Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH:11]=O)=[O:8])=[CH:3][CH:2]=1.C(C(P(O)(O)=O)/C(/CC)=[C:23](\[CH2:27][CH3:28])/[C:24]([O-:26])=[O:25])C.[H-].[Na+].[CH2:37]1COC[CH2:38]1>>[CH2:37]([O:26][C:24](=[O:25])/[CH:23]=[CH:27]/[CH:28]=[CH:11]/[CH2:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][CH:3]=1)=[O:8])[CH3:38]
Reactant: C1CCOC1
Reactant: O=CCCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC/C(C(=O)[O-])=C(/CC)C(CC)P(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/C=C/CCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of aldehyde 201 (180 mg, 0.75 mmol) in THF (10 mL), stirred at 0° C. under nitrogen, was added triethyl-4-phosphonocrotonate (220 μL, 0.98 mmol) followed by sodium hydride (40 mg, 0.98 mmol). The mixture was allowed to warm up to room temperature in 2 hours and then quenched by adding water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Purification by flash silica gel chromatography (30% ethyl acetate in hexane) afforded the corresponding diene 202 (100 mg, 40% yield). MS (ESI)=335 (MH+).
Reaction SMILES: [CH3:1]I.C(=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[S:18][C:17]([SH:19])=[N:16][C:13]2=[N:14][CH:15]=1.O>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]2[S:18][C:17]([S:19][CH3:1])=[N:16][C:13]2=[N:14][CH:15]=1
Reactant: Sc1nc2ncc(Cl)cc2s1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ncc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 68 h
Yield: 81.5 %

Procedure:
328 g (2.31 mol) of methyl iodide were added dropwise to a stirred suspension of 363 g (2.62 mol) of potassium carbonate and 354 g (1.75 mol) of 6-chloro-2-mercaptothiazolo[4,5-b]pyridine from Example 1.2 in 2.28 l of dimethylformamide at 5° C. The reaction mixture was stirred at ambient temperature for 68 h and then poured into 4.5 l of demineralized water. The precipitate was filtered, rinsed with water (2×500 ml) and then dried in vacuo at 45° C. to give 308.9 g (yield: 81%) of 6-chloro-2-(methylthio)thiazolo[4,5-b]pyridine.
Reaction SMILES: CN1CCCCC1.ClC(OCC(C)C)=O.[CH:16]([O:19][C:20]([NH:22][C:23](=[CH:27][CH3:28])[C:24]([OH:26])=O)=[O:21])([CH3:18])[CH3:17].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>ClCCl>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([NH:39][C:24](=[O:26])[C:23]([NH:22][C:20]([O:19][CH:16]([CH3:17])[CH3:18])=[O:21])=[CH:27][CH3:28])[CH3:38])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: CC=C(NC(=O)OC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC=C(NC(=O)OC(C)C)C(=O)NC(C)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
At -20° C., 0.5 g (0.005 mol) of N-methylpiperidine and then, dropwise with stirring at -20° C., 0.7 g (0.005 mol) of isobutyl chloroformate are added to 1.0 g (0.005 mol) of 2-(i-propoxycarbonylamino)-but-2-enoic acid in 10 ml of dichloromethane. After the addition is complete, stirring is continued at -20° C. for a further 10 minutes, and 0.75 g (0.005 mol) of 1-(4-methoxyphenyl)-ethylamine are added, the temperature being kept below -15° C. Stirring is then continued for a further 2 hours at -15° C. and for 15 hours at room temperature, the precipitated solid is filtered off and washed with dichloromethane, the filtrate is concentrated under reduced pressure, the residue is taken up in water and extracted repeatedly with ethyl acetate, the combined organic phases are washed with aqueous sodium bicarbonate solution and water and dried over sodium sulphate, and the solvent is removed under reduced pressure. 0.8 g (47% of theory) of N-[1-(4-methoxyphenyl)-ethyl]-2-(i-propoxycarbonylamino)-but-2-enoic acid amide are obtained as a colourless oil. 1H-NMR (CDCl3, TMS), δ (ppm): 1.25 (m, 6H), 1.50 (d, 3H); 1.74 (d, 3H); 3.79 (s, 3H).
Reaction SMILES: C(C(N1CCNCC1)C1C=CC([O:10]C)=C(OC)C=1)#N.N1C=CC=CC=1.N1(C(C[Cl:34])=O)CCCC1.[C:35]([CH:37]([N:48]1[CH2:53][CH2:52][N:51]([CH2:54][C:55]([N:57]2[CH2:61][CH2:60][CH2:59][CH2:58]2)=[O:56])[CH2:50][CH2:49]1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)#[N:36]>C1C=CC=CC=1>[OH2:10].[ClH:34].[C:35]([CH:37]([N:48]1[CH2:49][CH2:50][N:51]([CH2:54][C:55]([N:57]2[CH2:58][CH2:59][CH2:60][CH2:61]2)=[O:56])[CH2:52][CH2:53]1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)#[N:36]
Reactant: O=C(CCl)N1CCCC1
Reactant: COc1ccc(C(C#N)N2CCNCC2)cc1OC
Agent: COc1ccc(C(C#N)N2CCN(CC(=O)N3CCCC3)CC2)cc1OC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cl
Product: O

Procedure:
To 17.7 g. of N-(α-cyano-3,4-dimethoxybenzyl)piperazine was added 60 ml. of benzene and then 5.3 g. of pyridine. To the resulting solution was added dropwise 7.9 g. of pyrrolidylcarbonylmethyl chloride dissolved in 20 ml. of benzene over a period of about 10 minutes with stirring at room temperature. After dropping, the temperature was raised slowly and the mixture to separate benzene layer which was washed with water and dried over sodium sulfate. The solvent was distilled off to give 15 g. of N-(α-cyano-3,4-dimethoxybenzyl)-N'-pyrrolidinocarbonylmethylpiperazine as an oily substance. This product was dissolved in benzene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from iso-propanol afforded N-(α-cyano-3,4-dimethoxybenzyl)-N'-pyrrolidinocarbonylmethylpiperazine hydrochloride monohydrate having a melting point of 155° to 157°C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCc1nnc2ccccc2c1O
Product: CCCCc1nnc2ccccc2c1OCc1ccc(C#N)cc1

Procedure:
Using the procedure of Example 6, the product of Step B of Example 13 and 4-(bromomethyl)benzonitrile were reacted to obtain the desired product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:20])[CH:16]2[O:17][C:13]([CH:18]=[CH2:19])([CH2:14][CH2:15]2)[CH2:12][O:11]1.CO>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:20])[CH:16]2[O:17][C:13]([CH:18]=[CH2:19])([CH2:14][CH2:15]2)[CH2:12][O:11]1)(=[O:4])=[O:3]
Reactant: C=CC12CCC(O1)C(C)(CCCO)OC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CC12CCC(O1)C(C)(CCCOS(C)(=O)=O)OC2
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
Methanesulfonyl chloride (200 mg, 2.6 mM) is added slowly to a mixture of (1RS,4SR,5RS)-4-(3-hydroxypropyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane (333 mg, 1.6 mM) in methylene chloride (30 ml) and triethylamine (2 ml) at 0° C. and stirred for five minutes. The resulting mixture is treated with methanol (1 ml) and most of the solvent is removed in vacuo. The residue is filtered through a silica gel (20 g) column and washed with ether-petroleum ether (1:1, 300 ml). The solvent is removed in vacuo to give (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane (408 mg, 90%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>>[CH3:34][CH:32]1[O:33][CH:28]([CH3:27])[CH2:29][N:30]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:31]1
Reactant: CC1CNCC(C)O1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: CC1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CC(C)O1

Procedure:
The title compound was prepared following the procedure described for 6a using 2,6-dimethylmorpholine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.19 (6H, d, J=7.05 Hz), 2.36 (2H, t, J=12.09, 10.98 Hz), 3.75 (4H, brm), 7.16 (1H, tt, J=7.42, 1.09 Hz), 7.43 (4H, m), 7.56 (2H, d, J=9.06 Hz), 8.23 (2H, dt, J=8.79, 1.37 Hz), 8.56 (1H, s). m/z 376.5 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Br[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15])[CH3:2]
Reactant: O=CCBr
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(CC)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (120 grams), the diethyl acetal of 2-bromoacetaldehyde (78.8 grams) and sodium carbonate (42.4 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture was heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture was cooled to room temperature and was filtered. The filtrate was then distilled under vacuum to yield the desired product the diethyl acetal of 2-(2,6-diethylanilino)acetaldehyde as the residue having a boiling point of 130°C at 1 mm of Hg pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20]O)[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20][Br:24])[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1O[C@@H](Cn2cc(CO)nn2)CN1c1ccc(I)c(F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(CBr)nn2)CN1c1ccc(I)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A stirred mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (14.7 g, 35.1 mmol) and carbon tetrabromide (12.16 g, 36.7 mmol) in dichloromethane (1 L) was treated at 0° C. with triphenylphosphine (12.34 g, 61.2 mmol). The reaction mixture was stirred for 30 minutes at 0° C. and then at room temperature overnight. The reaction mixture was applied onto a silica-gel column and eluted with hexanes:ethyl acetate (1:1) and then with ethyl acetate:methanol (95:5) to give a product that was further purified by recrystallization from ethyl acetate to give the title compound as a colorless solid (14 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:24][OH:25])[NH:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH2:12].[CH2:36]([O:43][C:44]([NH:46][C@H:47]([C:53](O)=[O:54])[CH2:48][CH2:49][C:50](=[O:52])[NH2:51])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:24][OH:25])[NH:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:12][C:53](=[O:54])[C@H:47]([CH2:48][CH2:49][C:50](=[O:52])[NH2:51])[NH:46][C:44]([O:43][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:45]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A mixture of the product from (c) above, 1.4 g. of Nα -benzyloxycarbonyl-L-glutamine, 670 mg. of 1-hydroxybenztriazole and 50 ml. of dimethylformamide is stirred and cooled to -10° C., and 0.7 ml. of triethylamine is added. After 15 minutes, it is treated with 1.2 g. of dicyclohexylcarbodiimide and stirred a few hours at -10° C., then at room temperature for two days and finally let stand an additional three days. The solution is filtered and the filtrate evaporated at 50° C. under reduced pressure. The residue is precipitated from methanol with water and then crystallized from methanol three times; m.p. 245°-248° C.; [α]D25 -4.4° (c 1, DMF); ultraviolet in methanol, λmax 290 E11 75.7; λmax 280 E11 100.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CN(C)C1C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N+:1]([C:4]1[C:5]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:23])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(=O)c1ccncc1
Yield: 19 %

Procedure:
To a solution of ethyl 3-nitro-2-aminobenzoate (700 mg) in N,N-dimethylaniline (7 ml) was added dropwise isonicotinoyl chloride (2.96 g) at 120° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give ethyl 3-nitro-2-(4-pyridyl)carbonylaminobenzoate (200 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:22])[C:19]([CH3:21])=[CH2:20].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH3:21][C:19](=[CH2:20])[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
71.5 g (0.3 mol) of 4-(6-hydroxy-hexyloxy)-benzoic acid and 101.5 g (1.18 mol) of methacrylic acid were dissolved in 950 ml of chloroform. After the addition of 7.2 g (0.07 mol) of hydroquinone and 7.2 g (0.04 mol) of p-toluenesulphonic acid the batch was boiled under reflux on a water separator for 48 hours. The clear brown solution was subsequently evaporated, the residue was taken up in 1.5 l of diethyl ether, filtered and shaken five time with 300 ml of H2O each time. The organic phase was dried over Na2SO4, evaporated and the residue was recrystallized twice from methanol. After drying at 40° C. in a water-jet vacuum 47.33 g of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoic acid remained behind as a white powder; m.p. 83° C.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].[C:15](#N)C>>[NH2:9][C:8]1[N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]=[N:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)C#N
Reactant: CC#N
Reactant: CCCCN
Product: CCCCn1cnc(C(=O)OCC)c1N
Yield: 40 %

Procedure:
A solution of ethyl 2-amino-2-cyanoacetate (0.20 g, 1.56 mmol) and triethyl formate (0.30 mL, 1.72 mmol) in acetonitrile (5 mL) was refluxed for 1 h. After concentrating the residue was dissolved in a solution of acetonitrile (5 mL) and n-butylamine (0.17 mL, 1.72 mmol). The resulting mixture was stirred at reflux for 1 h. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (1:1 ethyl acetate/hexane) of the residue gave 0.12 g, 40% of the title compound as an oil: 1H NMR (250 MHz, CDCl3) δ 6.97 (s, 1H), 5.10 (s, 2H), 4.31 (q, 2H), 3.75 (t, 2H), 1.65 (m, 2H), 1.35 (m, 5H), 0.97 (t, 3H); MS(ESI) m/e 212.2 [M+H]+.
Reaction SMILES: C(O[C:9]([N:11]1CCN(CC(F)(F)F)C[CH:12]1C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.ClC(Cl)(Cl)S(OCC(F)(F)F)(=O)=[O:35].[OH:45][NH:46][C:47]([CH:49]1[CH2:54][N:53]([CH2:55]C(F)(F)F)[CH2:52][CH2:51][N:50]1[S:60]([N:63]1[CH2:68][CH:67]=[C:66]([C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=2)[CH2:65][CH2:64]1)(=[O:62])=[O:61])=[O:48]>>[OH:45][NH:46][C:47]([C@H:49]1[CH2:54][N:53]([C:55]([N:11]([CH3:12])[CH3:9])=[O:35])[CH2:52][CH2:51][N:50]1[S:60]([N:63]1[CH2:68][CH:67]=[C:66]([C:69]2[CH:70]=[CH:71][C:72]([F:75])=[CH:73][CH:74]=2)[CH2:65][CH2:64]1)(=[O:61])=[O:62])=[O:48]
Reactant: O=C(OCc1ccccc1)C1CN(CC(F)(F)F)CCN1C(=O)OCc1ccccc1
Reactant: O=C(NO)C1CN(CC(F)(F)F)CCN1S(=O)(=O)N1CC=C(c2ccc(F)cc2)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CC=C(c3ccc(F)cc3)CC2)[C@@H](C(=O)NO)C1

Procedure:
Proceeding as described in Example 28, Step 1 above, but substituting 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-(R)-carboxylic acid with benzyl 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-(RS)-carboxylate [prepared from 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-(RS)-carboxylic acid as described in Ono, N., et al. Bull. Chem. Soc. Jpn., 51, 2401, (1978)] gave benzyl 1-benzyloxycarbonylpiperazine-2-(RS)-carboxylate. This material was first converted to benzyl 1-benzyloxycarbonyl-4-(2,2,2-trifluoroethyl)piperazine-2-(RS)-carboxylate by reacting it with 2,2,2-trifluoroethyl trichloromethanesulfonate as described in Gao, Y., et al. J. Med. Chem., 33, 39, (1990) and then to N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(RS)-carboxamide by following Example 28, Steps 3-5 described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[C:33]([F:46])([F:47])[F:32])[CH2:45][CH2:44]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccccc2C(F)(F)F)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[2-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.99 (M+H+); retention time=1.10 minutes.
Reaction SMILES: NC1N(C2C=C(CC(OCC)=O)C=CC=2)N=C(C2SC=CC=2)C=1.[NH2:24][C:25]1[N:29]([C:30]2[CH:31]=[C:32]([CH:36]([CH3:42])[C:37]([O:39]CC)=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:28]=[C:27]([C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)[CH:26]=1.[Cl:48][C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[N:56]=[C:57]=[O:58]>>[Cl:48][C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[NH:56][C:57](=[O:58])[NH:24][C:25]1[N:29]([C:30]2[CH:31]=[C:32]([CH:36]([CH3:42])[C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:28]=[C:27]([C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)[CH:26]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CCOC(=O)C(C)c1cccc(-n2nc(-c3cccs3)cc2N)c1
Agent: CCOC(=O)Cc1cccc(-n2nc(-c3cccs3)cc2N)c1
Product: CC(C(=O)O)c1cccc(-n2nc(-c3cccs3)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1

Procedure:
Using the same general approach as for Example 524, ethyl 2-(3-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)acetate (0.202 g, 0.403 mmol, 1.00 eq) was transformed to ethyl 2-(3-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)propanoate. This, in turn, was combined with 2,3-dichlorophenyl isocyanate, according to general method A, to afford 2-(3-(5-(3-(2,3-dichlorophenyl)ureido)-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)propanoic acid. Using general method J, this product was combined with 0.5M NH3 in dioxane (4.03 ml, 2.01 mmol, 5.00 eq) to afford 0.145 g (72%) of 1-(1-(3-(1-amino-1-oxopropan-2-yl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3](Cl)=[O:4].CN1CCOCC1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[NH2:25]>O1CCCC1>[Br:1][CH:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([NH:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][N:19]=1)=[O:4]
Reactant: Nc1cnccn1
Reactant: O=C(Cl)C(Br)CC1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Nc1cnccn1)C(Br)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
A solution of 2-bromo-3-cyclopentyl-propionyl chloride (1.46 g, 6.09 mmol) in tetrahydrofuran (32.1 mL, 0.19M) cooled to 0° C. was treated with N-methylmorpholine (0.66 mL, 6.09 mmol). The reaction mixture was stirred at 0° C. for 5 min. After this time, the reaction was treated with pyrazin-2-ylamine (0.58 g, 6.09 mmol) and allowed to warm to 25° C. The reaction stirred at 25° C. for 2 d. After this time, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×150 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 115 g, 10-50% ethyl acetate/hexanes gradient) afforded 2-bromo-3-cyclopentyl-N-pyrazin-2-yl-propionamide (0.43 g, 24%) as a light brown solid; ES+-HRMS m/e calcd for C12H16N3OBr [M+H+] 298.0550, found 298.0550.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[N:5]2.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C1COCC1.O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH3:28])[CH:20]=3)=[O:27])=[CH:17][CH:18]=1)=[N:5]2
Reactant: Nc1ccc(C#Cc2ccc3nccn3n2)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(C#Cc3ccc4nccn4n3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A reaction mixture of 4-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline (93.6 mg, 0.4 mmol, 1 eq) and m-tolyl isocyanate (0.051 mL, 1 eq) in anhydrous THF (4 mL) was stirred at room temperature for four hours. It was then diluted with water and a solid which precipitated was filtered. The solid was further triturated with ethyl acetate and 1-[4-(imidazo[1,2-b]pyridazin-6-ylethynyl)phenyl]-3-(3-methylphenyl)urea was obtained as a yellow solid upon filtration in amount of 125 mg.