Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@@H:11](Br)[C@H:10](O)[C:9]=2[CH:18]=1)#[N:4].C[Si](C)(C)[O:21][CH:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27].[OH2:30]>CS(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@@H:11]([OH:30])[C@H:10]([N:24]3[CH2:25][CH2:26][CH:22]([OH:21])[C:23]3=[O:27])[C:9]=2[CH:18]=1)#[N:4]
Reactant: O
Reactant: C[Si](C)(C)OC1CCNC1=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCC(O)C2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Sodium hydride (80% dispersion in oil, 1.6 g) was added to a solution of (±)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-bromo-4-hydroxy-2H-1-benzopyran (14.86 g) in DMSO (100 mL) and the mixture stirred under a dry atmosphere for 45 min when a solution of the 3,4-epoxide resulted. The solution was then cooled to ca 10° C. before 3-trimethylsilyloxy-2-pyrrolidinone (12.86 g) was added along with further DMSO (20 mL) and sodium hydride (2.35 g). The mixture was stirred at room temperature for 22 h after which it was poured into water (600 mL) and extracted with ethyl acetate several times. The combined extracts were washed with water (4×150 mL), brine and dried (Na2SO4). Evaporation gave a crystalline greenish solid (14.4 g) which was triturated with a little ethyl acetate before filtering under suction and washing with a little ethyl acetate followed by 50% ether/ethyl acetate. The crystalline material (7.9 g, 50%) appeared to be a ca 50:50 mixture of the 3'-hydroxy isomers.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1)[CH3:30].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:29][CH3:30])[CH:32]=1)[CH3:28]
Reactant: CCc1cccc(O)c1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(CC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.54 g, 62%).
Reaction SMILES: N1CCCN2CCCCCC=12.[CH3:12][O:13][C:14](=[O:32])[CH:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1>CN(C)C=O.O>[CH3:12][O:13][C:14](=[O:32])[CH2:15][C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH:17]=1
Reactant: COC(=O)C=C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 72 h
Yield: 46.1 %

Procedure:
2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (2.71 mL, 18.2 mmol) was added to a solution of benzyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (5.25 g, 18.2 mmol) in N,N-dimethylformamide (120 mL). After 3 days, the reaction mixture was diluted with water and extracted with ether (4×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→85% dichloromethane/ethyl acetate)] gave the title compound (2.43 g). MS 290.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: COc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (112 mg, 1.19 mmol) was added in one charge to a stirred solution of 5-bromo-2-({[4-(methyloxy)phenyl]methyl}oxy)benzoic acid (may be prepared as described in Description 18; 200 mg, 0.59 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg, 0.71 mmol) and 1-Hydroxybenzotriazole (96 mg, 0.71 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 200 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=[CH:16][C:15](=[N+](C)C)[CH:14]=C1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][S:9]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (3 g; 9.955 mmol) prepared according to the procedure from Winum et al (Organic Letters 2001, 3, 2241) in DCM (24 mL) was treated with pyrrolidine (0.864 mL; 10.453 mmol) and stirred at rt for 24 h. The reaction mixture was chromatographed by FC on silica gel (eluent: CH2Cl2/EtOAc 100:1) to give [N-(tert-butoxycarbonyl)]-pyrrolidine-1-sulfonic acid amide. TLC: Rf (DCM/EtOAc 100:1)=0.40. A solution of [N-(tert-butoxycarbonyl)]-pyrrolidine-1-sulfonic acid amide (57.09 g; 223 mmol) in DCM (450 mL) was treated with TFA (120 mL; 1.56 mol) and stirred at rt for 7 h. The reaction mixture was concentrated in vacuo and the residual oil was triturated with diisopropylether. The resulting powder was washed with diisopropylether and dried under high vacuum to provide Compound 1a. TLC: Rf (DCM/EtOAc 50:1)=0.10.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:11][C@@H:12]2[CH2:20][C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]([CH3:22])([CH3:21])[CH2:13]2)=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Cl:10][C:7]1[N:6]=[C:5]([NH:11][C@@H:12]2[CH2:20][C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]([CH3:21])([CH3:22])[CH2:13]2)[C:4]([C:2]#[N:1])=[CH:9][N:8]=1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C(N)=O)C[C@@H]2CCCN21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of (7R,8aS)—N-(5-aminocarbonyl-2-chloropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (1.3 g) and triethylamine (1.72 mL) in THF (50 mL) was added trifluoroacetic anhydride (1.33 mL) at −78° C. After stifling for 2 h, the reaction was quenched with ice (150 mL). The aqueous solution was extracted with EtOAc (6×150 mL). The organic layers were evaporated under vacuum and the residue was purified by CombiFlash chromatography on silica gel (2N NH3 in MeOH/CH2Cl2=0-20%) to give the desired product (1.1 g, 89%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([NH:9][C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH3:20])[C:12]=2[N:13]=[C:14](Cl)[N:15]=1)([CH3:8])([CH3:7])[CH3:6]>O>[CH2:1]([NH:4][C:14]1[N:15]=[C:10]([NH:9][C:5]([CH3:8])([CH3:7])[CH3:6])[C:11]2[S:19][CH:18]=[C:17]([CH3:20])[C:12]=2[N:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Cc1csc2c(NC(C)(C)C)nc(Cl)nc12
Solvent: O
Product: C=CCNc1nc(NC(C)(C)C)c2scc(C)c2n1
Temperature: 140 °C
Yield: 89.4 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was dissolved 250 mg (1.0 mmol) of 4-t-butylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine, and the resulting solution was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 100 ml of water was added thereto, followed by extraction with ethyl acetate (20 ml×3). The organic layer was washed with 20 ml of water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1/4) to give 247 mg (yield: 91.5%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:15]([F:25])[C:14]=2[F:26])[N:5]=1)(=O)[CH3:2].[CH3:27]OC(OC)N(C)C.[C:35]1([NH:41][NH2:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:26][C:14]1[C:15]([F:25])=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH:17]=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]2[N:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:42]=[CH:27][CH:2]=2)=[N:5]1
Reactant: NNc1ccccc1
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(C)=O)c1=O
Product: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 3-acetyl-1-(2,3-difluoro-4-morpholin-4-ylphenyl)-5-methoxypyridazin-4(1H)-one (200 mg, 0.55 mmol) and N,N-dimethylformamide dimethyl acetal (2.0 mL) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (2.0 mL) and phenylhydrazine (0.11 mL, 1.1 mmol) was added. This mixture was stirred at room temperature for 1 h, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/MeOH (1/0 to 10/1) and recrystallized from iPr2O/AcOEt to give the title compound (141 mg, 55% yield) as a yellow solid: mp 182-183° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 2.98-3.22 (4H, m), 3.62-3.87 (7H, m), 6.78-6.92 (2H, m), 6.95 (1H, d, J=1.9 Hz), 7.21-7.54 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.48 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 466 [M+H]+. Anal. Calcd for C24H21F2N5O3: C, 61.93; H, 4.55; N, 15.05. Found: C, 61.90; H, 4.58; N, 14.87.
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[O:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[CH:5]([N:4]([CH2:8][C:9]1[O:13][C:12]([C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[O:16])=[CH:11][CH:10]=1)[CH:1]([CH3:2])[CH3:3])([CH3:6])[CH3:7]
Reactant: CCOC(=O)c1ccc(CN(C(C)C)C(C)C)o1
Reactant: NCCN
Product: CC(C)N(Cc1ccc(C(=O)NCCN)o1)C(C)C

Procedure:
Using Compound f and anhydrous ethylenediamine, the corresponding procedure of Example 1 was followed to give 5-(diisopropylaminomethyl)-N-(2-aminoethyl)-2-furancarboxamide as tan-colored oil. Reduction of this compound in the same manner as Example 1 without prior purification gave 5-(diisopropylaminomethyl)-N-(2-aminoethyl)furfurylamine (Compound g) as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[NH:27]1[C:31]2=[CH:32][NH:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]2[CH:29]=[CH:28]1>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:32][C:31]=12
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1=CN2Cc3ccccc3NC=C2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After stirring for 3 minutes, 5 mmol of 10, 1-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na2 SO4 and the volatiles concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(Br)s1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)s1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-5-(trifluoromethyl)thiophene.
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18].[Br:19]N1C(=O)CCC1=O>O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([Br:19])[CH:15]=[CH:14][C:13]1=[O:18]
Reactant: O=c1ccccn1-c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
Under ice-cooling, 15 ml of a dimethylformamide solution containing 1.50 g of 1-(2-pyridyl)-1,2-dihydropyridin-2-one was incorporated with 1.60 g of N-bromosuccinic acid imide. The mixture was stirred at room temperature for 2 hours, and then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:3), to give 1.13 g of the title compound as a pale brown powder.
Reaction SMILES: [C:1]1([CH:7](C)[C:8](O)=[O:9])C=CC=CC=1.O=S(Cl)Cl.[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCOC(C)=O>[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]([C:29]1[CH:28]=[CH:27][CH:32]=[CH:31][CH:30]=1)[C:8](=[O:9])[CH2:7][CH3:1]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CCCCCC
Reactant: COC(=O)c1ccccc1N
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(=O)N(c1ccccc1)c1ccccc1C(=O)OC
Yield: 95 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-phenyl-propionic acid (2.00 g, 13.3 mmol), SOCl2 (2.88 mL, 40.0 mmol) and 2-amino benzoic acid methyl ester (1.40 g, 9.31 mmol). After normal workup, the pure objective compound (2.50 g, 95%) was obtained as a pale yellow syrup by a flash column chromatography (n-hexane:EtOAc=20:1): 1H NMR (200 MHz, CDCl3) 51.60 (d, J=6.92 Hz, 3H, COCHCH3), 3.72-3.87 (m, 4H, OCH3, CH), 7.07 (td, J=6.10 Hz, 1.22 Hz, 1H, ArH), 7.23-7.55 (m, 6H, ArH), 7.95 (dd, J=7.73 Hz, 1.63 Hz, 1H, ArH), 8.69 (dd, J=8.55 Hz, 1.22 Hz, 1H, ArH).
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:10]([NH:12][C@H:13]([C:23]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:41][C@H:42]([C:47]([CH2:49][Cl:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45].Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:2]([C:10]([NH:12][C@H:13]([C:23]([NH:25][C@H:26]([C:28]([NH:41][C@H:42]([C:47]([CH2:49][Cl:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:29])[CH3:27])=[O:24])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)CCl
Reactant: C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl

Procedure:
Z-Phe-Ser(Bzl)-Ala-LeuCH2Cl was prepared by coupling Z-Phe-Ser(Bzl)-Ala-OH (1.37 g, 2.5 mmoles) to H-LeuCH2Cl.HCl by a mixed anhydride coupling procedure substantially analogous to that used for the preparation of Z-Phe-Gly-Leu-LeuCH2Cl in Procedure E. Product was obtained as a crystalline solid, 0.98 g (mp 167°-168°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[ClH:1].[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Solvent: CC(C)O
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(C)n1
Product: Cl

Procedure:
9.3 Grams (0.05 mol) of 4-chloro-2,6-dimethyl-3-nitropyridine and 10.7 g (0.1 mol) of benzylamine are heated for 5 hours at boiling point in 20 ml of isopropanol. After cooling, the mixture is concentrated, dissolved in water and extracted with chloroform. The chloroform phase is dried with sodium sulfate and concentrated. The residue is converted with ethanolic hydrochloric acid into the hydrochloride and recrystallized from isopropanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:40])[C:9]1[S:10][C:11]([S:38][CH3:39])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[CH:25][C:24]=3[CH3:37])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH3:39][S:38][C:11]1[S:10][C:9]([C:8]([NH2:40])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]([F:35])([F:34])[F:36])(=[O:31])=[O:32])=[CH:25][C:24]=2[CH3:37])[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(NS(=O)(=O)C(F)(F)F)cc2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccc(NS(=O)(=O)C(F)(F)F)cc2C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
A mixture of {imino-[5-methylsulfanyl-4-(2′-methyl-4′-trifluoromethanesulfonylamino-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (9 mg, 14 μmol) in TFA/DCM (1:1, 3 mL) was stirred at ambient temperature for 40 min. The mixture was concentrated, and flashed chromatographed on silica gel column, eluting with MeOH/DCM (5 to 8%) to give the title compound (5 mg, 54% yield) as a pale yellow solid. 1H NMR (CDCl3): δ 8.32 (s, 1H), 8.04–8.01 (m, 1H), 7.96–7.95 (m, 1H), 7.68–7.66 (m, 2H), 7.17 (m, 3H), 2.72 (s, 3H), 2.21 (s, 3H), ESI-MS (m/z): Cald. For C20H19F3N3O4S4: 550.0 (M+H); found: 550.0.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[K+].[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl>COCCOC.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: N#Cc1ccccc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CSC(=C(N)c1ccccc1)S(C)=O
Temperature: 25 °C
Yield: 69 %

Procedure:
1.753 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of 1,2-dimethoxyethane, and to the solution 580 mg of potassium hydride was added under cooling with ice, and the system was stirred for one and half hours at room temperature. Upon addition of 1.460 g of benzonitrile and subsequent stirring for 15 hours at room temperature and for one hour at 50°C., the system was added with 70 ml of methylene chloride and 2 ml of water, followed by stirring for one hour at room temperature. The mixture was dried with Glauber's salt, and filtrated. The filtrate was concentrated under reduced pressure and the resulting yellow solid was crystallized from methylene chloride-carbon tetrachloride-cyclohexane to obtain 2.208 g of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene. The isolation yield was 69%.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH2:32][CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35].N.FC(F)(F)C1CO1>CCCCO.CS(C)=O>[F:35][C:34]([F:37])([F:36])[CH:33]([OH:38])[CH2:32][NH:31][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: NCC(O)C(F)(F)F
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Agent: FC(F)(F)C1CO1
Agent: N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(NCC(O)C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (300 mg, 1.05 mmol) in n-BuOH/DMSO (5 ml, 4:1) at room temperature under an argon atmosphere was added DIEA (1.4 ml, 10 eq, 8 mmol) followed by 3-amino-1,1,1-trifluoropropan-2-ol (1 g, 7.8 mmol) [prepared from the reaction of ammonia with 2-(trifluoromethyl)oxirane]. The flask was fitted with a condenser and the reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 ml) and water (50 ml), the aqueous phase was extracted with more EtOAc (2×25 ml), and the combined organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient flash column chromatography on silica gel eluted with CHCl3:MeOH (100:0→95:5), to afford the title compound as a colorless oil (62 mg, 15%). δH (CDCl3, 500 MHz) 1.53 (6 H, d, J 7.5, CH[CH3]2), 3.64-3.6 (1 H, m, NHCHHCOH[CF3][CH3), 3.76-3.73 (1 H, m, NHCHHCOH[CF3][CH3), 4.18-4.16 (1 H, m, CHMe2), 4.62-4.56 (1 H, m, CHOHCF3), 4.72 (3 H, s, br, NHCH2Ar and NHCH2Ar), 7.22-7.2 (1 H, m, ArH), 7.52 (1 H, s, ArH), 7.66 (1 H, d, J 10, ArH), 8.47 (1 H, d, J 5, ArH), 8.58 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.77 (C), 154.68 (C), 149.04 (CH), 148.45 (CH), 135.44 (CH), 135.03 (CH), 134.44 (C), 125.91 (C), 123.49 (CH), 114.78 (C), 71.57 (CH), 46.76 (CH), 42.94 (CH2), 32.2 (CH2), 22.47 (2×CH3) 19FNMR δ −78.48; m/z 396.2 (M+H)