Further, adding 10 milliliter of methanol, the resultant solution was stirred for 3 hours. Subsequently, adding 100 milliliter of ethyl acetate and then, a solution provided by mixing 12 g (0.14 mmol) of sodium hydrogen carbonate and 125 milliliter of water was further added. The resultant solution was stirred for 1 hour, followed by extracting with ethyl acetate. After removing water layer, an organic layer was washed with 10% K2CO3 aqueous solution and with saturated solution of sodium chloride, followed by drying with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure and 7.8 g of 4′-bromo-N-methyl-2′-amino-benzanilide was obtained as white solids (yield: 90%). The white solids were used in the next reaction as crude products.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N+:20]([O-])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc(COc2ccc(N)c3ccccc23)ccn1
Yield: 94.5 %

Procedure:
2-Amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine (2) (4.50 g, 15.24 mmol) in MeOH (200 mL) and AcOH (200 mL) was passed through a Thales H-cube (2.0 mL·min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo. The crude product was subjected to SCX capture and release eluting with 1% NH3 in MeOH solution and the solvent was removed in vacuo to give 2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine (3) (3.82 g, 94%) as a purple solid: m/z 266 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21](I)[CH:20]=1>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:21]3[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[C:19]([F:18])[CH:20]=3)[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(F)cc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1-fluoro-3-iodo-5-nitrobenzene according to the coupling protocol of example 2. 1H NMR (DMSO-d6): δ 8.92 (s, 1H), 7.53 (t, J=1.8 Hz, 1H), 7.36 (dt, J=8.6, 2.2 Hz, 1H), 7.21 (dd, J=8.7, 2.4 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.03 (dt, J=11.1, 2.2 Hz, 1H), 3.29 (s, 3H), 2.01 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 374 ([M+H]+); MS (ESI) m/z 372 ([M−H]−); Anal. calcd for C19H20FN3O4: C, 61.12; H, 5.40; N, 11.25. Found: C, 60.33; H, 5.17; N, 10.51.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[K+]>O>[CH3:3][S:4][C:5]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1ccc(CC(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1ccc(CC(C)C)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
Water (2 ml) and 4 ml of methanol were added to 420 mg of methyl α-methylthio-α-(p-isobutylphenyl)propionate. Then, 280 mg (85% content) of potassium hydroxide was added, and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture, initially heterogeneous, became uniform. Water (30 ml) was added, and the mixture was extracted with 10 ml of methylene chloride. The aqueous layer was acidified with conc. hydrochloric acid to a pH of 1, and extracted three times with 20 ml of diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the diethyl ether. Thus, 394 mg of crude α-methylthio-α-(p-isobutylphenyl)propionic acid was obtained as an oil in a yield of 99%. The oil soon crystallized, and recrystallization from water-methanol afforded colorless crystals having a melting point of 89° to 92° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[Cl:10][CH:11]([C:15]1[O:20][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:17]=2[N:16]=1)[CH2:12][CH2:13][CH3:14]>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:10][CH:11]([CH2:12][CH2:13][CH3:14])[C:15]([NH:16][C:17]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](=[O:21])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:20]
Reactant: CC(=O)Nc1nccs1
Reactant: CCCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 72.6 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 6.94 g of N-(2-thiazolyl)-acetamide in 280 ml of tetrahydrofuran and 70 ml of a butyllithium-hexane solution and a solution of 7.8 g of the product of Step A in 40 ml of tetrahydrofuran were reacted to obtain 8.3 g of 2-[(2-chloro-1-oxo-pentyl)-amino]-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene propanamide melting towards 184°-186° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2.FC(F)(F)[C:23]([OH:25])=[O:24]>C(Cl)Cl>[C:3]([O:25][C:23]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:2]([F:19])([F:1])[F:20])=[CH:18][N:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:24])([CH3:8])([CH3:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: FC(F)(F)c1ccncc1-c1cnc2c(c1)CCCN2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cnccc3C(F)(F)F)cnc21

Procedure:
6-(4-Trifluoromethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method V, as illustrated above. It is then used in the synthesis of 6-(4-trifluoromethyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.[CH:27]([N-:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].[Li+].C1C(=O)N(Br)C(=O)C1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH2:26][N:30]([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Reactant: CC(C)[N-]C(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc4ccccc4nc3CN(C(C)C)C(C)C)c2cc1OC
Reaction time: 0.17 h
Yield: 16 %

Procedure:
6,7-Dimethoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 276) (108 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution. A lithiumdiisopropylamide/1.8 M heptane-tetrahydrofuran-ethylbenzene solution (0.3 ml) was added to the solution at −78° C., and the mixture was stirred for 10 min. N-Bromosuccimide (180 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 16%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:24])[C@@H:14]([NH2:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([O:24][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:14]([N:23]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)COC1(C)C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cccc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Reaction time: 0.17 h

Procedure:
Add tricaprylmethylammonium chloride (Aliquat® 336) (4.5 g, 11.2 mmol) and tetrabutylammonium bromide (TBAB) (5.7 g, 15.7 mmol) to a solution of 4-(R)-[2-(S)-amino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (16.45 g, crude) in tetrahydrofuran (200 mL). Add portionwise 95% sodium hydride (2.6 g, 90 mmol) and stir for 10 minutes. Add benzyl bromide (13.4 mL, 112.5 mmol) and heat at 60° C. for 40 minutes and concentrate. Add more 95% sodium hydride (5.4 g, 225 mmol) and benzyl bromide (27 mL, 225 mmol) in tetrahydrofuran (−5 mL) and stir overnight at 65° C. Dilute with ethyl acetate, quench with water (300 mL), wash with water, and saturated aqueous sodium chloride. Extract the aqueous washes with ethyl acetate, comvine the organic layers, dry (magnesium sulfate), filter and purify twice (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the desired compound as an orange residue (16.01 g, 49%).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.N1C=CC=CC=1.Cl.[NH2:32][OH:33]>O>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:32][OH:33])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A solution of 4-(2-phenyl-oxazol-4-ylmethoxy)benzaldehyde (4.3 g, 15.3 mmol), ethanol (100 mL), pyridine (45 mL) and hydroxylamine hydrochloride (2.2 g, 30.8 mmol) was refluxed for 1.5 hours. The solution is cooled to 25° C. and poured into water (600 mL). The resultant precipitate was filtered and dried at 25° C. for 18 hours to give the product as a white solid in 97.1% yield, m.p. 184°-186° C. MS (EI, m/e): 294 (M)+.
Reaction SMILES: [Na].[C:2](OCC)(=[O:6])[C@H:3]([CH3:5])[OH:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.Cl>C(O)C.O>[CH3:5][CH:3]1[C:2](=[O:6])[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:21])([F:22])[F:10])[CH:13]=2)=[C:19]([NH2:20])[O:4]1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H](C)O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1OC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Yield: 18.3 %

Procedure:
A dry, 500-ml, three-neck, round-bottom flask equipped with a mechanical stirrer, addition funnel and a reflux condenser was charged with 100 ml of ethanol. To the stirred solvent were added 3.5 g of sodium. After all the metal had dissolved, a solution of 13.0 g of ethyl L-(+)-lactate and 18.5 g of m-trifluoromethylphenylacetonitrile in 30 ml of ethanol was added dropwise to the reaction mixture. The mixture became a deep red and after the addition was complete, the mixture was heated at reflux overnight (about 18 hours). The mixture was then cooled to room temperature and added to 300 ml of water and the resulting mixture was acidified (pH about 1) with 10% hydrochloric acid. The mixture was then extracted with ether (three times) and the organic extracts were washed (two times) with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield a thick oil. This oil was taken up in a mixture of ether/petroleum ether and the desired compound crystallized as a yellow powder. Two crops of crystals were collected to afford a total of 4.7 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Br:15]N1C(=O)CCC1=O.O>C1COCC1>[Br:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl-2-indole carboxylate (1.89 g) and N-bromosuccinimide (1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL) and filtered. The filtrate was washed with THF, dried under vacuum at 60° C., and recrystallized from ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7]>C(OCC)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOCC
Product: Nc1ccc(Cl)cc1N

Procedure:
To a suspension in diethyl ether (50 mL) of 5-chloro-2-nitroaniline (2.70 g, 15.6 mmol) was added zinc powder (10.2 g, 156 mmol) in portions. The reaction mixture was filtered and concentrated in vacuo to give 5-chloro-2-aminoaniline which as was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>C(OCC)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)CSc1cccc(Br)c1
Temperature: 25 °C
Yield: 110.3 %

Procedure:
A solution of 8.0 g (42 mmol) of 3-bromothiophenol was treated with 7.1 g (47 mmol) of methyl bromoacetate and potassium carbonate. The resulting suspension was stirred at reflux for 24 hrs, cooled to RT and neutralized with a saturated aqueous solution of NH4Cl. Diethylether was added, the phases were separated and the aqueous one was extracted twice with diethylether. The combined organic phases were dried over Na2SO4, filtered and evaporated to give 12.1 g (99%) of (3-bromo-phenylsulfanyl)-acetic acid methyl ester as a light yellow oil, MS: 279 (MNH4+, 1Br).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][O:21][C:22]([F:25])([F:24])[F:23].C[Si](C)(C)[O:28][C@@H:29]1[C@@H:34]([O:35][Si](C)(C)C)[C@H:33]([O:40][Si](C)(C)C)[C@@H:32]([CH2:45][O:46][Si](C)(C)C)[O:31][C:30]1=O.[Li]CCCC.CS(O)(=O)=O.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1COCC1.C(Cl)Cl>[Cl:17][C:5]1[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:2]([C@H:30]2[C@H:29]([OH:28])[C@@H:34]([OH:35])[C@H:33]([OH:40])[C@@H:32]([CH2:45][OH:46])[O:31]2)=[C:3]([O:18][CH2:19][CH2:20][O:21][C:22]([F:25])([F:24])[F:23])[CH:4]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: CCc1ccc(Cc2cc(Br)c(OCCOC(F)(F)F)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OCCOC(F)(F)F)cc2Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-chloro-5-(4-ethylbenzyl)-2-(2-(trifluoromethoxy)-ethoxy)benzene (BP) (60 mg, 0.14 mmol) and (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (0.19 g, 0.41 mmol) in anhydrous THF (2 mL), was added n-BuLi (2.5 M, 0.11 mL) in a dropwise fashion at −78° C. over 15 min. The resulting solution was stirred at −78° C. for 1 h. Methanesulfonic acid (20 μL in 0.5 mL MeOH) was added and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 5% MeOH in CH2Cl, to collect the crude product. To a solution of the crude product (10 mg, 0.018 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. was added Et3SiH (6.3 mg, 0.05 mmol) and BF3.Et2O (3.7 mg, 0.05 mmol). After stirring the resulting mixture for 1 h at 0° C., it was partitioned between water and EtOAc. The organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was purified by preparative HPLC to give compound BQ. 1H-NMR (CDCl3, 300 MHz) δ 7.21 (s, 1H), 7.07 (m, 4H), 6.89 (s, 1H), 4.29 (d, J=3.9 Hz, 1H), 4.17 (m, 2H), 4.01 (m, 2H), 3.81 (m, 2H), 3.76 (m, 1H), 3.74-3.49 (m, 6H), 2.61 (m, 3H), 1.20 (m, 3H).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH3:14][N:15]([CH3:19])[CH2:16][C:17]#[CH:18].N(C(C)C)C(C)C.[N+:27]([C:30]1[CH:31]=[CH:32][C:33](Br)=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)([O-:29])=[O:28]>O1CCOCC1.CCOC(C)=O.O.[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH3:14][N:15]([CH3:19])[CH2:16][C:17]#[C:18][C:33]1[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][C:34]=1[C:36]([F:37])([F:38])[F:39]
Reactant: C#CCN(C)C
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
t-Bu3P (0.25 M in dioxane, 8.9 mL, 2.2 mmol, 0.2 equiv), 3-dimethylamino-1-propyne (FLUKA) (1.65 mL, 15.6 mmol, 1.4 equiv), and i-Pr2NH (2.0 mL, 14.4 mmol, 1.3 equiv) are added sequentially to a mixture of 5-nitro-2-bromobenzotrifluoride (ALDRICH) (3 g, 11.1 mmol), CuI (0.148 g, 0.78 mmol, 0.07 equiv), and Pd(PhCN)2Cl2 (0.427 g, 1.1 mmol, 0.1 equiv) in dioxane (10 mL). The reaction mixture is stirred for 48 h at rt. Then, Pd(PhCN)2Cl2 (0.100 g) is added. After stirring for additional 24 h, the reaction mixture is diluted with EtOAc and H2O and filtered through a pad of Celite. The filtrate is extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude material by silica gel column chromatography (CH2Cl2/NH3 (2 N in MeOH), 95:5) affords the title compound as a brown oil: ES-MS: 273.0 [M+H]+; single peak at tR=3.06 min (System 1); Rf=0.13 (CH2Cl2/NH3 (2 N in MeOH), 95:5).