Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)=[CH:25][C:6]=3[N:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)C[C@H]2C
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3cn[nH]c3)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
To a solution of (R)-4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (100 mg, 0.26 mmol) in DME/H2O (3:1, 2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.36 mmol), cesium carbonate (164 mg, 0.50 mmol) and Tetrakis(triphenylphosphine)palladium(0)(22 mg, 0.02 mmol). The mixture was stirred in the microwave at 130° C. for 20 min. The reaction mixture was concentrated and purified by prep-TLC (elute: DCM:MeOH=15:1) to give (R)-4-(1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (15 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1([CH3:51])[CH2:7][CH:6]([N:8]([CH2:45][CH2:46][CH2:47][CH3:48])[C:9]2[N:14]=[C:13]([N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)[N:12]=[C:11]([N:30]([CH2:41][CH2:42][CH2:43][CH3:44])[CH:31]3[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]3)[N:10]=2)[CH2:5][C:4]([CH3:50])([CH3:49])[NH:3]1.[C:52]([O:56]O)([CH3:55])([CH3:54])C>[Mo](=O)(=O)=O.C1CCCCC1>[CH:52]1([O:56][N:34]2[C:35]([CH3:38])([CH3:37])[CH2:36][CH:31]([N:30]([CH2:41][CH2:42][CH2:43][CH3:44])[C:11]3[N:10]=[C:9]([N:8]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:6]4[CH2:5][C:4]([CH3:49])([CH3:50])[N:3]([O:56][CH:52]5[CH2:55][CH2:49][CH2:4][CH2:5][CH2:54]5)[C:2]([CH3:1])([CH3:51])[CH2:7]4)[N:14]=[C:13]([N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]4[CH2:21][C:20]([CH3:22])([CH3:23])[N:19]([O:56][CH:52]5[CH2:55][CH2:21][CH2:16][CH2:17][CH2:54]5)[C:18]([CH3:24])([CH3:25])[CH2:17]4)[N:12]=3)[CH2:32][C:33]2([CH3:40])[CH3:39])[CH2:55][CH2:7][CH2:2][CH2:1][CH2:54]1
Reactant: CC(C)(C)OO
Reactant: CCCCN(c1nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CCCCN(c1nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To a refluxing mixture of 13.5 g (19.0 mmol) of 2,4,6-tris[N-(2,2,6,6-tetramethylpiperidin-4-yl)-n-butylamino]-1,3,5-triazine, 0.2 g of molybdenum trioxide, and 175 ml of cyclohexane are added 36.6 g (284 mmol) of 70% aqueous t-butyl hydroperoxide over a 10 minute interval. The red reaction mixture is heated at reflux for one hour and then transferred to a Fischer-Porter pressure bottle using 25 ml of fresh cyclohexane. The reaction mixture is then heated for 3 hours at 150° C. to discharge the red color. Solids are removed by filtration and the filtrate is concentrated to a residue which is purified by flash chromatography on silica gel (19:1 heptane:ethyl acetate). The product is crystallized from isopropyl alcohol to afford 7.6 g (40% yield) of a white powder, m.p. 189°-94° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl>[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][C:21]([CH:8]=[O:9])=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1
Reactant: COc1c(Br)cc(Br)cc1-c1ccc[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1c(Br)cc(Br)cc1-c1ccc(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus oxychloride (0.18 ml, 1.9 mmol) was added to N,N-dimethylformamide (0.15 ml, 1.9 mmol) at 0° C. under argon with constant stirring. The resulting mixture was allowed to warm to room temperature and was then stirred for 1.5 h. 1,2-Dichloroethane (1.5 ml) was added and a solution of 2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole (0.30 g, 0.91 mmol) in 1,2-dichloroethane (3 ml) was then added at 0° C. The reaction mixture was stirred at room temperature for 16 h. On cooling, the mixture was poured onto crushed ice and basified with aqueous sodium acetate (50%, 20 ml). The organic phase was separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with aqueous sodium hydrogen carbonate, dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on alumina (Brockmann grade 1) with ether - methanol (0-1% ) gradient elution gave the title compound (D29) as a beige solid (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) at ambient temperature. 4-Benzylpiperidine (89 mg, 0.51 mmol) were diluted in DCM (2.0 mL) and treated with DIPEA (0.205 mL, 1.174 mmol) at ambient temperature. To this mixture a solution of 4-bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) was added and the reaction stirred at ambient temperature for 17 hours. The reaction was then concentrated in vacuo to afford the title compound, which was used without further purification. LRMS (ESI) calc'd for C18H20BrNO2S [M+H}+: 394. found 394
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:50]6[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCCNCC4)c3)c2C)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) along with 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (48 μL, 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [40.6 mg (36%)]. LC-MS m/z 743.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in a 25 ml round-bottomed flask. 10 ml of dichloromethane are added, followed by 0.37 ml of triethylamine and finally 0.23 ml of ethylsulphonyl chloride. The reaction mixture is stirred at ambient temperature for 3 h, then washed twice with water and once with a saturated sodium chloride solution and then evaporated under reduced pressure. 0.98 g of 4-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[Cl:10][CH2:11][C:12]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:8]#[N:9])=[CH:3][CH:4]=1)=[O:13]
Reactant: N#CCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: N#CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 1 liter round bottomed, four-necked flask with condenser, CaCl2 drying tube, pneumatic stirrer and thermometer 88.2 ml of benzylcyanide, 105.6 ml of chloroacetylchloride, and 238.2 ml of carbon disulfide are added. After the solution has been cooled to 0° C., AlCl3 is slowly added. The reaction mixture is heated to 15° C. It is subsequently stirred for another 5 minutes at +2° C., 1.2 hour at room temperature and 2 hours at 40° C. CS2 is separated and the dark oil is placed on 2.5 kg ice while stirring vigorously. The resulting brown precipitate is filtered by suction over a D4 glass filter funnel, washed with 1N hydrochloric acid, sucked quite dry, and dried in a vacuum drying oven for 18 hours at room temperature. The raw product (104.9 g) is dissolved in boiling 6.4 l i-propanol containing 34 g of activated carbon and then the product is recrystallized upon cooling. After the crystals have precipitated at room temperature, the precipitation is completed. The product is left with the mother liquor for at least 24 hours at 4° C. The white crystals are filtered by suction by means of a D4 glass filter funnel, washed with cold i-propanol and dried in a vacuum drying oven for 18 hours at room temperature.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH3:18][CH2:19][CH:20]([NH2:24])[C:21]([OH:23])=[O:22].[OH-].[K+].Cl>O1CCCC1.O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:24][CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Reactant: CCC(N)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(Nc1nc(C#N)c(C#N)nc1-c1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (2.41 g; 0.01 mole) was dissolved in 30 ml of tetrahydrofuran, and with stirring at 15° to 20° C., a solution prepared from 2.04 g (0.02 mole) of DL-α-amino-n-butyric acid, 1.12 g (0.02 mole) of potassium hydroxide and 40 ml of water was added dropwise over the period of 5 minutes. The mixture was then sitrred at 30° C. for 30 minutes. After the reaction, the reactor was cooled with ice, and in the meanwhile, 2 ml of conc. hydrochloric acid was added to the reaction solution. The solution was then extracted with 100 ml of toluene. The toluene layer was washed with 50 ml of a saturated aqueous solution of sodium chloride and 50 ml of water, and the solvent was removed by concentration under reduced pressure to afford a yellowish white solid. Recrystallization of the solid from ethanol afforded 2.63 g (yield 86%) of 2,3-dicyano-5-(1-carboxy-n-propyl)amino-6-phenylpyrazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][NH2:19])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:25]([CH2:24][Cl:23])=[N:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
4.4 g (13.8 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide were stirred at room temperature overnight in 30 ml of N,N-dimethylformamide with 2.65 g (15.5 mmol) of chloroacetic anhydride. After evaporating the solvent the residue was stirred at room temperature for 48 hours with 20 ml of a 10% solution of phosphorus pentoxide in methanesulphonic acid. The reaction mixture was treated with ice, made alkaline with conc. sodium hydroxide solution and extracted four times with methylene chloride. By drying the organic phase over magnesium sulfate and evaporating the solvent there were obtained 3.39 g (60%) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 185°-189°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[CH:14][CH:13]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CO>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:31][CH2:32][OH:33])[CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(C=CC(=O)Nc2ccccc2N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)C=Cc1ccc(CN(CCO)CCc2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.2 %

Procedure:
To a stirred solution at −20° C. of 5 (1.49 g, 2.62 mmol) in anhydrous THF (30 mL) under nitrogen was slowly added a solution of TBAF (2.88 mL, 2.88 mmol, 1.0M in THF). The reaction mixture was allowed to warm-up to the room temperature over 1 h and was stirred for additional 22 hours. MeOH was added and the reaction mixture was concentrated, diluted with AcOEt, and successively washed with saturated aqueous solution of NaHCO3, H2O, a saturated aqueous solution of NH4Cl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95→10/90 plus several drops of NH4OH) and triturated with a mixture of AcOEt/CH2Cl2/hexane to afford the title compound 6 (956 mg, 2.10 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.76 (s, 1H), 9.39 (s, 1H), AB system (δA=7.58, δB=7.44, JAB=8.0 Hz, 4H), 7.56 (d, J=15.7 Hz, 1H), 7.42-7.34 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.05 (td, J=7.2, 1.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.90 (d, J=15.8 Hz, 1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.60 (ddd, J=7.5, 7.5, 1.4 Hz, 1H), 4.98 (bs, 2H), 4.43 (t, J=5.4 Hz, 1H), 3.78 (s, 2H), 3.56 (td, J=6.3, 5.6 Hz, 2H), 2.94-2.84 (m, 2H), 2.82-2.74 (m, 2H), 2.68 (t, J=6.5 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:15][C:14]3[CH:13]=[C:12]([C:16]([OH:18])=[O:17])[NH:11][CH2:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1([S:27]SC(=O)C)C=CC=CC=1.Cl>CN(C=O)C.O>[SH:27][C:13]1[C:14]2[O:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[CH2:10][NH:11][C:12]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)C1=Cc2oc(-c3ccccc3)cc2CN1
Reactant: CC(=O)SSc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1=C(S)c2oc(-c3ccccc3)cc2CN1
Temperature: 50 °C

Procedure:
As depicted in Scheme 35 below, 2-phenyl-4,5-dihydro-furo[3,2-c]pyridine-6-carboxylic acid (0.015 mol) is added in portions to a mixture of sodium hydride (60% dispersion in mineral oil, 0.045 mol) in anhydrous DMF (35 ml) under a nitrogen stream at 0° C. After 15 minutes phenylacetyl disulfide (0.02 mol) is added portion-wise, and the reaction is then heated to 50° C. and kept at that temperature overnight. The reaction mixture is then cooled to room temperature and poured onto crushed ice, turned acidic with 2N HCl, and extracted with ethyl acetate. The organic phase is separated, washed with brine, and dried over Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue is triturated with hexane and filtered. The obtained crude residue is then refluxed in the presence of HCl 6N and water to give 7-mercapto-2-phenyl-4,5-dihydro-furo[3,2-c]pyridine-6-carboxylic acid.
Reaction SMILES: [H-].[Na+].[I-].[CH4:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1)([O-:7])=[O:6].O>CN(C)C=O>[CH3:4][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=2)=[C:15]1[C:23]([NH2:25])=[O:24]
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc([N+](=O)[O-])cc1
Reactant: C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(N)=O)c(-c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.047 g of sodium hydride and then 73 μl of methane iodide are added to a solution of 0.3 g of 3-(4-nitro-phenyl)-1H-indole-2-carboxamide in 8 ml of anhydrous dimethylformamide under argon. The reaction mixture is stirred at ambient temperature for 2 hours and 45 ml of water are added. The solid formed is filtered off, washed with 3 times 15 ml of water, and filter-dried. After drying under vacuum, 0.22 g of 1-methyl-3-(4-nitrophenyl)-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:23])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:27][C:28]#[N:29]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:27][C:28]#[N:29])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccc(F)c(Cl)c2)C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2ccc(F)c(Cl)c2)C1
Temperature: -40 °C
Reaction time: 1 h
Yield: 113.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (5.1 g, 15 mmol) in CH3CN (150 mL), NaH (1.8 g, 45 mmol) was added at 0° C. The mixture was stirring for 1 hour. Then the mixture was cooled to −40° C., the bromoacetonitrile (5.4 g, 45 mmol) was added dropwise. The mixture was allowed to warm to 0° C. gradually. The addition of NaH and bromoacetonitrile was repeated three times. The mixture was quenched with H2O and exacted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrate to get the crude (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (6.5 g, 100%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:25]=[CH:24][C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.ClCCl.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NCCO3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(C2=NCCO2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg tert-butyl 4-[4-(4,5-dihydrooxazol-2-yl)-phenoxy]-piperidine-1-carboxylate are taken and mixed with 6 ml of a (5/1) dichloromethane/trifluoroacetic acid mixture. The reaction mixture is stirred at ambient temperature and after 15 min it is cautiously mixed with a saturated NaHCO3 solution. The organic phase is dried and evaporated to dryness. 20 mg (V-2) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6](C2C=C3C(=CC=2)NC(C)(C)C=C3C)[CH:7]=1.FC1C=CC=C([N+]([O-])=O)C=1[I:34].IC1C=C(C=C([N+]([O-])=O)C=1)N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([I:34])[CH:7]=1
Reactant: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc([N+](=O)[O-])c3)cc21
Reactant: O=[N+]([O-])c1cccc(F)c1I
Agent: Nc1cc(I)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-(5-Fluoro-3-nitrophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 280, structure 4 of Scheme II, where R1 =5-fluoro-3-nitrophenyl) 1-Fluoro-3-nitroiodobenzene To a 25 mL round-bottom flask equivuipped with a magnetic stir bar 3-iodo-5-nitroaniline (543.3 mg, 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 0° C. in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorobenzene was added. A distillation apparatus was fitted to the reaction flask. The flask was placed in an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mg (50%) of 5-fluoro-3-nitroiodobenzene. Data for 5-fluoro-3-nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 (s, 1 H), 8.00 (m, 2 H).