Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]=2[S:6][C:5]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:22])(=[O:3])[NH2:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[NH:20][C:5]2[S:6][C:7]3[CH2:8][NH:9][CH2:10][CH2:11][C:12]=3[C:4]=2[C:1]([NH2:2])=[O:3])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of compound A3 (16.0 g, 35.5 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (30.0 mL, 392 mmol) dropwise over 5 min at 0° C. After the addition complete, the reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with ethyl acetate (75 mL) to afford compound A4 as an off-white solid (16.5 g, quantitative yield): 1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.24 (s, 1H), 9.17 (bs, 2H), 7.60-7.12 (m, 6H), 4.25 (s, 2H), 3.37-3.34 (m, 2H), 3.01-2.98 (m, 2H). MS (M+H) 351.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[S:13][CH:14]=1)=[O:7].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH:17]([O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:18]2)[S:13][CH:14]=1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (426 mg, 1.72 mmol) (obtained as described in Reference Example 67(2)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.16 ml, 2.07 mmol) and triethylamine (0.29 ml, 2.07 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (20:1) as the eluant to afford 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (481 mg, yield 78%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5]2.[Br-].[Li+].[CH3:22][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[CH:3]=1
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Reactant: C[Mg]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 47 %

Procedure:
Under an atmospheric argon gas flow, trifluoromethane sulfonic acid-6-bromo-2-naphthyl ester in an amount of 32 g (90 mmol), dichloro(diphenylphosphinoferrocene)palladium in an amount of 3.6 g (5% by mol), lithium bromide in an amount of 7.8 g (90 mmol) and desiccated tetrahydrofuran in an amount of 100 milliliter were placed into a three neck flask with cooling pipe and having a capacity of 500 milliliter, and then, the resultant solution was cooled down to −20° C. After slowly dripping methylmagnesiumbromide in an amount of 90 milliliter (90 mmol, 1 mol/liter (tetrahydrofuran)) into the flask, the resultant solution was stirred under heating at the temperature of 80° C. for 4 hours. After the reaction terminated, adding dilute hydrochloric acid in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium bicarbonate solution and sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=90/10), and as a result, 9.4 g of aimed compound (white crystal) was obtained (yield: 47%).
Reaction SMILES: OC(=CC([O-])=O)C.CS(Cl)(=O)=O.[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:48])[N:24]2[C:27](=[C:41](OS(C)(=O)=O)[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCCC1.C(N(CC)CC)C>[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:48])[N:24]2[C:27](=[C:41]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CC(O)=CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 0.42 h

Procedure:
One suspends p-nitrobenzyl α-[3-benzyl-7-oxo-ethylidene)-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylideneacetate (2.265 g) in anhydrous tetrahydrofuran (30 ml), adds dropwise a solution of triethylamine (1.11 g) and methanesulfonyl chloride (630 mg) in tetrahydrofuran (2 ml) at 1° to 20° C., and stirs for 25 minutes. To the produced solution of p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds a solution of morpholine (480 mg) in tetrahydrofuran (2 ml), and stirs for 15 minutes to give a solution of p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1morpholinoethylidene)acetate, cools to -20° C., adds pyridine (396 mg) and a solution of bromine in carbon tetrachloride (1 mole/liter: 5 ml), pours into diluted hydrochloric acid after 15 minutes, and extracts with ethyl acetate. The extract solution is washed with water, dried over magnesium sulfate, and evaporated. Purification of the obtained residue by chromatography over silica gel (50 g), from the fraction eluted with a mixture of benzene containing 10% ethyl acetate gives p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidene)acetate (2.36 g). Yield: 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:14](=[CH:23]\[CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)/[C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1.[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][C:20]1[S:19][C:18]([NH:17][C:15](=[O:16])/[C:14](/[C:4]2[CH:5]=[CH:6][C:7]([N:8]3[C:12]([CH3:13])=[N:11][N:10]=[N:9]3)=[C:2]([Cl:1])[CH:3]=2)=[CH:23]/[CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2ncc(Br)s2)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A suspension of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide (300 mg, 0.69 mmol) and N-bromosuccinimide (123 mg, 0.69 mmol) in carbon tetrachloride (3 mL) at 25° C. was treated with benzoyl peroxide (8.4 mg, 0.035 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). The organic phase was then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3 cycloheptyl-acrylamide (118 mg, 33%) as an amorphous solid: EI-HRMS m/e calcd for C21H22BrClN6OS (M+) 520.0448, found 520.0448.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].N(C(OCC)=O)=NC(OCC)=O.[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1O)=[O:45]>C1COCC1.CN(C=O)C>[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:45]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Triphenyl phosphine (124 mg, 0.47 mmol, 1.5 Eq.) was added to a stirred solution of 1-(2-Chloro-phenyl)-ethanol (74 mg, 0.47 mmol, 1.5 Eq.) in anhydrous THF (5 mL) at 0° C. under nitrogen. The reaction was stirred at this temperature for 30 minutes, then diethyl azodicarboxylate (75 μL, 0.47 mmol, 1.5 Eq.) was added-dropwise and the reaction stirred at 0° C. for a further 1 hour. 3-Hydroxy-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl-ester (100 mg, 0.32 mmol, 1.0 Eq.) in anhydrous DMF (2 mL) was added and the reaction stirred for a further 1 hour at 0° C. then allowed to warm to ambient temperature overnight. The crude reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (88 mg, 0.19 mmol, 73%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.93 (3H, s), 5.84 (1H, q), 6.70 (1 h, br s), 6.74 (1H, s), 7.02 (1H, t), 7.21-7.40 (5H, m), 7.51 (1H, d), 7.63 (1H, d), 8.12 (1H, s).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].O.[NH2:15][NH2:16]>C(OCC)(=O)C>[CH3:12][C:11]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=2)[NH:16][N:15]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A solution of 1-(2-hydroxy-5-nitrophenyl)ethanone (0.54 g, 3 mmol) in anhydrous hydrazine (2 ml) was radiated with microwaves while being stirred at 150° C. for 5 min. Water (0.5 ml) was added at 0° C. to terminate the reaction. The reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. Recrystallization of the residue in dichloromethane produced the title compound (Yield 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH:3]1[F:10].N1C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[CH:3]([F:10])[C:4](=[O:9])[CH:5]=[C:6]([O:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:21]=2[N+:18]([O-:20])=[O:19])[CH2:7]1
Reactant: CC1(C)CC(=O)CC(=O)C1F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])=CC(=O)C1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5,5-Dimethyl-4-fluoro-1,3-cyclohexanedione [0.5 grams (g), 0.0032 mole, prepared according to the teaching of Liebigs Ann. Chem., 679, 9 (1964)] and 0.25 g (0.0032 mole) pyridine were dissolved in 20 milliliters (ml) methylene chloride at room temperature. 2-Nitro-4-trifluoromethylbenzoyl chloride (1.0 g, 0.0039 mole) dissolved in 20 ml methylene chloride was slowly added with cooling. The reaction mixture was stirred at room temperature for 24 hours and then washed two times with water, one time with saturated sodium bicarbonate aqueous solution and one with with water. The aqueous phases were discarded and the organic phase dried with MgSO4 and then evaporated to yield the intermediate enol ester, 5,5-dimethyl-6-fluoro-3-(2-nitro-4-trifluoromethylbenzoyloxy)cyclohex-2-enone. The 5,5-dimethyl-6-fluoro-3-(2-nitro-4-trifluoromethylbenzoyloxy)cyclohex-2-enone was dissolved in 30 ml acetonitrile and triethylamine (0.7 g, 0.007 mole) which was added all at once, followed by acetonecyanohydrin (0.05 g, 0.0006 mole). The solution was stirred for 24 hours. The solvent was evaporated and the residue washed with diethyl ether to yield the product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15]([CH3:23])([CH3:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[S:12][CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)/C=C/C(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Yield: 94.6 %

Procedure:
Methyl (2E)-4-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-4-methylpent-2-enoate (0.85 g, 2.6 mmol), prepared in step 1 of Example 87, was dissolved in ethyl acetate (10 mL) and 10% Pd on carbon (0.25 g, 0.20 mmol) was added. The mixture was shaken in a Parr apparatus under 40 psi of hydrogen for 16 h. The mixture was diluted with ethyl acetate, filtered through the Celite™ reagent and concentrated. Flash chromatography (10% acetone/hexane) afforded methyl 4-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-4-methylpentanoate (0.81 g, 95%) as a white solid. HRMS: calcd for C17H19N3O2S+H+, 330.12707; found (ESI, [M+H]+), 330.1292; Analytical HPLC: purity 100% at 210-370 nm, 11.2 min; 100% at 272 nm, 11.2 min; the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: O[C@@H:2]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][NH:30][CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@H:2]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Reactant: O=C(OCc1ccccc1)[C@@H](O)CC1CCCC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCCC2)C(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Yield: 87.5 %

Procedure:
The title compound was prepared from 100 mg (0.40 mmol) of 2-(S)-hydroxy-3-(cyclopentyl)propanoic acid, benzyl ester (from EXAMPLE 20, Step G) and 154 mg (0.49 mmol) of 3-(R)-(t-butyldimethylsilyloxy-methyl)-4-(S)-(3-fluorophenyl)pyrrolidine (from EXAMPLE 20, Step H) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 189 mg (87%) of the title compound: RF: 0.59 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.0 (s, 6H), 0.84 (s, 9H), 1.05-1.09 (m, 2H), 1.45-1.84 (m, 9H), 2.32 (m, 1H), 2.64 (br t, 1H), 2.74 (br t, 1H), 2.94 (br q, 1H), 3.04-3.15 (m, 2H), 3.37-3.57 (m, 3H), 5.16 (s, 2H), 6.83-6.98 (m, 3H), 7.16-7.39 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[Na].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: CC(c1cccnc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1cccnc1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (4.30 g) with 1H-1,2,4-triazole, sodium salt (3.0 g) in N,N-dimethylformamide (50 ml) according to the method of Example 1(ii), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (1.13 g), m.p. 113°-114° (from ether).
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:13].[K+].[K+].S(=O)(=O)(O)O>O>[F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])[C:3]([OH:13])=[O:4]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)C(F)(F)C(F)C(F)(F)F
Temperature: 100 °C
Yield: 91.8 %

Procedure:
First, 9.1 g (50 mmol) of 2,2,3,4,4,4-hexafluorobutan-1-ol was dissolved in 40 ml of water, to which 14.7 g (50 mmol) of potassium dichromate and 17 ml of concentrated sulfuric acid, and the mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 9.0 g of 2,2,3,4,4,4-hexafluorobutyric acid.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:15])[N:6]=1)[NH2:4].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[C:28]([C:30]([CH3:32])=O)[CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:15][C:7]1[N:6]=[C:5]([NH:3][N:4]=[C:30]([C:28]2[CH:29]=[C:24]([CH3:23])[CH:25]=[CH:26][CH:27]=2)[CH3:32])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: Cc1nc(NN)c2ccccc2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=NNc1nc(C)nc2ccccc12)c1cccc(C)c1

Procedure:
The title compound was prepared from 4-hydrazino-2-methylquinazoline dihydrochloride (250 mg, 1.01 mmol), triethylamine (0.35 mL, 2.02 mmol) and 3-methylacetophenone (0.35 mL, 2.63 mmol) in ethanol (5 mL) by a procedure similar to Example 4, step 4 yielding 11 mg (4%) of a yellow solid. HPLC Purity: 95%.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CCCCC>[C:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][C:20](=[NH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccccc1Sc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCC
Product: N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1
Yield: 69.4 %

Procedure:
Procedure as described for Amidine I using the following amounts and modifications: 10.06 g of 2-phenylthioaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.20 mL of benzonitrile (51.0 mmol). After refluxing overnight, the solution was green-brown. Addition of water yielded a light brown solution with suspended solid. Solution was taken to dryness, resuspended in 75 mL of pentane, filtered, washed with 10 mL of pentane and dried in vacuo yielding 10.56 g (69%) of beige powder. NMR (400 MHz, C6D6): 7.76 (d, 2H), 7.42 (d, 2H), 7.31 (d, 1H), 7.1-6.8 (m, 8 H), 6.78(t, 1H), 4.08 (s, 2H).
Reaction SMILES: CCN(CCCC([NH:11][C:12]1[CH:13]=CN=[C:16]2[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=12)C)CC.CC1N(/N=C/C2OC([N+]([O-])=O)=CC=2)CCS(=O)(=O)C1.C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)[CH2:68][C@H:67](O)[CH2:66][C@@:64]2(O)[O:65][C@H:60]([C@H:61]([C:93](O)=O)[C@@H:62](O)[CH2:63]2)C[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C=CC=CC=CC=CC=CC=CC=C1>>[CH3:93][C@@H:61]([CH2:62][CH2:63][CH2:64][CH2:66][CH2:67][CH3:68])[C:60]([NH:11][C@H:12]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]=1)[CH3:13])=[O:65]
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Reactant: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Agent: CC1CS(=O)(=O)CCN1/N=C/c1ccc([N+](=O)[O-])o1
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Product: CCCCCC[C@H](C)C(=O)N[C@@H](C)c1ccccc1

Procedure:
Bioassays. All bioassays were performed in duplicate, testing at 10, 2, 0.4, 0.08 and 0.016 μg/mL. Malaria bioassays were performed as previously reported by our program, using chloroquine as a positive control (IC50=80-100 nM). Chagas bioassays were performed following the protocol of Buckner et al, and using nifurtimox as a positive control (IC50 3-5 μg/mL). Leishmaniasis bioassays were performed using a method previously employed in our laboratory, based on parasite DNA fluorescence. In this latter assay, amphotericin-B was used as the positive control and had an IC50 value of 80 ng/mL. Cytotoxicity bioassays were performed following an MTT cell proliferation assay protocol with green monkey Vero kidney cells.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15]O)[C:10]=1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][Cl:20])[C:10]=1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCOc1ccnc(CCl)c1C
Yield: 180.7 %

Procedure:
14.5 g (0.061 mol, 1.0 eq.) of 4-heptyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 700 mL of chloroform, and 37.0 g (0.311 mol, 5.1 eq.) of thionyl chloride was added dropwise at 22 to 30° C. Subsequently, the mixture was heated to reflux for 30 minutes and then concentrated, to obtain 28.2 g of 4-heptyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.CNC(C1C2C=CC(O)=CC=2SC=1C)=O>>[OH:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(C)oc2c1
Agent: BrB(Br)Br
Agent: CNC(=O)c1c(C)sc2cc(O)ccc12
Product: Cc1cc2ccc(O)cc2o1
Yield: 75.5 %

Procedure:
This material was prepared from 6-methoxy-2-methylbenzofuran (1.00 g, 6.17 mmole) by treatment with BBr3 in a manner as previously described for 1d to give a colorless oil (690 mg, 75%) which solidified on standing. 1H NMR (DMSO-d6) δ9.32 (1H, s), 7.23 (1H, d, J=8.3 Hz), 6.80 (1H, s), 6.64 (1H, d, J=8.3 Hz), 6.37 (1H, s), 2.35 (3H, s).