Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:36]=[CH:35][C:22]([O:23][C:24]4[CH:25]=[CH:26][N:27]=[C:28]5[C:33]=4[NH:32][C:31](=[O:34])[CH:30]=[CH:29]5)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:40]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]([CH3:40])[C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][N:27]=[C:28]5[C:33]=4[NH:32][C:31](=[O:34])[CH:30]=[CH:29]5)=[CH:35][CH:36]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc(Oc2ccnc3ccc(=O)[nH]c23)cc1)c1nnc(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 20 mL sealed tube, was dissolved 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one (0.25 g, 0.508 mmol) in THF (2.2 mL), and the mixture was cooled to 0° C. Sodium Hydride, 60% in mineral oil (0.045 g, 1.12 mmol), was added and the mixture was stirred at 0° C. for 1 hour. Iodomethane (0.070 mL, 1.12 mmol), was added and the mixture was warmed to 60° C., and stirred for 3 hours. A mixture of products was revealed by LC/MS. The mixture was cooled to RT, quenched with water, extracted into ethyl acetate, washed 1× water, 1×NaCl, dried with Na2SO4, filtered through flitted funnel, and filtrate was concentrated. The crude concentrate was purified by reverse phase chromatography. The product containing fractions were extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through flitted funnel, and the filtrate was concentrated down to a light yellow solid containing two methylated products. The solids were suspended in methanol, filtered, rinsed with methanol, and air dried to yield 8-(4-((4-(4-chlorophenyl)phthalazin-1-yl)(methyl)amino)phenoxy)-1,5-naphthyridin-2(1H)-one. MS: [M+H]=506.0; Calc'd 505.9 for C29H20ClN5O2.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:23]
Reactant: Clc1cnc(-c2ccc(Oc3ccccc3)cc2)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cnc(-c2ccc(Oc3ccccc3)cc2)cn1

Procedure:
To a solution of 2-chloro-5-(4-phenoxyphenyl)pyrazine in 2 mL of ethanol was added hydrazine monohydrate (2 mL). The reaction mixture was heated at 110 C for 2 hours and evaporated in vacuo. The residue was dissolved in dicholomethane, washed with water, dried over Na2SO4, and evaporated in vacuo to afford 2-hydrazinyl-5-(4-phenoxyphenyl)pyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Zn].C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)c(Cl)c1
Yield: 63 %

Procedure:
A mixture comprising 10.0 g of 3,4-dichlorobenzoyl chloride, 9.31 g of ethyl 2-bromoisobutyrate and 90 ml of anhydrous diethyl ether, was dropwise added to 3.12 g of zinc in a nitrogen atmosphere, followed by a reaction for 15 hours under reflux. The reaction mixture was filtered through celite, and the filtrate was washed with 20% sulfuric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/19) to obtain 8.7 g of oily ethyl 2-(3′,4′-dichlorobenzoyl)isobutyrate. The NMR spectrum data of this product is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-].[CH3:11][S+](C)C.O.[OH-].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:11][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Brc1ccc(C2CO2)cc1
Temperature: 55 °C

Procedure:
A mixture of 4-bromobenzaldehyde (intermediate 29, 25.25 g, 136 mmol), trimethylsulfonium iodide (28.71 g, 141 mmol), water (6.5 ml, 361 mmol) and potassium hydroxide (15.56 g, 277 mmol) in acetonitrile (140 ml) was warmed to 55° C. for 2.5 hours. The resulting solution was partitioned between water and diethyl ether, and the organic layer was washed with water, diluted hydrochloric acid, and brine, and dried over sodium sulfate. Crude product of 2-(4-bromo-phenyl)-oxirane (intermediate 30) was obtained by removal of organic solvent under reduced pressure, which was used for next reaction without purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:6]#[N:7].[CH2:20](CN)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:29][N:30](C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[ClH:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]([CH2:4][CH2:3][CH2:2][N:30]([CH3:29])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]#[N:7])=[CH:14][CH:15]=1
Reactant: NCCc1ccccc1
Reactant: CN(C)C=O
Reactant: N#CC(CCCCl)(c1ccc(F)cc1)C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Product: CN(CCCC(C#N)(c1ccc(F)cc1)C1CCCC1)Cc1ccccc1
Product: Cl
Temperature: 50 °C

Procedure:
The product from Example 4, Step (b) (1.99 g, 7.06 mmol) was combined with N-benzylmethylamine (1.82 mL, 14.1 mmol), N,N-dimethylformamide (3.5 mL) and tetrabutylammonium iodide (130 mg). The mixture was heated at 50° C. overnight, then diluted with water (25 mL) and extracted with ethyl acetate (100 mL, then 2×25 mL). The combined organic layers were dried over MgSO4, filtered through silica, concentrated and subjected to chromatography. The product was converted to the hydrochloride salt using hydrogen chloride gas in methylene chloride. The salt was recrystallized from dichloromethane/methyl acetate/hexane, affording the a product compound which was characterized as follows: 13C NMR of free base (CDCl3), 100 MHz, partial): 62.1, 56.5, 52.4, 50.1, 42.0, 37.2, 29.5, 29.2, 25.4, 24.8, 23.1; Analysis Cal'd. for C24H30ClFN2•0.25 H2O: C, 71.09; H, 7.58; N, 6.91; Found: C, 70.92; H, 7.53; N, 6.84.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1)=[O:2])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CSCC
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CS(=O)CC
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of sodium periodate (43 mg, 0.2 mmol) in water (0.5 ml) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH (2 ml) and the solution was stirred for 18 hours. The MeOH was removed by evaporation and the aqueous residue was extracted with EtOAc. The extracts were combined, washed with brine, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) and the purified product triturated with ether to give the title compound (37 mg, 51%). NMR: 0.68 (t, 3H), 1.05 (t, 3H), 1.22 (t, 3H), 1.52 (m, 2H), 2.85 (m, 4H), 3.33 (m, 4H), 4.31 (d of d, 2H), 4.63 (m, 2H), 7.23 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.78 (s, 1H), 7.86 (d, 2H), 8.48 (d, 1H), 9.90 (s, 1H); m/z 521.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[Br:38]Br>O1CCCC1>[C:1]([N:20]1[C:24]([Br:38])=[N:23][CH:22]=[N:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cncn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Yield: 40.3 %

Procedure:
A stirred solution of 1-trityl-1,2,4-triazole (15.55 g, prepared as described in Example 1) and N,N,N',N'-tetramethylethylenediamine (5.8 g) in dry tetrahydrofuran (500 ml) was cooled to -70° C. under nitrogen and treated dropwise with n-butyllithium (37.5 ml, 1.6M in hexane). The deep-red solution was stirred at -70° C. for twenty minutes, then treated dropwise with a solution of bromine (10.4 g) in dry tetrahydrofuran (10 ml). The now brownish-yellow solution was allowed to warm to -20° C., quenched with 0.1M sodium thiosulphate solution (150 ml), and extracted with dichloromethane (500 ml). The organic layer was washed with water (4×100 ml), dried and evaporated. The residue was chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give 1-trityl-5-bromo-1,2,4-triazole (7.86 g, m.p. 239°-241° C.). NMR (CDCl3):δ7.1-7.3(15H,m), 7.95(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(Cl)Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([OH:14])[C:9]([CH3:12])([CH3:13])[CH2:10][OH:11])=[CH:20][CH:21]=1
Reactant: CC(C)(CO)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(CO)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.2 %

Procedure:
25 g (0.08 mol) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-4-hydroxy-butan-2-one were dissolved in 350 ml of isopropanol, and 3.5 g of sodium borohydride were added in portions at room temperature. The mixture was stirred at room temperature for 15 hours, 500 ml of water were added, the mixture was stirred at room temperature for a further 15 hours, 300 ml of methylene chloride were added and the organic phase was washed three times with 100 ml of water each time. The organic phase was dried over sodium sulphate, the solvent was distilled off under a waterpump vacuum and 100 ml of ether were added to the residue. 17 g (67.6% of theory) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-butane-2,4-diol were obtained as colorless crystals of melting point 110°-112° C. ##STR19##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][N:11]=1.[C:28]1(=O)[O:33][C:31](=[O:32])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C(N(CC)CC)C.O>CC1C=CC(C)=CC=1>[OH:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([C:4]2[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][N:11]=3)=[C:2]([N:1]3[C:31](=[O:32])[C:30]4[C:29](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:28]3=[O:33])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(N2CCN(CCO)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: O=C1c2ccccc2C(=O)N1c1cc(N2CCN(CCO)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 140 °C
Reaction time: 25 h
Yield: 3.3 %

Procedure:
(E)-2-(4-{3-amino-4-[2-(1H-indazol-3-yl)vinyl]phenyl}piperazin-1-yl)ethanol (0.10 g, 0.28 mmol) obtained in Step 3 of Example 273 was dissolved in p-xylene (3.5 mL) and the solution was added with phthalic anhydride (49 mg, 0.33 mmol), triethylamine (0.02 mL, 0.14 mmol), molecular sieves 3A (0.10 g), followed by stirring at 140° C. for 25 hours. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was reslurried with ethyl acetate to obtain Compound 299 (4.5 mg, 3%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH2:9][C:8]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3 ml of acetyl chloride in 10 ml of chloroform is added dropwise to a stirred suspension of 6.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 1C, and 14.0 g of sodium bicarbonate in 75 ml of chloroform. After total addition, the reaction mixture is successively stirred at ambient temperature for 16 hours, filtered, washed sequentially with water, dilute hydrochloric acid and a saturated sodium chloride solution, dried and the solvent removed under reduced pressure, leaving a residue which solidifies upon standing. The solid is recrystallized twice from hexane to give the product, 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine], mp 94°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[CH3:24][N+:25]([CH3:27])=[CH2:26].[I-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: ClCCl
Product: CCCc1cc(CN(C)C)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reaction time: 0.25 h
Yield: 124.1 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran (155 mg gm; 0.5 mmole) in methylene chloride (2 mL) was reacted with Eschenmoser's salt (dimethyl methylene ammonium iodide) (105 mg; 0.5 mmole) overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was taken up in ethylacetate, potassium carbonate was added and the mixture was stirred for a period of 15 minutes. The solids were separated and the ethylacetate solution was evaporated to yield 228 mg of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (0.100 g, 0.35 mmol) and triethylamine (0.10 mL, 0.71 mmol) in THF at 0° C. was added methanesulfonyl chloride (0.05 mL, 0.62 mmol) and the reaction stirred at 0° C. for 1 hour. The mixture was diluted with H2O and extracted with EtOAc, and the combined organic layers were washed with H2O, saturated aqueous NaHCO3, and brine. Dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O.[N+:40]([C:43]1[CH:44]=[CH:45][C:46]([NH:49][CH2:50][CH2:51][NH:52][S:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[N+:62]([O-:64])=[O:63])(=[O:55])=[O:54])=[N:47][CH:48]=1)([O-:42])=[O:41]>C(Cl)Cl>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][N:52]([CH2:51][CH2:50][NH:49][C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][N:47]=1)[S:53]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[N+:62]([O-:64])=[O:63])(=[O:55])=[O:54]
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(NCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To a solution of Ph3P (11 g, 42 mmol) and CH2Cl2 (20 mL) at 23° C. was added DIAD (6.6 mL, 42 mmol) and the resulting yellow solution was maintained at 23° C. for 30 min. To this solution was added 2-(dimethylamino)-ethanol (4.2 mL, 42 mmol) and the resulting solution was maintained at 23° C. for 5 min. then added to a suspension of resin-bound {2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine (3.0 g, 2.1 mmol) and CH2Cl2 (30 mL). The resulting mixture was shaken at 23° C. for 12 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([OH:16])[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[N:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1)#[N:24].ClCCl>C(#N)C>[C:23]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][O:9][CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:15]=2)[C:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)=[O:16])=[CH:27][CH:26]=1)#[N:24]
Reactant: O=C(c1ccccn1)C(O)c1ccccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(COC(C(=O)c2ccccn2)c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To 2.14 g (0.01 mole) of α-pyridoin in 50 ml of acetonitrile was added 0.80 g (0.01 mole) of pyridine and then 1.65 g (0.01 mole) of p-cyanobenzoyl chloride portionwise with stirring. Stirring was continued for 1/2 hour. Then 150 ml of dichloromethane was added, the organic phase washed thoroughly with water, dried and evaporated to an oily solid residue. The residue was stirred with 80% hexane and 20% acetone to obtain a solid, 1.7 g (50%). After recrystallization from hexane-acetone, 0.9 g (53%), m.p., 152°-154° C., of NA-VI was recovered.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([N:10]1[C:14](=O)[CH2:13][CH:12]([CH2:16][C:17]#N)[CH:11]1[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:27]>>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:27])=[O:1])[CH:11]1[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CCC1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl
Agent: [Na+]
Product: O=C(O)CC1CCN(Cc2ccccc2)C1c1c(Cl)cccc1Cl

Procedure:
To 90 ml of water containing 10 g of sodium hydroxide was added 5.0 g of 1-benzyl-3-cyanomethyl-2-(2,6-dichlorophenyl)-pyrrolidin-5-one. The reaction was refluxed 5 hours, cooled, and filtered. Extraction of the aqueous phase with ether followed by addition of ice and acidification with concentrated hydrochloric acid gave a solid which was then triturated with ether to yield beige crystals. Vacuum drying (0.1 Torr) under refluxing toluene for 15 hours followed by recrystallization from ethanol provided upon drying 1.50 g of colorless crystals, m.p. 186°-188°.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[CH3:12]O>>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([OH:2])=[N:4][CH:5]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)nc1

Procedure:
To 500 ml of methyl alcohol, cooled to 0°-5° C. is added HCl gas over 30 minutes. The solution is allowed to reach room temperature and 50 g of 6-hydroxynicotinic acid added. The reaction mixture is stirred at reflux for 2 days. The methyl alcohol is removed in vacuo and the residue suspended in 200 ml of water and poured into 300 ml of saturated aqueous NaHCO3. The insoluble crystals are collected by filtration, washed with 500 ml of water and dried under vacuum at 60° C. to give 53.9 g of the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH:18]([CH3:20])[CH3:19])([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>[Pd].CO>[C:14]([C:11]1([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:15])[NH2:16]
Reactant: CC(C)NC1(C(N)=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)NC1(C(N)=O)CCNCC1
Yield: 113.3 %

Procedure:
A mixture of the 1-benzyl-4-isopropylamino-4-piperidinecarboxamide (250 mg, 0.91 mmol) (commercially available from Aldrich Chemical, Milwaukee, Wis.), 10% palladium on charcoal (30% by weight, 81 mg) and formic acid (5 mmol) in methanol (4 ml) was stirred vigorously overnight at room temperature. The reaction mixture was filtered through a celite pad and concentrated in vacuo to provide the product 4-carbamoyl-4-(isopropylamino)piperidine (191 mg, 90%) as a formic acid salt. A mixture of the chloride I-1f (100 mg, 0.28 mmol), 4-carbamoyl-4-(isopropylamino)-piperidine (85 mg, 0.306 mmol) and triethylamine (0.13 ml, 0.92 mmol) in dry ethanol (2 ml) was refluxed for 3 hrs. The reaction mixture was cooled to room temperature and water was added to precipitate out solids. The filtrate was acidified and washed with ethyl acetate to remove impurities. The aqueous layer was basified with 1 N NaOH and extracted with dichloromethane, dried and concentrated to give crude solid. This was combined with the filtered solids and purified using short plug silica gel with 10% MeOH:EtOAc as eluant to provide the desired product 1A-1 (46 mg, 30%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 7.68–7.41 (m, 6H), 7.19–7.14 (t, 2H), 4.42 (br d, 2H), 4.16–4.13 (br t, 2H), 2.95–2.92 (m, 1H), 2.17–2.12 (m, 2H), 1.83–1.80 (br d, 2H), 1.10 (d, 6H); MS (m/z): 524.5 (M+H); Ret time (RT): 1.7 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])(OCC)(SCC)=[S:25].C([O-])(O)=O.[Na+]>ClCCl.O.C(OCC)(=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](=[S:25])[NH2:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=S)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (2 g, 6.4 mmol), diethyl dithiophosphate (15 mL, 8.9 mmol), and water (1.5 mL) were combined and stirred at ambient temperature for 5 hours, 55° C. for 2 hours then 70° C. for 2 hours. The reaction mixture was diluted with dichloromethane (100 mL) and basified to pH 8 with a saturated solution of NaHCO3 in water, and solid NaHCO3. The layers were separated, and further dichloromethane (100 mL) was used to extract the product. The combined organics were dried using Na2SO4, filtered and concentrated in vacuo to leave a yellow oil. The compound was purified with column chromatography on 50 g of silica, eluting with dichloromethane:methanol:ammonia (96:4:0.4) to dichloromethane:methanol:ammonia (90:10:1) to give a clear oil. The clear oil was dissolved in ethyl acetate (150 mL) and washed with 10% Na2CO3 solution. The organic layer was dried using Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid (0.61 g, 28%).