Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CN(C)CCCCl
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1cccc(C=O)c1
Yield: 66.6 %

Procedure:
The reaction between 61.0 g (0.50 mole) of 3-hydroxybenzaldehyde, 24.0 g of 50% NaH (0.50 mole), and 396 ml of 1.89N (0.75 mole) of 3-dimethylaminopropyl chloride in toluene in a procedure described for Example 2, part A, gives 69.0 g (66%) of colorless product, bp 155°-158°/3 mm.
Reaction SMILES: FC1C=CC=C([N+:8]([O-:10])=[O:9])C=1F.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](NC(=O)OC(C)(C)C)[CH2:13]1>C(#N)C.C(N(CC)C(C)C)(C)C>[N+:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])N1CCCCC1
Yield: 189532 %

Procedure:
A mixture of 1,2-difluoro-3-nitrobenzene (2.38 g, 0.015 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (3.0 g, 0.015 mmol) and N,N-diisopropylethylamine (5.2 ml, 0.030 mmol) was heated in acetonitrile (20 mL) at 80° C. overnight. The solvents were removed in vacuo, and chromatographic purification (ethyl acetate-hexanes) of the residue gave a nitropiperidine as orange oil (3.7 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][O:12][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Li+].[N-:21]=[N+:22]=[N-:23].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:14]1[C@H:9]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:11][O:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C2CCOCC21
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
3-Oxa-7-aza-bicyclo[4.1.0]heptane-7-carboxylic acid tert-butyl ester (intermediate E) (5.2 g, 26 mmol) was dissolved in 100 mL acetonitrile. Lithium perchlorate (23 g, 207 mmol) and sodium azide (6.8 g, 104 mmol) were added and the reaction mixture was stirred at 80° C. overnight. 200 mL Water was added. The mixture was extracted three times with diethylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→1:1) yielded the title compound as a colorless oil (3.3 g, 52%), MS: m/e=186 [(M-butene)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH3:36])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]([CH3:36])[C:18](=[O:20])[CH2:17][O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 150.7 %

Procedure:
Compound 9 (74.74 g), 1-benzyl-N-methylpiperidine-4-amine (66.78 g: 1.3 eq.) and triethylamine (127.20 g: 5 eq.) were suspended in acetonitrile (800 mL). While the suspension was cooled on ice, a 50% propanephosphonic acid anhydride ethyl acetate solution (191.99 g) was added portionwise. The equipment used to add 50% propanephosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (192 mL) and stirred at room temperature (20 to 30° C.) overnight. Subsequently, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform (250 mL) and a saturated aqueous sodium bicarbonate solution (140 mL) were sequentially added and the mixture was transferred to a separation funnel. The reaction container was thoroughly washed with chloroform (175 mL) and separation was performed. Once the organic layer was separated, chloroform (175 mL) was added to the aqueous layer and separation was performed again. The collected organic layer was dried over magnesium sulfate and was suction-filtered. The filtrate was evaporated under reduced pressure to give 183.27 g of the crude desired product of Compound 30 as a yellow amorphous.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cc(CO)ccn2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cc(COS(C)(=O)=O)ccn2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-4-yl]-methanol (530 mg, 2.72 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.50 mL, 3.56 mmol) followed by DMAP (34 mg, 0.27 mmol) and Ms-Cl (0.27 mL, 3.46 mmol). After stirring at rt for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a light brown oil. TLC: rf (1:2 hept-EA)=0.36.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(Cl)(=[O:29])C.O>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An alternative procedure to prepare compound B from compound A is as follows: Compound A (1.0 g) in 25 ml dry methylene chloride and 10 ml of 2.5 N NaOH was cooled to 0° C. and treated with 0.25 ml of acetyl chloride dropwise. After 2 hours the solution was allowed to warm up to room temperature and stirring was continued overnight. The solution was treated with distilled water and extracted with methylene chloride. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, filtered and evapotated to give 1.33 g of crude amide reaction product, which was purified by flash column (silica, methylene chloride:methanol:25% NH4OH 90:9:1) to yield 0.7 g of 2-(4-fluorophenyl)-5-(N-acetylpiperidin-4-yl)-3-(4-pyridyl)pyrrole. This amide was dissolved in 15 ml of tetrahydrofuran and treated with 3 ml of 1M lithium aluminum hydride (LAH) in THF under an atmosphere of nitrogen at room temperature. After completion of addition of LAH, the solution was refluxed for two hours, cooled to 0° C., quenched with water (0.19 ml) and 2.5 N NaOH (0.19 ml) and filtered. The filtrate was dried over sodium sulfate, filtered, evaporated and purified by flash column as shown above to give compound B (0.65 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:13]1[CH:14]=[CH:15][C:16]([N+:28]([O-:30])=[O:29])=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1.[H-].[Na+]>CN(C)C=O>[CH3:27][N:19]([C:17]1[CH:18]=[C:13]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)[CH:14]=[CH:15][C:16]=1[N+:28]([O-:30])=[O:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Yield: 20.4 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-trifluoromethylphenol (3.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (4.3 g), sodium hydride (55 wt. %, 1.1 g) and anhydrous N,N-dimethylformamide (70 ml) and the reaction mixture was purified to give the title compound (1.26 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[CH:8]=[N:19][OH:20]
Reactant: Cc1cc(O)ccc1-c1ccc(C=O)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)ccc1-c1ccc(C=NO)c(Cl)c1

Procedure:
The title compound was prepared by reacting 3-chloro-4′-hydroxy-2′-methyl-1,1′-biphenyl-4-carbaldehyde (500 mg, 2.03 mmol) with hydroxylamine hydrochloride (425 mg, 6.10 mmol) in anhydrous tetrahydrofuran (50 mL) and methanol (20 mL) according to Method C to yield 350 mg (57% over two steps) of white solid: mp 169-171° C.; 1H NMR (DMSO-d6): δ 2.19 (3H, s), 6.65-6.70 (2H, m), 7.06 (1H, d, J=8.14 Hz), 7.31 (1H, d, J=8.05 Hz), 7.41 (1H, d, J=1.40 Hz), 7.83 (1H, d, J=8.08 Hz), 8.38 (1H, s), 9.51 (1H, s), 11.69 (1H, s); MS (ESI) m/z 260/262 (M−H)−, 262/264 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1)[NH2:15]
Reactant: Clc1cccc(-c2ccccn2)n1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cccc(-c2ccccn2)n1

Procedure:
A mixture of 4.0 g of 6'-chloro-2,2'-bipyridine and 10 ml of anhydrous hydrazine in 50 ml of dry pyridine was refluxed for 48 hours. Additional hydrazine (10 ml) was added and the solution was refluxed for an additional 72 hours while 5 ml portions of hydrazine were added at 18 hour intervals. The volatiles were removed under vacuum, the residue dissolved in ether, dried over sodium sulfate and concentrated to a solid. This solid was recrystallized from ether-heptane, giving 3.0 g of 6'-hydrazino-2,2'-bipyridine as white crystals, mp 69°-70° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][C:23]([CH3:39])([C:27]([NH:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:28])[C:24](O)=[O:25]>C(Cl)(Cl)Cl>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[C:23]([CH3:22])([CH3:39])[C:27]([NH:29][CH2:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:36])([F:34])[F:35])=[O:28])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide (epimers) as white solid, [α] 589=−64.9° (1% in CHCl3), MS m/e (%): 538.3 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]1[CH2:24][CH2:23][O:22][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCC3CCOC3)c2n1
Yield: 53 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-{3-[(tetrahydro-3-furanylmethyl)amino]propyl}-9H-purin-6-amine (11 mg, 0.029 mmol) and 4M HCl in 1,4 dioxane (0.160 ml, 0.639 mmol) were stirred at 20° C. for 16 hours in methanol (1 ml). The solvent was removed by N2 blowdown. The sample was loaded in methanol and purified by SPE on an aminopropyl (NH2) cartridge (2 g) using methanol. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product as a white solid. The sample were dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as a white solid (5.6 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1.[CH3:15]O.S(=O)(=O)(O)O>CCCCCC.C(OCC)(=O)C>[CH3:15][O:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: Cc1ccc(C)c2c1SCCC2CO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCC1CCSc2c(C)ccc(C)c21
Temperature: 25 °C
Yield: 60 %

Procedure:
To a mixture of 1.32 g (6.33 mmol) of 4-hydroxymethyl-5,8-dimethylthiochroman with 13 ml of methanol was added 0.1 ml of concentrated sulfuric acid, and the mixture was reacted at reflux under heat for 10 hours. The reaction mixture was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The extract was washed with water and with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate=2/1)to give 0.84 g (yield 60%) of the titled compound.
Reaction SMILES: [CH3:1][SH:2].C(N(CC)CC)C.[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[N:15][C:14]([Cl:19])=[C:13](Cl)[N:12]=1>CN(C)C=O>[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[N:15][C:14]([Cl:19])=[C:13]([S:2][CH3:1])[N:12]=1
Reactant: CS
Reactant: N#Cc1nc(Cl)c(Cl)nc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(N)c(C#N)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dimethylformamide (1.5 ml) there was dissolved 2-amino-3-cyano-5,6-dichloropyrazine (200 mmg, 1 mM) and then cooled in an ice bath. Through the solution there was then bubbled methanethiol gas for 5-10 minutes. The reaction mixture was then stirred overnight at room temperature. Triethylamine (0.14 ml) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was then placed under a nitrogen atmosphere to remove solvent and excess methanethiol. The product was passed through a silica gel column, eluting with dichloromethane. The product was recrystallized from hexane/ether (139 mg). Elemental Analysis for C6H5N4ClS: :
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[C:6]([C:13]#[N:14])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.O.C(=O)([O-])[O-:19].[Na+].[Na+].OO>CC(C)=O>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[C:6]([C:13]([NH2:14])=[O:19])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cnc(C#N)c(CC(OC)OC)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cnc(C(N)=O)c(CC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a 1 L round-bottomed flask was added 3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile (8.550 g, 38.5 mmol), water (480 ml), and acetone (120 ml). An aqueous solution of sodium carbonate (3M; 154 ml, 462 mmol) was added followed by hydrogen peroxide (35 wt. % solution in water; 138 ml, 1347 mmol). The tan mixture was stirred vigorously at rt for 2 h. The organic solvent was removed under reduced pressure and the aqueous residue was extracted with DCM (3×). The combined organic fractions were dried over sodium sulfate. The filtrate was concentrated under reduced pressure to afford 3-(2,2-dimethoxyethyl)-5-methoxypicolinamide (8.200 g, 34.1 mmol, 89% yield) as an off-white solid that was advanced without further purification. MS m/z=263.2 (M+Na)+
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][NH2:21])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:25]=[CH:24][CH:23]=[N:22][C:10]1=2)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.6 g (0.0045 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in dry methylene chloride was added 0.53 g (0.0052 mole) of triethylamine. To this solution was added dropwise, while cooling, 0.54 g (0.0050 mole) of ethyl chloroformate. The mixture was stirred at room temperature for 2 hr. The methylene chloride solution of the product (as indicated by chemical ionization mass spec) was washed with dilute sodium hydroxide-sodium chloride saturated aqueous solution and dried and concentrated to dryness. The residue was triturated in isopropyl ether. Yield was 1.5 g of title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]2[O:13][C:14]([CH2:17]Cl)=[N:15][N:16]=2)=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[I-].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]2[O:13][C:14]([CH2:17][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:15][N:16]=2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(CCl)o1
Agent: [I-]
Agent: [K+]
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(CN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine (46) (60 mg, 0.2 mmol) was taken in a rbf, added morpholine (4 mL) to the rbf followed by the addition of potassium iodide (0.2 mmol), stirred the reaction mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure to remove excess of morpholine. The crude material obtained was taken to next step as such, without purification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.608 min; LCMS (ES-API), m/z 338.2 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[I:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:12]3[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([I:9])[CH:11]=3)=[O:31])=[CH:20][N:21]=2)[CH2:26][CH2:27]1)=[O:5]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)nc2)cc1I
Temperature: 25 °C

Procedure:
6-[4-(3,3-Dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the addition 3,3-dimethyl-butyryl chloride (0.055 mmol) to N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide (0.05 mmol) partially dissolved in DCM followed by the addition of TEA and stirred at room temperature over night. The reaction was diluted with ethyl acetate washed with water and brine, dried over sodium sulfate, concentrated and the residue was trirturated with ether and hexanes to afford the product, 6-[4-(3,3-dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide. LCMS calcd for C23H29IN4O2 (m/e) 520, obsd 521 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].C([Li])CCC.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>CCOCC>[CH3:19][Si:20]([CH3:22])([CH3:21])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]=1[Cl:13]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Et2O (200 mL) was added to a Schlenk flask under nitrogen containing 2,6-dichloro-4-trifluoromethylaniline (14.39 g, 62.6 mmol) and was cooled to −78° C. n-butyllithium (2.5M in hexane, 26.3 mL, 65.7 mmol) was added over 15 min to the stirred solution. The solution was stirred at −78° C. for 2 h and was then taken out of the cold bath, during which time a dark red/brown color evolved. Trimethylsilyl chloride (15.9 mL, 125 mmol) was then added dropwise to afford a light yellow slurry. This mixture was allowed to warm to room temperature and was filtered through Celite. The yellow filtrate was concentrated under reduced pressure to give an analytically pure orange oil; yield 18.90 g, (98%): 1H NMR (C6D6, 20° C.) δ 7.24 (s, 2H, Ar), 4.21 (bs, 1H, NH), 0.16 (s, 9H, TMS); 13C NMR (C6D6, 20° C.) δ 145.68, 125.4 (m), 123.90 (q, 1JCF=271 Hz), 123.44, 121.29 (q, 2JCF=33.8 Hz), 2.23 (m); 19F NMR (C6D6, 20° C.) δ −61.77. Anal. Calcd for C10H12Cl2F3NSi: C, 39.75; H, 4.00; N, 4.64. Found: C, 40.06; H, 3.84; N, 4.42.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([F:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[C:4]([F:20])=[CH:3][C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])=[CH:18][C:17]=2[F:19])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(F)c(Oc2ccnc(N)c2[N+](=O)[O-])c(F)c1
Product: Nc1nccc(Oc2c(F)cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2F)c1[N+](=O)[O-]
Yield: 23.8 %

Procedure:
Method H3 was used with 4-(4-amino-2,6-difluorophenoxy)-3-nitropyridin-2-amine (0.20 g, 0.709 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.16 g, 0.709 mmol) to afford the title compound (0.085 g, 24%). 1H NMR (250 MHz, 6, ppm, DMSO-d6): 6.11 (d, 1H, J=5.7 Hz), 7.28 (s, 2H), 7.46 (d, 2H, J=10.3 Hz), 7.61-7.71 (m, 2H), 8.04 (d, 1H, J=5.7 Hz), 8.09 (d, 1H, J=2.1 Hz), 9.36 (s, 1H), 9.40 (s, 1H). m/z 504.0 [(M+H)+ calcd. for C19H11ClF5N5O4 503.0].