Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([C:23]1[N:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:16]([C:23]1[N:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(-c2ccc(Cc3ccccc3)nn2)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Cc5ccccc5)nn4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-Chloro-6,7-dimethoxy-quinoline (0.19 g, 0.85 mmol), 4-(6-benzyl-pyridazin-3-yl)-2-fluoro-phenol (Step 3, 0.2 g, 0.71 mmol) and DMAP (0.1 g, 0.85 mmol) in 6 mL of toluene was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of brine 2×, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide title compound as a white solid. MS (ESI pos. ion) m/z: 487.3 (M+H). Calc'd Exact Mass for C28H22FN3O3: 467.49.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)(Cl)Cl>[CH3:8][C:2]1[CH:3]=[CH:4][C:5]([CH3:7])=[CH:6][N+:1]=1[O-:14]
Reactant: Cc1ccc(C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
2,5-Lutidine (1419 g) was dissolved in chloroform (13.5 L) and cooled to below 10° C. m-Chloroperoxybenzoic acid (70%, 3354.21 g) was added portion-wise to maintain the temperature at below 10° C., and then the reaction was warmed to room temperature and stirred overnight. Once no starting material was seen by tlc analysis, the mixture was cooled to 10° C. and quenched with aqueous 20% sodium hydroxide (2.5 L to 3 L) dropwise while maintaining a temperature below 20° C., which resulted in the formation of a very thick suspension. The mixture was stirred for 30 minutes and then allowed to separate. Water (5 L) was added, the organic layer was separated, and the aqueous layer was extracted twice with chloroform (4 L). The combined organic layers were washed with aqueous 1% sodium hydroxide, followed by aqueous 1N hydrochloric acid, and then concentrated under vacuum to give the desired product (1365 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[S:23][C:13]=3[N:14]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Fc1ccc(CNc2nc(-c3ccncc3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:23])[CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C.ClCCl.ClCCl.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:23])[CH2:19][CH:20]2[CH2:21][CH2:22]2)=[CH:16][CH:17]=1
Reactant: OC(CC1CC1)c1ccc(Cl)cc1
Agent: C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CC1CC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Oxalyl chloride (14.3 ml, 160 mmol) was added dropwise to a stirred solution of dimethylsulphoxide (14.3 ml, 200 mmol) in dry dichloro-methane methane (350 ml) at -78° C. After 15 minutes 1-(4-chlorophenyl)-2-cyclopropylethanol (12.98 g, 66 mmol) in dry dichloromethane (120 ml) was added to the mixture. After an hour triethylamine (71.4 ml), 510 mmol) was added and the mixture warmed to room temperature and poured into water. The mixture was extracted with dichloromethane and the combined extracts washed with water, dried and evaporated in vacuo to give crude 1-(4-chlorophenyl)-2-cyclopropylethanone which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]#[N:13])=[CH:5][C:4]=1[CH3:14].[CH2:15](N)[CH2:16][NH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>[NH:13]1[CH2:15][CH2:16][N:17]=[C:12]1[CH:9]1[C:10]2[C:6](=[CH:5][C:4]([CH3:14])=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: NCCN
Reactant: COc1cc2c(cc1C)CCC2C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2c(cc1C)CCC2C1=NCCN1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 2.4 grams (0.013 mole) of 6-methoxy-5-methylindanecarbonitrile (iv) and 11.2 grams (0.045 mole) of the ethylenediamine salt of p-toluenesulfonic acid was stirred and heated to about 140° C.-160° C. where it was maintained for about 4.5 hours. The reaction mixture was then cooled to ambient temperature and dissolved in a mixture of aqueous 5% potassium carbonate and methylene chloride. The organic layer was removed, and the aqueous layer was extracted with two portions of methylene chloride. The combined extracts and organic layer were washed with one portion of aqueous 5% potassium carbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was purified by column chromatography on Grade II basic alumina (3% water) using mixtures of methylene chloride and methanol as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding about 2.1 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])(=O)C.Cl>O1CCOCC1>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:14])([F:15])([F:16])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Yield: 98.7 %

Procedure:
4-Acetamido-3-nitrophenylsulphur pentafluoride (29.0 g) was heated at reflux with hydrochloric acid (6N) and dioxan for 40 minutes and concentrated to low volume, basified with sodium carbonate solution and extracted (ether). The extract was washed (water), dried (magnesium sulphate) and evaporated to give 4-amino-3-nitrophenylsulphur pentafluoride (24.7 g), m.p.132-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:10]2([C:29]([F:32])([F:31])[F:30])[O:14][N:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([CH3:28])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:10]2([C:29]([F:31])([F:32])[F:30])[O:14][N:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:28])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 0 °C
Yield: 98.3 %

Procedure:
A 100 mL vessel was charged with tert-butyl 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (3.1 g, 6.3 mmol) and dissolved in CH2Cl2 (30 mL) and then cooled down to 0° C. To this mixture 2,2,2-trifluoroacetic acid (4.3 g, 38 mmol) was added over 10 min. After addition the reaction was brought to room temperature and the mixture stirred over night after which time LC-MS analysis showed a complete conversion. The crude mixture was concentrated and the residue dissolved in 300 mL of ethylacetate, washed with brine, dried over MgSO4 and evaporated to yield 2.7 g of the crude title product which was directly used for the step D.
Reaction SMILES: [OH-].[Na+].[N:3]1([CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=[CH:6][N:5]=[CH:4]1>CO.O>[N:3]1([CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCCCCCCCCCC(CCCCCCC(=O)[O-])n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCC(CCCCCCC(=O)O)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 125.7 %

Procedure:
Sodium hydroxide (0.67 g, 1.68 mmol) was added to a stirred solution of 8-(1H-imidazol-1-yl)octadecanoate (0.305 g, 0.84 mmol) in a mixture of methanol (9 ml) and water (3 ml) at 0° C., warmed to room temperature and stirring continued another 3 h. Methanol was removed from the mixture by evaporation. The pH was adjusted to 4 with 1N HCl, and the mixture extracted with dichloromethane (3×15 ml). The combined organic layers were washed with brine solution, dried on anhydrous MgSO4, and concentrated. Crude product was purified on silica gel column (5% methanol in dichloromethane) to obtain a gummy liquid (370 mg, 83%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:3]1=2.[CH2:20]([N-:22][CH2:23][CH3:24])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=1)=[O:18])[CH3:21]
Reactant: CC[N-]CC
Reactant: O=C(O)c1ccc2c(c1)OCc1ccccc1C2=O
Product: CCN(CC)C(=O)c1ccc2c(c1)OCc1ccccc1C2=O

Procedure:
A sample of compound 4c (5.5 g, 21.6 mmol) was converted to its corresponding diethylamide (4.28 g, 13.8 mmol) following an adaptation of Procedure 6.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:9][C:10](O)=[O:11].O.[OH-].[Na+]>O1CCCC1>[CH3:13][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:7])[CH2:9][CH2:10][OH:11]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of lithium aluminum hydride (8.62 g, 228 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of 3-methyl-3-phenylbutanoic acid (20.26 g, 113.7 mmol) in tetrahydrofuran (100 ml) under ice-cooling, and the mixture was stirred overnight at room temperature. After ice-cooling the reaction solution, water (8 ml), 15% aqueous sodium hydroxide solution (8 ml) and water (20 ml) were successively added dropwise to decompose excess lithium aluminum hydride. The mixture was stirred as it was at room temperature for 2 hrs. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the recovered filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the objective substance.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:33])[O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, n-eicosanol (182 g) was dissolved in toluene (1250 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, and the mixture was stirred at room temperature for 10 minutes and then heat-refluxed for 30 minutes. When the reaction liquid was cooled to room temperature, crystals precipitated. The crystals were collected by filtering and washed with toluene. n-eicosyl p-nitrophenylcarbamate (270 g) was obtained at a yield of 96%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[CH3:19][N:20]1[C:27](=[O:28])[CH:26]([C:29](OCC)=[O:30])[C:24](=[O:25])[N:23]([CH3:34])[C:21]1=[O:22]>C1(C)C=CC=CC=1>[CH3:34][N:23]1[C:24](=[O:25])[CH:26]([C:29](=[O:30])[NH:16][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[C:27](=[O:28])[N:20]([CH3:19])[C:21]1=[O:22]
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: Nc1ccc(Oc2ccc3ccccc3n2)cc1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc4ccccc4n3)cc2)C(=O)N(C)C1=O
Reaction time: 3 h

Procedure:
6.1 g of 4-(quinolin-2-yloxy)aniline and 5.8 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid are heated under reflux in 50 ml of toluene. When the temperature is at 80° C., a thick crystalline slurry is formed which at 120° C. is again of a stirrable consistency. After stirring for 3 hours, the mixture is cooled and the crystals are isolated by suction filtration.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:10][CH:11]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].[ClH:30]>CO.C(Cl)(Cl)Cl.CCOCC.C(OCC)(=O)C>[ClH:30].[CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:10][CH:11]=2)[CH:6]1[OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCc2ccc(OCc3ccc4ccccc4n3)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCC1CCc2ccc(OCc3ccc4ccccc4n3)cc2C1O

Procedure:
To a stirring solution of 2-butyl-3,4-dihydro-7-(2-quinolylmethoxy)-1(2H)-naphthalenone (718 mg) in methanol (7 ml) in an ice bath was added dropwise a solution of sodium borohydride (114 mg) in methanol (7 ml). The mixture was stirred for half an hour at the same temperature and then diluted with chloroform (80 ml). The solution was washed with water (80 ml). The aqueous layer was extracted three times with chloroform. The combined organic layers were washed with water, dried and concentrated in vacuo to give an oily residue. The residue was dissolved in ether (200 ml) and thereto 2N-hydrogen chloride in ethyl acetate (1 ml) was added dropwise with stirring in an ice bath. The precipitates were collected by filtration and washed with ether to yield 2-butyl-7-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1naphthol hydrochloride (700 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21])[CH3:16].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:22])[C:19](=[C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[C:20]#[N:21])[CH3:16]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[N:8]=[C:5]2[S:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]2[N:4]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N+:17]([O-:19])=[O:18])[N:8]=[C:5]3[S:6][CH:7]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CCl)csc2n1
Product: CN1CCN(Cc2csc3nc(-c4ccccc4[N+](=O)[O-])cn23)CC1
Temperature: 110 °C

Procedure:
Displacement: 3-Chloromethyl-6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole (126 mg, 0.300 mmol) in 2 ml of 1-methyl-piperazine was microwave heated at 110° C. for 30 minutes. The reaction mixture was concentrated to dryness, and chased with methanol to obtain crude 3-(4-Methyl-piperazin-1-ylmethyl)-6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>[Cu]I.C(#N)C>[F:19][CH:20]([F:28])[O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Yield: 60.7 %

Procedure:
A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), CuI (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL). The reaction was heated to 45° C. (ext. oil bath). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45° C. over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21 [M+H-Boc]+.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][CH:7]([CH3:15])[CH2:8][CH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14].C(N(CC)CC)C.C1(C)C=CC=CC=1>CCCCCC>[CH3:6][CH:7]([CH3:15])[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([Si:2]([CH3:4])([CH3:3])[CH3:1])[C:10]1=[O:14]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC1CCNC1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)CC1CCN([Si](C)(C)C)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
TMSCl (2.2 mL, 18 mmol) is added dropwise to a solution of 3-(2-methylpropyl)-2-pyrrolidinone (2.25 g, 15.9 mmol), triethylamine (2.7 mL, 19 mmol), and toluene (16 mL) at room temperature. The mixture is heated at 40° C. for 3 hours and diluted with hexane (50 mL). After stirring for 10 minutes at 0° C., the mixture is filtered and the filtrate concentrated. Distillation (1 mm, 62°-68° C.) of the residue gives 2.40 g (71%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Yield: 47.5 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (300 mg, 0.88 mmol) and pyridin-2-ylmethylamine (115 mg, 1.06 mmol) were dissolved in 10 mL of THF, triethylamine (141 mg, 1.4 mmol) was added dropwise, added HATU (405 mg, 1.06 mmol) under ice-water-bath, reacted at room temperature for 4 h, to the reaction solution was added 100 mL of water, then extracted with dichloromethane, dried with anhydrous sodium sulfate, dried by rotation, then the solid was separated with silica gel column (dichloromethane:methanol=20:1) to obtain a white solid 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide 180 mg, yield 48%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[OH:28])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2O)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 30, 13.5 mg, 0.03 mmol) in ethanol (0.32 mL) cooled to 0° C. was treated with sodium borohydride (1.2 mg, 0.03 mmol). The reaction mixture was stirred at 0° C. for 20 min. At this time, the reaction was diluted with water (25 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacua. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-hydroxy-cyclopentyl)-N-pyrazin-2-yl-propionamide (10.1 mg, 75.5%) as a white foam: EIHRMS m/e calcd for C19H22ClN3O4S (M+Na)+ 446.0912, found 446.0916.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12](Cl)(=O)C>CO>[CH3:12][O:2][C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
4-Carboxybenzaldehyde (2 mmol) was diluted in 6 mL of anhydrous MeOH. The mixture under N2 was placed in an ice bath and acetyl chloride (10 mmol) was added dropwise. The ice bath was removed and the mixture was stirred overnight at room temperature. The methanol was removed under reduced pressure and the mixture was diluted in 35 mL of EtOAc. The organic phase was washed with 5×10 mL of 1N NaOH and 3×10 mL of brine, dried with MgSO4 and filtered. The volatiles were removed and the product was obtained as a pale yellow solid (96% yield). mp 142-144° C. 1H RMN (CDCl3) δ 10.04 (s, 1H), 8.13 (d, 2H, J=8.2 Hz), 7.89 (d, 2H, J=8.1 Hz), 3.90 (s, 3H). 13C NMR (CDCl3) δ 191.91, 166.26, 139.35, 135.27, 130.40, 129.74, 52.81. HRMS (FAB) calcd for C9H9O3 ([M+H]+): 165.0546. found 165.0543.