Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].C([O-])([O-])=O.[K+].[K+].Br[CH:29]1[C:34](=O)[CH2:33][CH2:32][N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30]1.O>CN(C=O)C.CC(=O)OCC>[C:20]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:5][N:6]2[C:29]3[CH2:30][N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:33][C:34]=3[NH:1][C:2]=12)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(C#N)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.5 g, 5.4 mmol) and K2CO3 (2.24 g, 16.3 mmol) in 50 mL of DMF at 80° C. was stirred under N2 for 45 min before tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (4.5 g, 16.3 mmol) was added in one portion. Then the mixture was stirred at 80° C. for 1 hr. After cooling down to RT, 150 mL of water and 150 mL of EA was added. Aqueous phase was further extracted with EA (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to get crude product which was chromatographed on 15 g of silica gel using DCM/MeOH (400/1 to 200/1) as eluant to afford 850 mg (35%) of tert-butyl 3-cyano-2-(4-phenoxyphenyl)-5,6-dihydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-7(8H)-carboxylate as an off-white solid. MS (ESI) m/e [M+1]+ 455.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[CH:2]1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39](=[O:40])[N:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)([CH3:27])[CH3:28]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2c[nH]c3ccccc23)cc1
Product: CCCCCCCCc1ccc(N(Cc2c[nH]c3ccccc23)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 12.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(1H-indol-3-yl)methyl](4-octylphenyl)amine (0.61 g) and 2,6-diisopropylphenyl isocyanate (0.41 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(1H-indol-3-yl)methyl]-N-(4-octylphenyl)urea (0.12 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][N:16]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)CNc2ccc(C)cc2)cc1OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)CN(C(=O)OCc2ccccc2)c2ccc(C)cc2)cc1OC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
A mixture of N-[2(3,4-dimethoxyphenyl)ethyl]2-(p-toluidino)acetamide (3.6 g) and anhydrous potassium carbonate (2.5 g) was added to anhydrous dimethylformamide (25 ml). The mixture was vigorously stirred under ice cooling and to the solution was dropwise added over 20 minutes an anhydrous chloroform solution (5 ml) containing benzyl chloroformate (2.04 g). The reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with water, dried and the solvent was distilled off. The residue was crystallized by treating with ether to give N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-toluidino)-acetamide (4.3 g), mp 81° to 85° C.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]>CN(C=O)C>[CH:17]([C:14]1[CH:15]=[CH:16][C:9]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])=[C:10]([CH:13]=1)[C:11]#[N:12])=[O:18]
Reactant: CC[C@H](C)O
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1ccc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
(2S)-2-Butanol (0.99 g, 0.013 mol) was dissolved in DMF (50 ml) and the solution cooled to 0° C. To this was added sodium hydride, (60% dispersion in mineral oil, 1.54 g, 0.036 mol) in a portion-wise manner, the mixture was stirred at 0° C. for 10 minutes after complete addition. 2-Fluoro-5-formylbenzonitrile (2.0 g, 0.013 mol) was then added and the reaction mixture allowed to warm to room temperature (slowly within the ice bath) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc (˜25 ml). The mixture was partitioned and the organic fraction extracted with water (˜30 ml), the combined organics were dried by passing through a phase separating cartridge and then evaporated to dryness under reduced pressure to give the crude product. The crude residue was purified on a 40+M Biotage cartridge, eluting with a 20 to 50% mixture of EtOAc in hexane. This gave the title compound (220 mg) as a white solid. MS (ES): C12H13NO2 requires 203; found 204 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].BrC1C=C2C(CCCC2(C)C)=CC=1>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][C:6]2([CH3:14])[CH3:15])=[CH:11][CH:12]=1)[CH3:2]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: CC1(C)CCCc2ccc(Br)cc21
Product: CCc1ccc2c(c1)C(C)(C)CCC2

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 2.1 g (8.8 mmol) of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene was converted into the title compound using 10 ml (93.9 mmol) of trimethylsilyl acetylene, 1.25 g (1.8 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.53 g (2.8 mmol) of cuprous iodide and 10 ml (20.0 mmol) of K2CO3 (2M solution in methanol).
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH:14](I)([CH3:16])[CH3:15].IC1C(C2SC=CC=2)=NN(C(C)C)C=1>CN(C)C=O.CC(OC)(C)C.O>[I:1][C:2]1[CH:6]=[N:5][N:4]([CH:14]([CH3:16])[CH3:15])[C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)I
Reactant: Ic1c[nH]nc1-c1cccs1
Agent: CC(C)n1cc(I)c(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)n1ncc(I)c1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-iodo-3-(2-thienyl)-1H-pyrazole (1.1 mmol) in 3 mL dry N,N-dimethylformamide under argon atmosphere was added sodium hydride (1.3 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at room temperature, then isopropyl iodide (1.7 mmol) was added dropwise. After 2 h at room temperature, water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 350 mg of a mixture of 4-iodo-1-isopropyl-3-(2-thienyl)-1H-pyrazole and 4-iodo-1-isopropyl-5-(2-thienyl)-1H-pyrazole (75:25; 99% yield). The mixture was purified by chromatography on silica gel (cyclohexane:ethyl acetate 100:0 to 0:100) to afford 151 mg 4-iodo-1-isopropyl-3-(2-thienyl)-1H-pyrazole (42% yield) and 42 mg of 4-iodo-1-isopropyl-5-(2-thienyl)-1H-pyrazole (11% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.O.[C:14]([OH:18])(=O)[CH:15]=O.[CH3:19][NH:20][NH2:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:11])=[N:21][N:20]([CH3:19])[C:14](=[O:18])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CNN
Reactant: O=CC(=O)O
Solvent: O
Product: COc1ccc(-c2cc(=O)n(C)nc2C)cc1
Temperature: 135 °C
Yield: 18.2 %

Procedure:
A mixture of 1-(4-methoxyphenyl)propan-2-one (16.4 g, 100 mmol) and glyoxalic acid hydrate (9.20 g, 100 mmol) were heated to 135° C. overnight, then the water was distilled off at 120° C. for 2 h. The residue was taken up in 40 mL of ethanol with stirring as methylhydrazine (10.5 mL, 200 mmol) was added dropwise. The reaction was heated to 85° C. overnight. The solvent was evaporated and the residue was dissolved in 200 mL of methylene chloride and washed with 5% NaHCO3 solution (2×20 mL), saturated NaCl solution, then dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (2% MeOH in CH2Cl2) to give 5-(4-methoxyphenyl)-2,6-dimethyl-2H-pyridazin-3-one (4.2 g) MS m/z 231 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH:24]([C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][CH:27]=1)=O>CO>[N:19]1([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:7]3[N:8]=[C:9]4[NH:10][C:24]([C:26]5[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][CH:27]=5)=[N:3][C:4]4=[CH:5][CH:6]=3)[CH2:12]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc(C=O)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1

Procedure:
(R)-Methyl 6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)picolinate (150 mg) was prepared by a method analogous to the one used for Example 112, but using (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3), methyl 6-formylpicolinate, and methanol as the solvent. MS (ES+) (M+H) 434.67; LCMS retention time 5.39 min (Method H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].O.Cl.[NH2:9][N:10]=[CH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:5]([O:4][C:2]([NH:9][N:10]=[CH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:3])[CH3:6]
Reactant: NN=Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NN=Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl chloroformate (0.44 ml) was added slowly to a suspension of the product of Stage (ii) (0.8 g) and diisopropylethylamine (1.0 ml) in freshly distilled tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 24 h and then reduced to dryness. The residue was chromatographed on silica (D) to give the title compound as an oil (0.4 g). T.l.c. SiO2 : ethyl acetate, Rf. 0.80 (Ceric).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.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:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(-c2ccccc2C(F)(F)F)n1
Yield: 39.9 %

Procedure:
Part A: To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (3.12 g, 15 mmol, J. Chem. Soc 3832 (1954); ibid 677 (1944)) and 2-(trifluoromethyl)phenylboronic acid (3.42 g, 18 mmol) in benzene (50 ml) was added 1M aqueous sodium carbonate (20 ml) and 500 mg of tetrakis(triphenylphosphine)palladium. This mixture was refluxed for 4.5 hours, then was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (10% then 20% ethylacetate in hexanes) afforded 4-Chloro-2-methyl-5-nitro-6-(2-(trifluoromethyl)phenyl)-pyrimidine (1.90 g) as a pale yellow solid. CI Mass Spec. (M+H)+ =318.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])SCCCS1.BrN1C(=[O:24])CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][C:5](=[O:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COCCC(=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of tert-butyl 2-(2-methoxy-ethyl)-[1,3]dithiane-2-carboxylate (1.14 g, 4.09 mmol) in acetone (23 mL) was then added water (1.14 mL), and subsequently the solution was cooled to −15° C., to which N-bromosuccinimide (NBS, 4.37 g, 24.6 mmol) was gradually added. After stirring for 30 minutes and confirming the consumption of the starting materials by TLC, to the solution was added a solution of sodium bicarbonate (1.71 g, 20.35 mmol) in water (9.0 mL), and subsequently, an aqueous solution (8 mL) of 5% sodium thiosulfate. After extraction with dichloromethane, the organic layer was washed with water, and dried over anhydrous sodium sulfate. The organic layer was filtered and the solvent was distilled off. The resulting residue was purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.4) to obtain tert-butyl 4-methoxy-2-oxo-butyrate (550 mg, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])=[N:4][CH:5]=[C:6]([C:8](=[N:10][OH:11])[NH2:9])[CH:7]=1.Br[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=O)=[CH:25][C:24]=1[CH2:33]OC.[CH2:36](Cl)[CH2:37]Cl>CC#N.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[C:33]([C:24]3[CH:23]=[CH:32][C:31]([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][C:36]=4[CH3:37])=[C:26]([CH2:27][O:29][CH3:30])[CH:25]=3)[O:11][N:10]=2)[CH:7]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C(N)=NO)cc1Cl
Reactant: ClCCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: COCc1cc(-c2nc(-c3cnc(N[C@H]4CCC[C@H]4C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cis-methyl 2-(3-chloro-5-(N′-hydroxycarbamimidoyl)pyridin-2-ylamino)cyclopentanecarboxylate (0.172 g; 0.55 mmol) and Intermediate A1 (0.155 g; 0.60 mmol) in MeCN (2 mL) was added EDC (0.117 g; 0.61 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. in the microwave for 30 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (4:1) to afford the title product. 1H NMR (CDCl3, 400 MHz) δ 8.84 (1H, d, J=2 Hz), 8.40 (1H, s), 8.21 (1H, d, J=2), 8.15-8.10 (1H, m), 7.34-7.26 (4H, m), 7.13 (1H, d, J=7.5 Hz), 5.91 (1H, d, J=8.3 Hz), 4.83 (1H, m), 4.22-4.13 (2H, m), 3.63 (3H, s), 3.33 (3H, s), 3.23-3.17 (1H, m), 2.21-1.63 (9H, m).
Reaction SMILES: C1(C[CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)C=CC=CC=1.[CH3:21][S:22]([O:25]S(C)(=O)=O)(=O)=[O:23].[C:30](#N)[CH3:31]>>[C:30]1([CH2:31][N:12]2[CH2:13][CH2:8][N:9]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:22]([CH3:21])(=[O:25])=[O:23])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: CC#N
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Nc1ccc(N2CCNCC2Cc2ccccc2)cc1
Product: CS(=O)(=O)Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a chilled solution of 9150 g (35.5 mmol) of 4-[4-(phenylmethyl-1-piperazinyl]benzenamine in 100 mL of acetonitrile, add 6.49 g (37 mmol) of methanesulfonic anhydride in 50 mL of acetonitrile. Allow the reation mixture to stir at room temperature for 5 h. After this time, filter the resulting precipitate, add 100 mL of saturated aqueous sodium bicarbonate solution and extract this solution with 2×100 mL of methylene chloride. Wash the combined methylene chloride layers with 100 mL of saturated aqueous sodium chloride solution. Remove the solvent in vacuo. Dissolve the residue in 100 mL of methanol and acidify the solution with hydrogen chloride gas to pH=1. The solution is cooled and the resulting solid filtered to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:13]=1[CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:17])=[O:11])(=[O:5])[CH3:4]>O1CCCC1>[C:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:13]=1[CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[O:11])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CNC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 ml of 2N sodium hydroxide solution are added to a solution of 1.50 g (0.004 mol) of ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]glycinate in 15 ml of tetrahydrofuran and the mixture is stirred at room temperature for 1 hour. After acidification with 17 ml of 2N hydrochloric acid, the mixture is extracted with ethyl acetate/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from ethyl acetate/ether yields N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]glycine as white crystals with melting point 88°-89°.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18]O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.CCCCC>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:26])([F:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:10])=[O:11]
Reactant: OCC(F)(F)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CCCCC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Yield: 64.4 %

Procedure:
Add triflic anhydride (1.28 mL, 2.14 g) dropwise to a stirred solution of 2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06 mmol) and 2,6-di-tert-butyl-4-methylpyridine (1.556 g, 7.59 mmol) in anhydrous dichloromethane (25 mL) at −78° C. Stir the reaction overnight while the temperature warms up. Dilute the mixture with pentane and filter the precipitate over Celite®. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (95:5) to provide the title compound (946 mg, 64%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH:19][CH3:20])[S:17][CH:18]=2)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]=[C:23]=[O:24].[OH2:25]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([N:19]([CH3:20])[C:23]([NH:22][CH3:21])=[O:24])[S:17][CH:18]=2)=[O:25])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Reactant: CN=C=O
Reactant: O
Solvent: c1ccncc1
Product: CNC(=O)N(C)c1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1

Procedure:
A 4.0 g sample (0.013 mole) of 4-(5-tert-butyl-1,3,4-thiadiazol-2-ylcarbamoylmethyl)-2-methylaminothiazole was dissolved in 30 ml of pyridine and 1.1 g (0.02 mole) of methyl isocyanate was added. The solution was stirred and heated at 50° for twelve hours. Water was added and the mixture was stirred for two hours at ice-bath temperatures. After most of the oil-like material had crystallized, the product was collected and washed with water. There was obtained 3.2 g of white solid, m.p. 175°-77°. N.M.R. (CDCl3) ∂ 1.5 [C(CH3)3 ], 2.7-2.9 (CH3, doublet), 3.4 (CH3, singlet), 4.1 (CH2), 6.9 (hetero-aromatic).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:23])[N:13]([CH3:22])[C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>O>[C:5]1([NH:8][C:9]([C:11]2[C:12](=[O:23])[N:13]([CH3:22])[C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(=O)c(C(=O)Nc2ccc(N)cc2)c(O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(=O)c(C(=O)Nc2ccccc2)c(O)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2 parts of N-(4-aminophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide, 5 parts of pyridine, and 10 parts of acetic anhydride is left overnight at room temperature. Water is added and the precipitate is filtered off and washed with 2M aqueous hydrochloric acid, water, methanol and ethylether to give N-(4-acetylaminophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1). M.p. 231°-4° C. (The same compound as 1:41.)
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[CH2:17]([NH2:31])[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30].C(N)(N)OOOCCCCCCCCC.[K+].[Br-]>CO.C(N(CC)CC)C.CN(C=O)C>[NH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][CH2:17][NH:31][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: NCCCOCCOCCOCCCN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCCCCCCCCOOOC(N)N
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: NCCCOCCOCCOCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Biotin TFP ester (5 g, 12.8 mmol) was added to a dry flask containing 200 mL anhydrous DMF. In another dry flask containing 28 g (128 mmol) 4,7,10-trioxa-1,13-tridecanediamine, 8, was added 4 mL of triethylamine. Both flasks were cooled to 0-5° C. with ice-water baths. The TFP ester of biotin was added dropwise to the tri-oxatridecanediamine solution over the period of 1 h. The reaction was stirred at room temperature for 30 min and the solvent was removed under vacuum. The resulting oil was triturated in 500 mL ether and was stirred for 30 min. The solid was filtered, then dissolved in methanol:ethyl acetate (4:1), and loaded onto a silica column (2.5 cm×35 cm). The column was eluted with the same solvent mixture. Fractions containing product were collected, and solvent was removed under vacuum. The isolated product was dried under vacuum to yield 4.5 g (79%) of, 9, as a colorless solid, mp 104-106° C. 1H NMR (MeOH, ( ): 1.46 (m, 2H), 1.6-1.8 (m, 9H), 2.2 (t, 2H), 2.7 (d, 1H), 2.75-2.9 (m, 3H), 3.2-3.3 (m, 5H), 3.5-3.6 (m, 14H), 4.3 (m, 1H), 4.5 (m, 1H); IR (KBr, cm-1): 3280, 2910, 2850, 1690, 1640, 1110, 940. Analysis calc. for C20H38N4O5S.H2O: C, 51.70; H, 8.68; N, 12.06. Found: C, 51.95; H, 7.98; N, 11.65.