Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25].[OH-:26].[Na+].Cl>CO.O>[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:2]([NH:3][C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25])=[O:1])([OH:26])=[O:11]
Reactant: [OH-]
Reactant: O=C(O)c1cccc2c1OB(O)[C@@H](N1C(=O)c3ccccc3C1=O)C2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 mg of (R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid in a mixture of methanol and H2O (2 mL, 1:1) was added 1 N NaOH (0.5 mL) and the resulting reaction mixture was stirred at room temperature for 3 hr. 1N HCl was added to adjust the pH of the solution to 3. The product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 356 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.Br[C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=[CH:2]2)[CH:12]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: c1cnc2nc[nH]c2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cccc(-n3cnc4cccnc43)c2)cc1

Procedure:
A mixture of imidazo[4,5-b]pyridine (595 mg, 5 mmol), 3-bromobiphenyl (1.16 g, 5 mmol), potassium carbonate (1.03 g, 7.5 mmol), and copper powder (2.0 g) in N-methylpyrrolidone (10 ml) was heated to 200° under nitrogen for 4 h. After dilution with ethyl acetate the mixture was filtered through celite. Water was added and the phases were separated. After two more extractions with ethyl acetate the combined organic phases were dried and evaporated to give a light brown oil. Column chromatography on silica gel gave the two products as separate fractions with 1-(3biphenylyl)imidazo[4,5-b]pyridine being the more polar one. This product was precipitated as the oxalate. Yield: 100 mg, 0.3 mmol, 5%. mp 174°-176° C. Yield of 3(3-biphenylyl)imidazo[5,4-b]pyridine: 270 mg, 1 mmol, 20%. mp 89°-91° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)[CH:11]=[CH:10][CH:9]=1)=[O:7].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>O1CCCC1>[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:30]
Reactant: O=C(CCCCCl)c1cccc2cc3c(C(=O)CCCCCl)cccc3cc12
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CCCCC(=O)c1cccc2cc3c(C(=O)CCCCN(CC)CC)cccc3cc12
Temperature: 110 °C

Procedure:
In each of four Carius tubes is placed 10 g of 1,5-bis(5-chlorovaleryl)anthracene (0.024 mole), 80 ml of diethylamine and 40 ml of tetrahydrofuran. The tubes are heated to 110° C. for 30 hours, cooled and their contents combined. The volatile components are evaporated in vacuo and the residue is slurried with 400 ml of chloroform. The organic phase is extracted twice with 100 ml portions of water, and two additional times with 100 ml portions of 10% HCl solution. The combined acid extracts are neutrallized using a cold 50% sodium hydroxide solution and reextracted with two 100 ml portions of chloroform. The combined chloroform extracts are dried over magnesium sulfate, filtered, evaporated to dryness and the residue is crystallized from n-heptane to give 36 g of 1,5-bis(5-diethylaminovaleryl)anthracene having a m.p. of 65°-7° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C-:9]#[N:10].[Na+]>CS(C)=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[CH2:2][C:9]#[N:10]
Reactant: ClCc1ncccn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ncccn1
Temperature: 50 °C

Procedure:
A solution of 6.8 g. of 2-(chloromethyl)pyrimidine is added dropwise to a solution of 5.2 g. of sodium cyanide in 100 ml. of dimethylsulfoxide. The mixture is heated at 50°C. for 2 hours, then diluted with 150 ml. of 5% aqueous sodium carbonate solution and extracted with ether. The extract is dried and concentrated to give 2-(2-pyrimidyl)acetonitrile.
Reaction SMILES: [Pt:1].[C:2]([O:19]C(=O)CCCCCCCCCCCCCCC)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(=O)(O)[O-].C([NH+](CC)CC)C.C(O)(C)C.O>[C:2]([Pt:1])(=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCC
Reactant: [Pt]
Agent: CC[NH+](CC)CC
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[Pt]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An estimated 30 nmol of the amino-derivatized 2-3 nm platinum cluster dissolved in 0.6 M triethylammonium bicarbonate in 20% isopropanol/water was evaporated to dryness five times from methanol, then dissolved in 3 mL of diclhoromethane, and treated with 200 nmol of palmitic anhydride. The mixture was stirred for one hour at room temperature, then washed three times with 0.1 M sodium phosphate buffer at pH 6.5. The remaining reaction mixture was evaporated to dryness, redissolved in 2:1 methanol/chloroform, then separated by gel filtration (GH25, Amicon eluted with 2:1 methanol:chloroform); the first species to elute is the dark brown palmitamido-platinum cluster. After evaporation to dryness, lipid conjugation was demonstrated by the extraction of the cluster into the chloroform layer when the palmitoyl cluster was shaken in a chloroform/water mixture with a small amount of methanol as a phase transfer agent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1Br.[CH3:12][C:13]1([CH3:22])[CH2:18][CH2:17][C:16](B(O)O)=[CH:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13]([CH3:22])([CH3:12])[CH2:14][CH:15]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: N#CCc1ccc(N)c(Br)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: [Na+]
Product: CC1(C)CC=C(c2cc(CC#N)ccc2N)CC1

Procedure:
The title compound was prepared from (4-amino-3-bromo-phenyl)-acetonitrile (as prepared in the previous step, 805 mg, 3.81 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (705 mg, 4.57 mmol), Pd(PPh3)4 (440 mg, 0.380 mmol), and 2M Na2CO3 (15.2 mL, 30.5 mmol) according to the procedure in Example 34, step (b) (417 mg, 46%). 1H—NMR (CDCl3; 400 MHz): δ 6.89 (1H, dd, J=8.1, 2.0 Hz), 6.84 (1H, d, J=2.0 Hz), 6.59 (d, 1H, J=8.1 Hz), 5.60 (m, 1H), 3.71 (br s, 2H), 2.19-2.15 (m, 2H), 1.90-1.88 (m, 2H), 1.45-1.42 (m, 2H), 0.92 (s, 6H).
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=C.[O:15]=[O+][O-].S(C)C>C(Cl)Cl>[CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=[O:15]
Reactant: C=CC1COCc2c(C#N)cccc21
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: N#Cc1cccc2c1COCC2C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-ethenyl-3,4-dihydro-1H-isochromene-8-carbonitrile (62 mg, 0.334 mmol) in DCM (10 mL) was bubbled with O3 for 10 mins at −78° C. until the blue color appeared. Then Me2S (1 mL) was added and the mixture was stirred at r.t. for 5 hours. Then the mixture was concentrated in vacuo to give the desired product 4-formyl-3,4-dihydro-1H-isochromene-8-carbonitrile, which can be used for next step without further purification.
Reaction SMILES: [Na].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[C:7]=1[OH:14])([CH3:5])([CH3:4])[CH3:3].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C(O)(=O)C>C1(C)C=CC=CC=1>[C:2]([C:6]1[C:7]([OH:14])=[C:8]([CH3:13])[C:9]([CH3:12])=[C:10]([CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reaction time: 2 h

Procedure:
1.53 grams of sodium metal was added in small pieces to 240.6 grams of 2-tert.-butyl-5,6-dimethylphenol warmed at 60°. The reaction mixture was then heated at 120° with stirring for 2 hours, during which time the sodium metal was completely reacted. 174 grams of methyl acrylate was then added gradually over a period of 1 hour so that the temperature was maintained at 120°. The reaction mixture was then heated at 120° to 130° for an additional four hours. 3.9 ml. of acetic acid was then added. The reaction mixture was diluted with 600 ml. of toluene and warmed to dissolve a precipitate. The toluene solution was washed successively with 2N sodium carbonate, saturated sodium chloride, water, dilute aqueous hydrochloric acid and finally with water until the water washings were almost neutral. After drying over sodium sulfate, the clear toluene solution was evaporated at 20 mm Hg. pressure and finally at 1 mm. Hg. pressure for two hours. The crude residual product was crystallized from a mixture of 450 ml. of isopropanol and 200 ml. water and kept at about 15° C overnight. The thick crystalline slurry was filtered, the filter cake being washed with a little cold isopropanol-water mixture. After drying and recrystallization, the desired product was obtained as white crystals melting at 74° to 76° C (Compound 1).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[OH-].[Na+].[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8]>O>[CH3:2][N:3]([CH3:4])[C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(=O)N(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
In 50 g of water is dissolved 36.0 g (442 mmole) of dimethylamine hydrochloride. 50 g of ice and 36 g (450 mmole) of 50% sodium hydroxide solution are added. While maintaining the internal temperature below 10° C, 35 g (208 mmole) of 4-ethylbenzoyl chloride is added. The mixture is stirred 20 minutes, extracted with ethyl ether, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 36.2 g of N,N-dimethyl-4-ethylbenzamide.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH:6]1([C:12]2[N:17]=[C:16](O)[C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[Cl:3][C:16]1[C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=[C:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C2CCCCC2)nc(O)c1C
Product: Cc1nc(C2CCCCC2)nc(Cl)c1C
Temperature: 25 °C

Procedure:
POCl3 (220 ml, 2.4 mol, ˜26 eq) was cooled to ˜−50° C. before being carefully treated with 2-cyclohexyl-5,6-dimethylpyrimidin-4-ol (28.9 g, ‘92 mmol’, 1 eq). The cooling bath was then removed and the pot allowed to warm to RT followed by heating to reflux for 6 h. The RM was concentrated, treated with ice and saturated NaHCO3 and extracted into Et2O before being dried (sodium sulfate)/concentrated. The resulting oil was subjected to column chromatography using EtOAc (10%): 40-60 Petrols (90%) as eluent to yield 4-chloro-2-cyclohexyl-5,6-dimethylpyrimidine as an oil (5.7011 g, 28% over first two steps). 1H (400 MHz, DMSO) 1.16-1.90 (10H, m), 2.26 (3H, s), 2.46 (3H, s), 2.60-2.75 (1H, m). ES+225.
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][N:5]2[C:6](=[O:14])[NH:7][C:8](=[O:13])[C:9]([CH:10]3[CH2:12][CH2:11]3)=[C:4]2[C:3]=1[O:18][CH3:19].[N+:20](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>>[NH2:20][N:7]1[C:8](=[O:13])[C:9]([CH:10]2[CH2:11][CH2:12]2)=[C:4]2[C:3]([O:18][CH3:19])=[C:2]([Cl:1])[C:16]([F:17])=[CH:15][N:5]2[C:6]1=[O:14]
Reactant: COc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Product: COc1c(Cl)c(F)cn2c(=O)n(N)c(=O)c(C3CC3)c12
Yield: 71.5 %

Procedure:
The title compound (0.09 g) was prepared from 6-chloro-4-cyclopropyl-7-fluoro-5-methoxypyrido[1,2-c]pyrimidine-1,3-dione (0.12 g, 0.42 mmol [Example 11]) and 2,4-dinitrophenylhydroxylamine (0.11 g, 0.5 mmol) using the procedure used to prepare Example 3. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, 1H), 5.52 (bs, 2H), 3.84 (s, 3H), 1.90-1.82 (m, 1H), 1.07-1.00 (m, 2H), 0.62-0.55 (m, 2H). MSCI: m/z 300 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[N+:9]([C:5]1[CH:6]=[C:7]2[N:8]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:1][C:2]2=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cnc2[nH]c(-c3ccccc3)nc2c1

Procedure:
14.05 g 2,3-diamino-5-nitropyridine and 9.68 g benzaldehyde in 250 mL nitrobenzene were heated to 140-150° C. for 15 hours (hrs). The solvent is removed by vacuum distillation and the residue is dispersed in ethyl acetate, filtered, and the filter residue washed thoroughly with ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[H-].[Na+].[C:35]([O:39][CH3:40])(=[O:38])[CH2:36][SH:37].CN(C=O)C>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:4]3=[N:5][CH:6]=[CH:7][C:2]([S:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])=[C:3]3[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: COC(=O)CS
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Yield: 15 %

Procedure:
A mixture of the title compound from Example 250 (0.26 grams), sodium hydride (0.08 grams, 60% in mineral oil), methyl thioglycolate (0.19 mL) and anhydrous DMF (15 mL) was stirred while being irradiated with a 200 W lamp for 16 hours. The mixture was diluted with MeOH, concentrated in vacuo, diluted with CH2Cl2 and water, and washed with 1N aqueous NaOH and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo and the residue purified by preparative plate chromatography (silica gel) using 3% MeOH-CH2Cl2 to afford the title compound (0.05 grams, 15%, MH+ 534).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][NH:18][OH:19].[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C.[OH-].[Li+]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][N:18]([OH:19])[C:20](=[O:22])[CH3:21]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CNO)c1Cl
Reactant: CC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(=O)N(O)Cc1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 43.4 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxybenzenemethanamine (1.00 g, 3.4 mmol) is reacted with acetyl chloride (0.58 g, 7.4 mmol), triethylamine (1.0 g, 10.1 mmol), and lithium hydroxide (0.40 g, 16.8 mmol) according to the procedure of Example 48 to give 0.5 g (43% yield) of N-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide; mp 155°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.CO.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:13][OH:14])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
5-Bromo-pyridine-2-carbaldehyde (60 g, 322 mmol) was added to methanol (700 ml) and then water was added (700 ml) followed by addition of hydroxylamine hydrochloride (28 g, 403 mmol). Sodium carbonate (20.5 g, 193.2 mmol) in water (200 ml) was added and the reaction was stirred for 30 minutes. Water (500 ml) was then added and the precipitate was filtered and washed with water (2×300 ml) to give the desired product (60 g).
Reaction SMILES: Cl.[O:2]=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C@H:22]1[CH2:26][N:25]([C:6](=[O:8])[CH2:5][CH2:4][C:3](=[O:2])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1ccccc1
Yield: 39.7 %

Procedure:
Proceeding as in Example 1, but substituting 4-oxo-4-phenylbutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 124, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxo-4-phenylbutanoyl)pyrrolidine-2-carboxamide (13.1 mg, 39.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.87 (s, 1H), 7.94-7.99 (m, 2H), 7.60-7.605 (m, 2H), 7.50-7.56 (m, 3H), 7.30-7.34 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.46 (m, 1H), 3.73 (m, 1H), 3.28 (m, 4H), 3.13 (m, 1H), 2.66 (m, 3H), 1.93 (m, 2H). MS (EI) for C34H31FN2O4. found 551.6 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:31])C(=O)C1>CC#N>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([I:31])=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3OC)c(C)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3OC)c(C)nc12
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.75 g, 2.28 mmol) and CH3CN (10 mL) is added NIS (0.54 g, 2.39 mmol). The solution is stirred overnight, concentrated, diluted with EtOAc (30 mL), washed with water (30 mL), sat. NH4Cl (30 mL), 20% (NaHSO3) (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.91 g, 2.00 mmol, 88%). 1H NMR (CDCl3) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.46 (s, 3H), 2.52 (s, 3H), 3.25-3.35 (m, 1H), 3.83 (s, 3H), 6.64 (s, 1H), 7.12 (s, 1H). LC/MS (m/z): calcd. for C18H22IN3OS (M+H)+: 456.4; found: 456.0.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:23]([NH2:26])[CH:24]=[CH2:25]>ClCCl>[CH2:23]([NH:26][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:8])[C:18]=1[N+:19]([O-:21])=[O:20])[CH:24]=[CH2:25]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Yield: 105.2 %

Procedure:
Triethylamine (17.0 mL, 123 mmol) was added to a 0° C. solution of 2,4-dichloro-3-nitroquinoline (20.0 g, 82.3 mmol) in dichloromethane (350 mL) followed by the dropwise addition of allylamine (5.90 mL, 78.2 mmol). The solution was allowed to stir and warm to room temperature overnight. The solvent was evaporated under reduced pressure and the resulting orange solid was suspended in water (300 mL). Solid sodium carbonate was added to adjust the pH to 10-11 and the suspension was stirred for 2 hours at 0° C. A yellow solid was isolated by filtration and dried under vacuum overnight to yield N-allyl-2-chloro-3-nitroquinolin-4-amine (21.7 g) that contained small amounts of an impurity and water.
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C.CCOCC>C(O)(=O)C.[Zn]>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][C:9](=[O:10])[CH2:2]2
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC1CCC2C1CC(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CC2CCC(CCCCCO)C2C1
Temperature: 70 °C

Procedure:
The starting material, 6,6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichloro-4-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]hexahydro-2(1H)-pentalenone}(12.1 g, 0.30 moles) is dissolved in glacial acetic acid (85 ml) and the solution is stirred while zinc (25 g) is slowly added. The reaction is heated at 70° C. for 1 hour, after which time ether (100 ml) is added and the solution filtered. The filtrate is washed with brine and then neutralized with saturated sodium bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (0.72 g, 3.4 mmoles).
Reaction SMILES: [C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:22]([NH:26][OH:27])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=[N+:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[O-:27])=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)C(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 50.8 %

Procedure:
To a solution of 4-isobutanoyl-3,5-di-tert-butylbenzaldehyde (7.00 g, 0.023 mol) in benzene (200 mL) was added tert-butylhydroxylamine (2.56 g, 0.029 mol) and p-toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (Rf=0.30 for product and 0.89 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated in 50.8% yield as a white solid, m.p. 197.1-208.1° C.