Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])[NH:8][NH2:9].[CH2:11]([N:13]1[C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]([CH3:21])=[N:14]1)[CH3:12].C(Cl)(=O)C(Cl)=O>>[CH2:11]([N:13]1[C:17]([C:18]([NH:9][NH:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[S:10])=[O:19])=[CH:16][C:15]([CH3:21])=[N:14]1)[CH3:12]
Reactant: COCCCNC(=S)NN
Reactant: CCn1nc(C)cc1C(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Product: CCn1nc(C)cc1C(=O)NNC(=S)NCCCOC

Procedure:
The title compound was synthesized in a manner similar to that described in Example 1. 3-Methoxy-n-propyl isothiocyanate was prepared from 3-methoxy-n-propylamine and thiophosgene at high temperature and then reacted with hydrazine in pyridine to give the intermediate 4-(3-methoxy-n-propyl)-3-thiosemicarbazide. 4-(3-Methoxy-n-propyl)-3-thiosemicarbazide (1.64 g) was reacted with 1-ethyl-3-methylpyrazole-5-carboxylic acid chloride (1.73 g, prepared from the acid and oxalyl chloride) to give 2 g of 1-(1ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide. Treatment of 1-(1-ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide with potassium hydroxide in ethanol gave 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole. Reaction of the sodium salt of 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole(0.73 g) with 2-bromo-5-nitrothiazole (0.52 g) yielded crude 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole as in Example 1. Crystallization from ethanol and water gave 0.3 g of 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 117-118° C.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])(=[O:13])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[O:5].N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])(=[O:13])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH:9]=[O:10])=[O:5]
Reactant: CC(C)(C=O)COC(=O)/C=C\C(=O)OCC(C)(C)C=O
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: CC(C)(C=O)COC(=O)/C=C/C(=O)OCC(C)(C)C=O
Temperature: 25 °C

Procedure:
Crude bis (2,2-dimethyl-3-oxopropyl) maleate was treated with a catalytic amount of morpholine (10 wt. %) in refluxing toluene for 4 hrs. The resulting solution was cooled to room temperature, washed with diluted hydrochloric acid and brine, then dried over magnesium sulfate. Evaporation of volatiles in vacuo gave crud bis (2,2-dimethyl-3-oxopropyl) fumarate in essentially quantitative yield. NMR* (CDCL3): 9.7 (s, 1H,--CHO), 6.93 (s, 2H, trans --CH=CH--), 4.33 (s, 2H, --CO2CH2 --), and 1.2 (s, 6H, --C(CH3)2 --).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH:12]([CH3:14])[CH3:13])=[CH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[C@@H:4]([CH:12]([CH3:14])[CH3:13])[CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)C1CCC(=O)C=C1C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)C[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
The product of Step 1 (5.11 g, 26.0 mmol) was dissolved in MeOH (80 ml). Palladium on carbon (0.416 g, 0.391 mmol) was added, and the flask was fitted with a hydrogen balloon. The flask was evacuated and backfilled with hydrogen (3×) and stirred 15 h at room temperature. The reaction was then filtered through Celite and the celite was washed with EtOAc. The filtrate was concentrated in vacuo. Purification via silica gel flash chromatography (0-15% EtOAc:Hexanes) gave methyl(cis)-4-oxo-2-(propan-2-yl)cyclohexanecarboxylate (2.63 g, 51%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[N:13]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][N:40]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:7]([C:8](=[O:21])[NH:9][C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[N:13]=4)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)Cl)cc3)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(OC)nc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Title compound E, 4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl chloride (120 mg, 0.2499 mmol) was dissolved in dichloromethane. To this was added a solution of piperidine-4-carboxylic acid ethyl ester (38 μL, 0.2499 mmol) and diisopropylethylamine (87 μL, 0.4998 mmol) in dichloromethane. The reaction was stirred at room temperature for 1 hour, then concentrated. The residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a yellow oil. The crude was then purified via column chromatography 10-90% ethyl acetate in hexanes to afford the desired product as a yellow foam (107 mg, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.07 Hz, 3 H) 1.10-1.22 (m, 2 H) 1.50 (d, J=2.78 Hz, 2 H) 1.49 (br. s., 1 H) 1.63 (dd, J=14.91, 7.83 Hz, 2 H) 1.62 (br. s., 1 H) 1.81 (dd, J=13.64, 3.79 Hz, 3 H) 1.95 (t, J=7.07 Hz, 2 H) 1.91 (d, J=7.83 Hz, 1 H) 2.21-2.31 (m, 2 H) 2.53 (td, J=11.43, 2.91 Hz, 2 H) 3.61-3.71 (m, 3 H) 4.00 (s, 3 H) 4.09 (q, J=7.07 Hz, 2 H) 6.80 (d, J=8.84 Hz, 1 H) 7.52 (d, J=8.59 Hz, 2 H) 7.74-7.84 (m, 3 H) LC/MS 601.3 (M+1) 599.4 (M−1)
Reaction SMILES: [Na].[C:2]([OH:5])(=[S:4])[CH3:3].[CH3:6][O:7][C:8](=[O:15])/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11]Cl>CO>[CH3:6][O:7][C:8](=[O:15])/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11][O:5][C:2](=[S:4])[CH3:3]
Reactant: COC(=O)/C=C(\CCl)OC
Reactant: CC(O)=S
Agent: [Na]
Solvent: CO
Product: COC(=O)/C=C(\COC(C)=S)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
4.07 g (0.177 mol) of sodium is dissolved in 180 ml of methanol and cooled to 0° C. 13.47 g (0.171 mol) of thioacetic acid is instilled in this solution. Then this solution is mixed at 0° C. with a solution of 29.15 g (0.150 mol) of 3-methoxy-4-chloro-2E-butenoic acid methyl ester in 40 ml of methanol. It is stirred again overnight at room temperature. The precipitated salt is filtered off, the solvent is evaporated on the rotary evaporator and mixed with a little methylene chloride for precipitation of the remaining salt. After filtering off, evaporation of the solvent and drying of the residue in a high vacuum, 36.53 g of a yellow-colored liquid with a content according to GC of 82.8 percent is obtained. This corresponds to 30.25 g of 100 percent product ≐98.7 percent yield. Further data concerning the compound is:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([Si:13]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][Si](C)(C)C)=[CH:30][CH:29]=2)([CH3:27])[O:14][Si:15]([CH3:26])([CH3:25])[O:16][Si:17]([CH3:24])([CH3:23])[O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=1)(C)C.CO.C1COCC1>CO.C1COCC1.N.O>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([Si:13]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[CH:32][CH:33]=2)([CH3:27])[O:14][Si:15]([CH3:26])([CH3:25])[O:16][Si:17]([CH3:23])([CH3:24])[O:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc([Si](C)(O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: N
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc([Si](C)(O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C)c2ccc(C#C)cc2)cc1
Reaction time: 24 h
Yield: 61 %

Procedure:
Tetramethylsilane (TMS) was deprotonated through a reaction with an ammonia solution to produce the target monomer bis-(4-ethynylphenyl)-octamethyltetrasiloxane. Specifically, 1.00 g bis-(4-trimethylsilylethynylphenyl)-octamethyltetrasiloxane in MeOH/THF/NH3—H2O mixture (generally 1:1:1, but sometimes it is necessary to adjust MeOH/THF ratio to obtain transparent reaction mixture) was placed in a round-bottomed flask equipped with a magnetic stirring bar. The flask was placed in an ice-water bath and stirred for 24 h (monitored by TLC). Then, the reaction was stopped, and the mixture was extracted via DCM and water. After removing the solvent of the organic layer, Bis-(4-ethynylphenyl)-octamethyltetrasiloxane was obtained in a 61% yield as a light yellow liquid by running silica column with hexane/DCM (10:1) as eluent.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][C:37]([F:41])([F:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:41][C:37]1([F:40])[CH2:38][CH2:39][N:34]([CH:32]2[CH2:33][N:30]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:31]2)[CH2:35][CH2:36]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1(F)CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.1 g, 0.26 mmol), 1-azetidin-3-yl-4,4-difluoropiperidine (0.087 g, 0.38 mmol) and 4A molecular sieves (0.6 g) in DCE (6 mL) was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.109 g, 0.51 mmol) was added and the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 3:97) to give 492 as a yellow solid (0.097 g, 69%). LCMS (Method I): RT=2.82 min, [M+H]+ 552.3. 1H NMR (400 MHz, DMSO-d): δ 8.03-7.99 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.30-4.23 (m, 4 H); 3.87 (s, 2 H); 3.80-3.75 (m, 7 H); 3.46-3.43 (m, 2 H); 3.25 (q, J=7.4 Hz, 2 H); 3.01-2.98 (m, 3 H); 2.37-2.33 (m, 4 H); 2.00-1.87 (m, 4 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [C:1]1([C:7]2([CH2:15]C#N)[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[K+].C(O)C[OH:22]>>[C:1]1([C:7]2([C:15]([OH:22])=[O:18])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CCCC(CC#N)(c2ccccc2)C1
Reactant: OCCO
Reactant: [OH-]
Agent: [K+]
Product: CC1(C)CCCC(C(=O)O)(c2ccccc2)C1
Temperature: 25 °C
Yield: 27 %

Procedure:
NaH (60% dispersion in mineral oil, 72.3 mmol) was washed several times with n-hexane and suspended in DMF. A mixture of phenylacetonitrile (24.1 mmol) and de-O-p-toluene-sulfonyl-2,2-dimethyl-1,5-pentanediol (24.1 mmol) in DMF was added dropwise. The reaction mixture was stirred at 70° C. for 3 h and DMF was evaporated under reduced pressure. Excess hydride was then decomposed by the cautious addition of H2O. Extraction with Et2O, drying of the organic layer (MgSO4) and evaporation of the solvent afforded 1-phenyl-3,3-dimethylcyclohexaneacetonitrile that was chromatographed on silica using petroleumether-EtOAc 98:2 as eluent; 1H NMR (CDCl3) δ 0.96 (s, 3H), 1.26 (m, 1H), 1.31 (m, 3H) 1.59 (m, 2H), 1.78 (m, 2H), 1.92 (m, 2H), 2.23 (m, 1H), 7.49 (m, 5H). 7.0 mmol of the nitrile was refluxed with KOH (40%, 15 mL) in ethyleneglycol (40 mL) for two days. It was then allowed to cool to room temperature and was extracted with Et2O. The aqueous layer was acidified and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated to provide 1.5 g (27%) of the desired carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:13][CH2:14][C@@H:15]1[CH2:20][NH:19][C@@H:18]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][N:16]1[C:27]([O:29][CH3:30])=[O:28].[OH-].[Li+]>ClCCl.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:19]2[C@@H:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:17][N:16]([C:27]([O:29][CH3:30])=[O:28])[C@H:15]([CH2:14][OH:13])[CH2:20]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)N1C[C@H](CN2CCCC2)NC[C@H]1CO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1C[C@H](CN2CCCC2)N(C(=O)Cc2ccc(Cl)c(Cl)c2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 1,1'-carbonyldiimiazole (0.20 g, 1.26 mmol) in dichloromethane (10 mL) was added portionwise 3,4-dichlorophenylacetic acid (0.25 g, 1.26 mmol) and the resulting solution stirred under nitrogen for 1 hr, at room temperature. A solution of 8 (0.13 g, 0.5 mmol) in dichloromethane (10 mL) was added and the mixture was allowed to stand at room temperature for 18 hr. The reaction mixture was washed with sodium carbonate solution (2 N, 2×10 mL), dried, and evaporated to give a viscous oil. This material was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) and treated with lithium hydroxide (42 mg, 1.0 mmol). The reaction mixture was removed, and the aqueous residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried and evaporated to give a colorless gum which was purified by flash column chromatography on silica gel, eluting with ethyl acetate-methanol (40:1) to give 9 (155 mg, 70%) as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]Cl)[CH:9]=2)=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[N:11]=[C:10]([CH2:23][C:25]#[N:26])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: NS(=O)(=O)c1ccc(-n2nc(CCl)cc2-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A solution of 4-[5-(4-chlorophenyl)-3-chloromethyl-1H-pyrazol-1-yl]benzenesulfonamide from step 1 (350 mg, 0.9 mmol) and sodium cyanide (200 mg), dissolved in 15 mL of dimethylsulfoxide, was warmed to 100° C. for 4 hours. The solution was cooled to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed with water, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 1:1 (v:v) hexane/ethyl acetate. The appropriate fractions were combined and concentrated, and the residue crystallized from ethanol/water to give 4-[5-(4-chlorophenyl)-3-cyanomethyl-1-H-pyrazol-1-yl]benzenesulfonamide as a white solid (251 mg, 75%): mp 212-214° C., Anal. Calc'd. for C17H13ClN4O2S1: C, 54.77; H, 3.51; N, 15.03. Found: C, 54.94; H, 3.61; N, 14.88.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[CH3:18][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH3:18][C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[Sn](C)(C)C
Reactant: Brc1c(NC2=NCCN2)ccc2nccnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(NC2=NCCN2)ccc2nccnc12
Temperature: 145 °C
Yield: 56.8 %

Procedure:
A sealable reaction tube was charged with 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (104 mg., 0.36 mmol) (prepared as noted above), tetramethyl tin (214 mg., 1.2 mmol) and (Ph3P)2PdCl2 (10 mg) and dry dimethylformamide (2 ml) in a reaction tube. The reaction mixture was purged with dry nitrogen gas. The tube was sealed and heated to 145° C. for 6 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The dark brown residue was chromatographed (SiO2 ; 5/1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 46.5 mg (53%) of the title compound as a light yellow solid. An analytical sample was prepared by recrystallization from CHCl3 /CH3OH and had a melting point of 183°-186° C. The title compound was characterized by 1H and 13CNMR, IR and mass spectral analysis.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=O)[CH2:15][C@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:17]([OH:19])=[O:18].[OH2:28].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:37]O>CO>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[N:37][OH:28])[CH2:15][C@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:17]([OH:19])=[O:18]
Reactant: NO
Reactant: O
Reactant: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc2oc3ccccc3c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)[C@H](CC(=NO)c1ccc2oc3ccccc3c2c1)NC(=O)C(F)(F)F
Temperature: 24 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of (S)-4-dibenzofuran-2-yl-4-oxo-2,2,2-trifluoroacetylamino)-butyric acid (1.0 g, 0.0026 mol) from Example 1 in 50 mL of methanol was added sodium acetate trihydrate (1.08 g, 0.0079 mol). The solution was stirred at 24° C. while an aqueous solution (5 mL) of hydroxylamine hydrochloride (0.37 g, 0.00527 mol) was added in one portion. The reaction mixture was stirred for 3 hours at 24° C., and then heated to reflux for 2 hours. The solution was cooled to 24° C. and concentrated to dryness by evaporation under reduced pressure. The solid was rinsed with 10 mL of water, and crystallized from ethyl acetate and hexane to afford 0.13 g of (S)-4-dibenzofuran-2-yl-4-hydroxyimino-2-(2,2,2-trifluoroacetylamino)-butyric acid; mp 128-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Br)ccc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (4 g, 19.28 mmol), tetrahydro-4-pyranol (2.20 ml, 23.13 mmol) and polymer supported triphenylphosphine (17.29 g, 39.29 mmol; purchased from Argonaut, loading 2.23 mmol/g) was suspended in dichloromethane (250 ml) and then cooled to 0° C. Di-tent-butyl azadicarboxylate (6.65 g, 28.92 mmol) was added portionwise and the reaction mixture was warmed to room temperature and shaken for 2 hours. The resin was filtered off and washed with dichloromethane. The combined filtrates were evaporated till dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 2%). The desired fractions were collected and evaporated in vacuo to yield intermediate 14 as a colorless oil (5.38 g, 95%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)C>ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)=[CH:2]1
Reactant: O=Cc1csc2ccccc12
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Product: c1ccc(N2CCN(Cc3csc4ccccc34)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Benzothiophene-3-carbaldehyde (6.17 mmole), 1-(2-pyridinyl)piperazine (6.17 mmole), and sodium triacetoxyborohydride (9.26 mmole) were combined in 25 mL of 1,2-dichloroethane and stirred at 0° C. for one hour. The mixture was allowed to warm to room temperature and stir for 12 hours. The mixture was poured into a diethyl ether:dichloromethane mixture and washed with a solution of saturated aqueous NaCl made basic with sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography with 96:4:0.5 dichloromethane/methanol/saturated aqueous ammonia to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.62 (t, 4H, J=4.5 Hz), 3.51 (t, 4H, J=4.5 Hz), 3.82 (s, 2H), 6.65 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 7.40 (m, 2H), 7.48 (s, 1H), 7.53 (m, 1H), 7.86 (m, 1H), 8.04 (m, 2H); MS (DCI/NH3) m/z 310.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](Cl)=[N:17][CH:16]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=C(NCCCCCCCCCCCO)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: O=C(NCCCCCCCCCCCO)c1ccc(N2CCNCC2)nc1
Reaction time: 5 h

Procedure:
2.36 g of N-(11-hydroxy-1-undecanyl)-6-chloronicotinamide and 3.15 g of piperazine were suspended in 50 ml of toluene and the suspension was stirred at 120°-130° C. for 5 hrs. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to obtain quantitatively N-(11-hydroxy-1-undecanyl)-6-piperazinylnicotinamide. This compound was added under ice-cooling to 10 ml of fuming nitric acid and the mixture was stirred below 5° C. for 4 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=5:1) and recrystallized from chloroform/hexane to give 0.5 g (15%) of the title compound.
Reaction SMILES: O1CCOCC1.C([C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([Cl:34])[C:16]=1[CH:17]([S:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])(C)(C)C.[C:36]([O:40][C:41](=[O:50])[NH:42][CH2:43][CH:44]1[O:49][CH2:48][CH2:47][NH:46][CH2:45]1)([CH3:39])([CH3:38])[CH3:37]>C(OCC)(=O)C>[C:36]([O:40][C:41](=[O:50])[NH:42][CH2:43][CH:44]1[O:49][CH2:48][CH2:47][N:46]([C:12]2[CH:11]=[C:16]([CH:17]([S:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:15]([Cl:34])=[CH:14][N:13]=2)[CH2:45]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: CC(C)(C)c1c(Cl)ncc(Cl)c1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CN(c2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)CCO1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the t-butyl 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (60 mg, 0.14 mmol) obtained in Example 54 and t-butyl(morpholin-2-yl)methylcarbamate (200 mg) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml). The diluted mixture was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ether=5:1) to give the title compound (45 mg, 52%) as an oil.