Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](#[N:12])[CH2:9][C:10]#[N:11].[Cl-].Cl[C:15]([Cl:21])=[N+:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClC1C=CC=CC=1>[Cl:21][C:15]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[C:9]([C:8]#[N:12])[C:10]#[N:11]
Reactant: CC[N+](CC)=C(Cl)Cl
Reactant: N#CCC#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: CCN(CC)C(Cl)=C(C#N)C#N
Reaction time: 4 h
Yield: 33.7 %

Procedure:
A solution of 12.1 g of triethylamine, 4.0 g of malononitrile, and 20 ml of chlorobenzene was added to a slurry of 11.4 g of N-(dichloromethylene)-N,N-diethylammonium chloride and 50 ml of chlorobenzene, at ambient temperature. The reaction temperature was kept below 50° by controlling the rate of addition (time required for complete addition, 30 minutes). After addition, the reaction mixture was stirred for four hours while it returned to ambient temperature. The reaction mixture was filtered and the filtrate concentrated on the rotary evaporator to give a brownish-red liquid. Vacuum distillation gave 3.7 g of liquid 3-chloro-2-cyano-3-(diethylamino)propenenitrile; b.p. 127°-131°/0.05 mm Hg. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:29](=[O:39])[C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:30](=[C:31](/[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)\[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)/[C:29]2=[O:39])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccc(Cl)cc2)c2ccccc2)c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccc(Cl)cc3)c3ccc(C(F)(F)F)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-4-trifluoromethyl-benzene (commercially available) and 3-({[3-(4-chloro-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.37 (d, 1H), 6.66-6.71 (m, 2H), 7.08 (t, 1H), 7.26-7.52 (m, 9H), 7.73 (d, 2H), 7.94 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([Cl:12])[N:3]=1.S(Cl)(Cl)=O.[CH2:17](N(CC)CC)[CH3:18].C(O)C.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:17][CH3:18])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([Cl:12])[N:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2,6-Dichloro-5-fluoropyridine-3-carboxylic acid (5.00 g, 23.81 mmol) was mixed with ~13 mL of thionyl chloride under nitrogen. The reaction was heated and the excess thionyl chloride was distilled off. The resulting liquid was diluted with ~5 mL methylene chloride, cooled to 0° C. and treated with 4.98 mL (1.5 equivalents) of triethylamine followed by 2.79 mL (2.0 equivalents) of ethanol dropwise. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. A 1:1 mixture of sodium bicarbonate solution and ether (~80 mL) was added and the organic layer was washed with saturated sodium bicarbonate solution, 1N phosphoric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue obtained was flash chromatographed on silica gel eluting with 5% ethyl acetate in hexane to give the title compound (5.32 g, 94%) as a yellow liquid. 1H NMR (CDCl3, 300 MHz) δ 1.42 (t, 3 H), 4.43 (q, 2H), 8.00 (d, 1H). MS (DCl/NH3) m/e 239 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Cl:11]Cl.CCOC(C)=O.CCCCCC>CC(O)=O.CCOC(C)=O>[Cl:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2ncsc2c1
Reactant: ClCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Nc1ccc2ncsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 6-aminobenzothiazole (2.0 g, 13.4 mmol) in 100 mL of AcOH was added a solution of Cl2 saturated AcOH and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80% ) of the desired product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[NH2:22][C:23]1[N:32]=[C:31]([NH2:33])[C:30]2[C:25](=[N:26][CH:27]=[C:28]([CH2:34]O)[N:29]=2)[N:24]=1.[O-2].[Ba+2].[NH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=1>O.CO.C(Cl)Cl.CC(N(C)C)=O>[CH:41]1[C:42]([C:43]([OH:45])=[O:44])=[CH:46][CH:47]=[C:39]([NH:38][CH2:34][C:28]2[N:29]=[C:30]3[C:31]([NH2:33])=[N:32][C:23]([NH2:22])=[N:24][C:25]3=[N:26][CH:27]=2)[CH:40]=1
Reactant: Nc1nc(N)c2nc(CO)cnc2n1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: BrBr
Agent: [Ba+2]
Agent: [O-2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1nc(N)c2nc(CNc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 5 °C
Reaction time: 17 h
Yield: 97.5 %

Procedure:
To a 2 L 3-necked round bottom flask, equipped with a dropping funnel, a thermometer, and a drying tube, were added triphenylphosphine (216 g, 0.83 mol) and anhydrous dimethylacetamide (0.66 L). The resulting clear solution was cooled to 5° C. and bromine (132 g, 0.83 mol) was added over 45 min while maintaining the temperature below 8° C. To the resulting white slurry was added 2,4-diamino-6-hydroxymethyl pteridine (53 g, 0.28 mol). The temperature rose to 35° C. due to exothermic effect. The rust colored slurry slowly dissolved over 1 h to become a dark red solution. The mixture was stirred at ambient temperature overnight (ca. 17 h) forming a dark red slurry. Barium oxide (53 g, 0.35 mol) and 4-aminobenzoic acid (57 g, 0.42 mol) were added in one portion each with vigorous stirring. The temperature rose to 70° C. due to exothermic effect and the mixture turned to a rust-colored slurry within 15 min. The reaction mixture was stirred at 55±2° C. for 24±2 h. The resulting yellow-brown slurry was cooled to 20° C., then poured into a mixture of CH2Cl2 (6.9 L) and MeOH (0.2 L). The solids were isolated by filtration, slurried in H2O (2.5 L), and the mixture was filtered again to isolate the solids. The solids were slurried in MeOH (2.5 L), isolated by filtration, and air-dried at ambient temperature, to give 85 g (99%) of crude product as a brownish-yellow powder, Lot BM-02G-54.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.Cl.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[NH:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>C(#N)C.O>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[NH:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:21]=2)=[CH:17][CH:16]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: COc1ccccc1C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccccc1-c1c[nH]c(-c2ccc(F)cc2)n1
Yield: 255.8 %

Procedure:
A mixture of 2-bromo-2′-methoxy-acetophenone (514 mg), 4-fluorobenzamidine hydrochloride (392 mg) and potassium carbonate (930 mg) in acetonitrile (5 ml) was refluxed for 2 hours. After cooling, to the reaction mixture were added chloroform and water, the organic layer was collected and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from methanol to obtain 2-(4-fluorophenyl)-4-(2-methoxyphenyl)imidazole (1.54 g) as pale yellowish crystal. This compound was treated with hydrogen chloride-ethanol solution to be converted into a hydrochloride salt form.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (40 mg, 0.290 mmol) similar to Example 77 and isolated as a tan oil (33 mg, 48%). 1H NMR (CDCl3): 8.46-8.42 (m, 2H), 7.50-7.46 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.80 (dd, J=2.6, 8.6 Hz, 1H), 6.61 (s, 1H), 3.81 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:52][C:53]1[CH:77]=[CH:76][C:75]([N:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)=[CH:74][C:54]=1[C:55]([NH:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([NH:52][C:53]2[CH:77]=[CH:76][C:75]([N:78]3[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]3)=[CH:74][C:54]=2[C:55](=[O:56])[NH:57][C:58]2[CH:63]=[N:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:65]=3)=[CH:60][N:59]=2)=[O:15])[CH:11]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCOCCO)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)-ethyl)carbamoyl)benzoic acid (189.3 mg, 0.75 mmol, 1.10 equiv) in N,N-dimethylformamide (2.5 mL), HATU (1034 mg, 2.72 mmol, 4.00 equiv), and N-ethyl-N-isopropylpropan-2-amine (351 mg, 2.72 mmol, 4.00 equiv). This was followed by dropwise addition of a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)-pyrazin-2-yl)benzamide (300 mg, 0.68 mmol, 1.00 equiv) in N,N-dimethylformamide (2.5 mL) with stirring. The resulting solution was stirred overnight at 40° C. in an oil bath. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:47]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:40])([F:41])[F:42])[CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)=[CH:5][CH:4]=2)=[N:2][N:49]=[N:48]1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2C(F)(F)F)CCc2ccc(C#N)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2C(F)(F)F)CCc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 212 mg (0.26 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-{[2-(trifluoromethyl)benzyl]oxy}phenyl)but-3-en-1-yl)benzoate in 3 ml of toluene is mixed with 450 mg (3.91 mmol) of trimethylsilyl azide and 97.3 mg (0.39 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 1:1). 120 mg (0.19 mmol, 75% of theory) of a colorless foam are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OCC2C=CC=CC=2)=[O:17])=[C:14]([OH:26])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:28])=[O:27].[NH2:29][C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:29][C:30]2[S:31][CH:32]=[C:33]([CH3:35])[N:34]=2)=[O:17])=[C:14]([OH:26])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:28])=[O:27]
Reactant: Cc1csc(N)n1
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Solvent: Cc1ccccc1C
Product: Cc1csc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)n1
Yield: 67 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 2 from benzyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole in xylene; M.p.: 270° C. (decomp.); Yield: 67% of theory;
Reaction SMILES: [CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[I-].[Na+].[CH2:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:16]>CC(C)=O.C(C(C)=O)C>[I-:12].[CH2:1]([N+:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CCN(CC)CC
Agent: C=CCCCCCCCCCI
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: C=CCCCCCCCCC[N+](CC)(CC)CC

Procedure:
Example IX involves the procedures followed above to prepare undecylenyl chloride, undecylenyl iodide, and triethylammonium undecylenyl iodide. All reagents were obtained from Aldrich unless specified otherwise. Undecylenyl iodide was made stepwise from undecylenol (Aldrich). Undecylenol was allowed to react with thionyl chloride and pyridine to form undecylenyl chloride which was then converted to undecylenyl iodide by reaction with sodium iodide in acetone or methyl ethyl ketone. Undecylenyl triethylammonium iodide was formed by the reaction of undecylenyl iodide and triethylamine in alcohol. Polyalkylenes were then made by polymerization of the corresponding 1-olefins using the isotactic catalyst TiCl3AA (Alpha Products)/diethylaluminum chloride.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([OH:18])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[K+].Cl>CN(C)C(=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([OH:18])=[O:17])([CH3:15])[CH3:14])/[C:8]([O:10][S:20]([CH3:19])(=[O:22])=[O:21])=[O:9])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(O/N=C(\C(=O)O)c1nsc(N)n1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(O/N=C(\C(=O)OS(C)(=O)=O)c1nsc(N)n1)C(=O)O
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 31.2 %

Procedure:
To a solution of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid (2.74 g) in N,N-dimethylacetamide (45 ml) were added methanesulfonyl chloride (1.15 g) and potassium bicarbonate (1.20 g) under cooling in an ice bath. The mixture was stirred for 2.5 hours at 5° C. and poured into a cold mixture of water (200 ml), ethyl acetate (200 ml) and 1N hydrochloric acid (6 ml). The mixture was stirred for 5 minutes under cooling in an ice bath. The organic layer was separated, washed with cold water (200ml×2) and with a cold saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. Toluene was added to the residue. To the mixture was added methylene chloride and the mixture was cooled for 10 minutes in an ice bath. The crystals were collected by filtration, washed with methylene chloride and air-dried to give methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetate (1.1 g).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=1[F:33])#[N:16]>>[F:29][C:28]1[C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:25]=[C:24]([F:33])[C:23]=1[C:18]1[C:17]([C:15]#[N:16])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: N#Cc1ccccc1-c1c(F)ccc(B(O)O)c1F
Product: N#Cc1ccccc1-c1c(F)ccc(-c2cnc3nc(C(F)(F)F)ccn23)c1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine and 2′-cyano-2,6-difluorobiphenyl-3-boronic acid were coupled using the procedure described in Example 1 to give 2′,6′-difluoro-3′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white solid: δH (360 MHz, CDCl3) 7.30-7.34 (2H, m), 7.59-7.68 (3H, m), 7.75-7.79 (1H, m), 7.88 (1H, dd, J 7 and 1), 8.13 (1H, s), 8.78 (1H, dd, J 7 and 4).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[CH2:39][OH:40])(=[O:13])=[O:12].[CH3:41][S:42](Cl)(=[O:44])=[O:43].N1C=CC=CC=1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:16][C@H:15]1[CH2:39][O:40][S:42]([CH3:41])(=[O:44])=[O:43])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
A solution of 14.14 g (25 mmol) of (2S,4R)-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol in 300 ml CH2Cl2 was treated at 0° C. with 2.14 ml (27.7 mmol) methane sulfonylchloride, 3.02 ml (37.5 mmol) pyridine, 3.05 g (25 mmol) DMAP and stirred at room temperature for 4 h. The reaction mixture was poured into EtOAc/H2O acidified with 1 N HCl. The organic phase was washed with 10% aqueous NaCl, dried over Na2SO4 and evaporated to give 15.98 g (99%) of methanesulfonic acid (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl ester, MS: 644 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:16]=C[C:11]3[N:12]=[CH:13]S[C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C=CC2[N:22]([N:24]=CN=2)C=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[N:22]([N:24]=[CH:13][N:12]=3)[CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccc2ncnn2c1
Reactant: Clc1ncccc1-c1ccc2ncsc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ncccc1-c1ccc2ncnn2c1
Yield: 58 %

Procedure:
6-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine was synthesized in the similar to 6-(2-chloropyridin-3-yl)benzo[d]thiazole from 6-bromo[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 5.0 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.45 g, 6.0 mmol), Pd(PPh3)4 (300 mg, 0.26 mmol) and 2M aq.Na2CO3 (8 mL, 16 mmol) in 1,4-dioxane (50 mL). Upon workup, the crude residue was dissolved in CH2Cl2 (10 mL) and stirred with 50% EtOAc/hexanes (40 mL). The resulting off-white precipitate was filtered and dried to provide 6-(2-chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (0.68 g, 58%). 1H NMR (DMSO-d6): δ 9.18 (dd, 1H, J=0.86 and 1.7 Hz), 8.57 (s, 1H), 8.50 (dd, 1H, J=1.7 and 4.9 Hz), 8.05 (dd, 1H, J=2.0 and 7.8 Hz), 7.94 (dd, 1H, J=0.9 and 9.1 Hz), 7.80 (dd, 1H, J=1.7 and 9.1 Hz), 7.59 (dd, 1H, J=4.7 and 7.6 Hz).LCMS: rt 5.00 min (A), purity 97%, MS (m/e) 231.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](=O)[CH3:24])=[CH:14]1>O.C(O)C>[Cl:9][C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](=[N:2][OH:3])[CH3:24])=[CH:14]1
Reactant: NO
Reactant: CC(=O)Cc1cn(Cc2ccccc2Cl)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(Cc1cn(Cc2ccccc2Cl)c2ccccc12)=NO
Yield: 79 %

Procedure:
2.5 G of hydroxylamine hydrochloride and 2.5 g of sodium acetate dissolved in 10 ml of water are added to 2 g (0.023 mole) of 1-(2-chlorobenzyl)-3-(2-oxopropyl)indole dissolved in 100 ml of 96% ethyl alcohol. Stirring takes place for 12 hours at 20° and the oxime formed is filtered. The product is recrystallised from di-isopropyl ether.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:3]1[C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
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+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccccc1-c1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 91.9 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 50.3 mg, 0.161 mmol), o-tolylboronic acid (Aldrich; 32.8 mg, 0.241 mmol), Na2CO3 (51.1 mg, 0.482 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 9.29 mg, 8.04 μmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.500 mL) was stirred under argon at 100° C. for 45 min. The mixture was concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(2-methyl-3-(o-tolyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (54.6 mg, 0.148 mmol, 92% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.12 (1H, br. s.), 8.11 (1H, dd, J=7.4, 0.8 Hz), 7.90 (1H, dd, J=8.3, 0.9 Hz), 7.77 (1H, t, J=8.0 Hz), 7.31-7.49 (4H, m), 7.25 (1H, d, J=2.2 Hz), 5.38 (1H, br. s.), 3.58 (2H, td, J=6.7, 2.1 Hz), 2.85 (2H, t, J=6.8 Hz), 2.59 (3H, s), 2.21 (3H, s). m/z (ESI, +ve) 368.9 (M+H)+.