Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: BrCCCCCBr
Reactant: COC(=O)[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@]1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 88.5 %

Procedure:
Using the procedure and molar proportions of example 71, (S)-(-)-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was alkylated with 1,5-dibromopentane giving (S)-(-)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester, [α]D25 -35.60° (c2, CHCl3), in 88.5% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:4]=1.C(=O)([O-])O.[Na+].[O-:23][C:24]#[N:25].[K+].[ClH:27].C(=O)([O-])[O-].[K+].[K+]>O>[ClH:27].[ClH:27].[NH2:16][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][NH:1][C:24]([NH2:25])=[O:23])[CH:8]=[CH:7][N:6]=2)[N:10]=1)[NH2:17]
Reactant: N#C[O-]
Reactant: NCc1ccnc(-c2csc(N=C(N)N)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: NC(=O)NCc1ccnc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.09 g) was dissolved in water (10 ml) and the solution was adjusted to pH 4 with aqueous sodium hydrogen carbonate. Potassium cyanate (0.25 g) was added to the solution and the mixture was stirred for one hour at ambient temperature. After the pH was readjusted to 4 with 6N-hydrochloric acid, additional potassium cyanate (0.25 g) was added and the mixture was further stirred for 6 hours. The reaction mixture was made basic with aqueous potassium carbonate and the resulting precipitate was collected by filtration. The crude product was chromatographed on silica gel with use of chloroform-methanol (8:2) as eluent and converted to the dihydrochloride in a usual manner. This salt was recrystallized from an aqueous ethanol to give 2-(diaminomethyleneamino)-4-(4-ureidomethylpyridin-2-yl)thiazole dihydrochloride (0.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:29])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH3:30][CH2:31][CH2:32][CH2:33][N:34]=[C:35]=[O:36]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:29])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][O:28][C:35](=[O:36])[NH:34][CH2:33][CH2:32][CH2:31][CH3:30])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: CCCCN=C=O
Reactant: CN(CC[C@H]1CC[C@H](C(=O)N2CCCN(CCO)CC2)CC1)c1ncc(Br)cn1
Solvent: ClCCl
Product: CCCCNC(=O)OCCN1CCCN(C(=O)[C@H]2CC[C@H](CCN(C)c3ncc(Br)cn3)CC2)CC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 0.10 g (0.21 mmol) of trans-(4-{2-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexyl)-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone in 2 mL of CH2Cl2 was cooled (0° C.) and treated with 0.048 mL (0.43 mmol, 2 eq) of N-butyl isocyanate. After 20 h and 48 h the reaction was again cooled (0° C.) and treated with 0.048 mL (0.43 mmol, 2.0 eq) and 0.024 mL (0.21 mmol, 2.0 eq) of N-butyl isocyanate, respectively. The reaction was evaporated and dissolved in 5 mL of CH2Cl2/0.5 mL of MeOH and stirred for 1.5 h. After evaporation, the reaction was purified by flash-chromatography on 5 g silica gel (CH2Cl2:MeOH 99:1 to 4:1) to give 0.081 g (68%) of pure trans-butyl-carbamic acid 2-[4-(4-{2-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-[1,4]diazepan-1-yl]-ethyl ester, MS: 567 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[O:32]1[C:37]2[CH:38]=[CH:39][C:40]([S:42](Cl)(=[O:44])=[O:43])=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1>>[O:32]1[C:37]2[CH:38]=[CH:39][C:40]([S:42]([N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]3)(=[O:44])=[O:43])=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccc3c(c2)OCCO3)c1-c1ccccc1
Yield: 102.1 %

Procedure:
Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and 2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (352 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 391 mg, about 100%).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][C@@H:10]1[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:8]([CH3:26])[C@@H:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][C@@H:10]1[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: OC[C@H]1Cn2c(cc3cc(Br)ccc32)[C@H]1NCc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
The product of Step 1 (710 mg, 2 mmol) was suspended in 1,2-dichloroethane with formaldehyde (0.4 mL of 37% aqueous solution, 5 mmol). Sodium triacetoxyborohydride (848 mg, 4 mmol) was added to the mixture. The mixture stirred vigorously at room temperature for 30 min. The mixture was washed with aqueous saturated NaHCO3 and run through a plug of silica gel, eluting with EtOAc, to give the product (690 mg, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].FC(S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O)(F)F.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-2-hydroxytoluene (5 g, 33 mmol) in DMF (75 mL) at 0° C. was added 2,2,2-trifluoroethyl trifluoromethylsulfonate (13 g, 62 mmol) and Cs2CO3 (20 g, 62 mmol). The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 2 h. The mixture was diluted with EtOAc (150 mL) and filtered. The filtrate solvents were removed under reduced pressure and the residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered, and the volume was reduced to ~50 mL under reduced pressure, at which point the product had begun to crystallize. The mixture was cooled to -20° C. for 14 h, filtered, and the solids were washed with cold EtOAc. 4-Nitro-2-(2,2,2-trifluoroethoxy)toluene was obtained as a crystalline solid (HPLC retention time=10.0 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH3:23])[C:8]([C@@:10]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:12][C@H:11]2[CH2:13][OH:14])=[O:9])=[CH:4][CH:3]=1>CC(C)=O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH3:23])[C:8]([C@@:10]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:12][C@H:11]2[CH:13]=[O:14])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(F)cc1)C(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1CO
Solvent: CC(C)=O
Product: CN(Cc1ccc(F)cc1)C(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1C=O
Temperature: 25 °C
Yield: 78.2 %

Procedure:
(1S,2R)-1-(3,4-Dichloro-phenyl)-2-hydroxymethyl-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide (4.60 g, 12.0 mmol) is dissolved in acetone (240 ml) and IBX (10.1 g, 36.1 mmol) is added (IBX concentration 0.15M). The mixture is heated to reflux for 2 hours, then cooled to ambient temperature. The solids are filtered off and the filtrate concentrated in vacuo. The crude product is eluted through a short silica gel column with ethyl acetate:heptane (50:50). 3.57 g (78%) of the product is obtained as a highly viscuous light yellow oil. LC/MS (m/z) 380.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([C:25](O)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH2:36]>CCCCCCC.CC(=O)OCC>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH:36][C:25]([C:20]1[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: NCCc1ccccn1
Reactant: O=C(NCc1ccccc1-c1ccccc1C(=O)O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)OCc1ccccc1

Procedure:
From 0.28 mmol of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor 6) and 2-(2-pyridyl)ethylamine, according to ,the general working procedure and subsequent purification by flash chromatography 85 mg of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 140° C. (heptane/EA); MS (ES+): m/e=466 (M+1).
Reaction SMILES: [CH:1]([NH:4][N:5]=[CH:6][C:7]1[C:12](F)=[CH:11][C:10]([F:14])=[CH:9][C:8]=1[F:15])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>C1(C)C=C(C)C=C(C)C=1>[F:15][C:8]1[CH:9]=[C:10]([F:14])[CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][N:4]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)NN=Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: CC(C)n1ncc2c(F)cc(F)cc21
Temperature: 170 °C
Reaction time: 6 h

Procedure:
1 N-Isopropyl-N′-[1-(2,4,6-trifluoro-phenyl)-methylidene]-hydrazine ((xix), 865 mg, 4 mmol) was dissolved in 5 mL mesitylene, K2CO3 (1.65 g, 12.00 mmol) were added and stirred at 170° C. for 6 h. The RM was cooled, filtered, washed with EtOAc and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow oil (tR 6.86 min (conditions 5), MH−=195, 1H-NMR in CDCl3: 7.25 (s, 1H); 6.89 (d, 1H), 6.60 (m, 1H), 4.70 (m, 1H), 1.58 (d, 6H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=1)[CH2:18]Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[C:17]([CH:16]=[C:15]([O:14][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:22]=1)[CH2:18][N:1]=[N+:2]=[N-:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Sodium azide (3.25 g, 50.0 mmol) and DMF (25 mL) were introduced into a 1 L RBF containing 3,5-dinonoxybenzylchloride (10.0 g, 25.0 mmol) and a stir bar. The reaction mixture was then capped with a septum and an out-vent needle. The mixture was heated until warm to touch, allowed to cool to room temperature, then heated again (repeated 4 times). The mixture was then transferred to a separatory funnel and diluted with 500 mL distilled water and washed with ether (4 times using 100 mL). The combined ether layers were washed with ammonium chloride (2 times with 50 mL), then dried with magnesium sulfate and gravity filtered into a 1 L RBF. The solvent was removed under reduced pressure and the trace solvent was removed with a high vacuum. The compound was purified by flash column chormatography (silica gel using 1 L pure hexanes, 1 L 5% ether and hexanes, 1 L 10% ether and hexanes). The product was present in all fractions, the solvent was removed by rotary evaporation and then the trace solvent was removed by a high vacuum. The resulting yellow oil was dissolved in 400 mL ethanol and placed in a freezer overnight. Extreme crystal growth was present in the morning. The mixture was then vacuum filtered and the crystals were collected and air dried while the filtrate was placed in the freezer. Analysis of the crystals indicates they are impurities. As a result, the solvent was removed from the filtrate using rotary evaporation and the trace solvent was then removed using high vacuum. There was a 5.3 g yield or a 51.4% yield of the derivative. The NMR characterization data for this derivative is as follows. 1H NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.93 (t, J=6.6, 4H,), 4.24 (s, 2H,) 6.42 (q, J=2.2, 1H, ArH). 13C (75 MHz, CDCl3): 160.68, 137.45, 106.52, 101.10, 68.19, 55.01, 31.95, 31.02, 29.47, 29.34, 29.31, 26.12, 22.76, 14.20.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl.[F:5][CH:6]([F:15])[C:7](=O)[CH2:8][C:9](OCC)=[O:10]>C(O)C>[F:5][CH:6]([F:15])[C:7]1[CH:8]=[C:9]([OH:10])[N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(F)F)cc1O
Yield: 33.3 %

Procedure:
8.3 g (180.6 mmoles) of methylhydrazine and 5 ml of concentrated hydrochloric acid were added to a solution of 30.0 g (180.6 mmoles) of ethyl difluoroacetoacetate dissolved in 200 ml of ethanol. The mixture was refluxed for 2 days with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was poured into water. The mixture was allowed to have a pH of 4 using citric acid and extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 8.9 g (yield: 33.3) of 3-difluoromethyl-1-methyl-1H-pyrazol-5-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:9]([CH3:24])([CH3:23])[CH:8]2O)=[O:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:9]([CH3:24])([CH3:23])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a stirred mixture solution of 4-hydroxy-2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (3.4 g, 10.2 mmol) and triethylsilane (6.0 mL) at 25° C. was added trifluoroacetic acid (3.0 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.6 g, 50%) as a white solid: LC/MS m/e calcd for C20H23NO3 (M+H)+: 326.41, observed: 326.2.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][C@@H:11]([O:18][C:19]1[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[C:30](=[NH:34])(OC)[CH3:31].C(N(CC)CC)C.Cl>C1COCC1.CO.CCOCC.O>[ClH:27].[Cl:27][C:25]1[C:24]([F:28])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH:26]=1)[O:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][NH:9][C:30](=[NH:34])[CH3:31]
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CN)c1ccccc1
Reactant: COC(C)=N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=N)NCC(Oc1cc(Cl)c(F)cc1C#N)c1ccccc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
The title compound was prepared by treating the product of Example 1 step (c) (0.2 g) in dry THF (10 ml) with methyl acetimidate hydrochloride (75 mg) followed by triethylamine (0.1 ml) and stirring overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was evaporated and the residue purified by chromatography (silica, 2–20% 7M ammonia in methanol/dichloromethane as eluent) to give a glassy solid. The solid was dissolved in methanol (10 ml), treated with 1M HCl in ether (1 ml) then evaporated. The residue was triturated with ether to give the title compound as a cream solid (90 mg). M.p. 133–135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>O1CCCC1>[C:26]([N:19]1[CH2:20][CH2:21][CH:17]([NH:16][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:22]([O-:24])=[O:23])[CH:11]=2)=[O:15])[CH2:18]1)(=[O:28])[CH3:27]
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.15 g, 0.36 mmol) and acetyl chloride (41.0 mg, 0.54 mmol) in tetrahydrofuran (5.0 mL), was added triethylamine (54.2 mg, 0.54 mmol). The resulting reaction mixture was stirred at ambient temperature for 4 hours. After this time, the reaction mixture was quenched with ice water and stirred at room temperature for 20 minutes and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight to afford the title product as an solid (80 mg, 48% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.91 (1H, d), 8.51(1H, m), 3.68 (1H, m), 3.50 (2H, m), 3.23 (2H, m), 2.09 (1H, m), 1.94 (3H, m). MS m/z: 461.17, 363.17 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1COCC1.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>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
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: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)s1
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
5-Bromothiophene-2-carboxaldehyde (1.0 g, 5.2 mmol) is added to a solution of tetrakis(triphenylphosphine)palladium(0) (180 mg, 0.16 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 min. A solution of phenylboronic acid (760 mg, 6.2 mmol) in THF (10 mL) is added followed by aqueous Na2CO3 (2M, 5.2 mL). The mixture is heated at reflux for 24 h. The reaction mixture is allowed to cool, poured into ether, and washed twice with water. The ether layer is dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (1:1 hexanes:CH2Cl2) to yield 5-phenylthiophene-2-carboxaldehyde (900 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.45, 7.65-7.68, 7.73, 9.88.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH2:1]([NH:7][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]2)=[N:16][N:17]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CCCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-hexylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.62 g, yield 48%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.75. (m, 1H), 7.52-7.65 (m, 2H), 7.30-7.36 (m, 1H), 6.98-7.06 (m, 1H), 4.00-4.09 (m, 1H), 3.81-3.91 (m, 1H,), 3.62-3.70 (m, 2H), 3.48-3.55 (m, 2H), 3.29-3.43 (m, 4H), 1.52-1.62 (m, 2H), 1.20-1.40 (m, 6H), 0.80-0.90 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.6, 158.2, 156.0, 134.0, 133.9, 132.4, 129.6, 129.0, 127.0, 126.9, 121.8, 49.5, 49.0, 45.9, 40.7, 39.7, 31.4, 29.4, 26.5, 22.5, 14.0. MS (ES+) m/z 470 (M+1).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:30])[C:25](OCC)=[O:26])[CH:21]=[CH:20][N:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl>[OH:26][CH2:25][CH:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:23]=1)[CH3:30]
Reactant: CCOC(=O)C(C)c1ccnc(NC(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(CO)c1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of DIBAL (1M in DCM, 13.8 mL, 13.8 mmol) was added dropwise over 10 min to a stirred solution of the ester (52) (1.35 g, 4.59 mmol) in THF (25 mL) under nitrogen at −78° C. The reaction mixture was warmed to RT and then re-cooled to −78° C. and a second aliquot of DIBAL (1M in DCM, 4.5 mL, 4.5 mmol) was added. The reaction mixture was allowed to warm to RT, then cooled to 0° C. and water (5 mL) and then MgSO4 were added. The mixture was diluted with DCM and filtered to remove the solids. The filter cake was washed with EtOAc, MeOH and DCM and the combined filtrate and washings were evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 25-50% EtOAc in isohexane, gradient elution) to afford the title compound (53) (0.62 g, 50%): m/z 253 (M+H)+ (ES+).