Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][NH:13][S:14]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[CH:23][S:22][C:21]=12)(=[O:16])=[O:15].[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C(OCC)(=O)C>[CH3:12][NH:13][S:14]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[C:23]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=12)(=[O:15])=[O:16]
Reactant: CNS(=O)(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)NC)c2s1
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (1.6 ml ) was added to a solution of 0.26 g of 7-(N-methylsulfamoyl)imidazo[5,1-b]thiazole in 8 ml of dry THF and 4 ml of HMPA in an argon atmosphere at −50° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.34 ml) was added thereto. The mixture was stirred for 30 min. A 1.6 N n-butyllithium/n-hexane solution (0.8 ml) was further added thereto. The mixture was stirred for 30 min. Tri-n-butylstannyl chloride (0.2 ml) was added thereto, followed by stirring at the same temperature for 30 min. A saturated aqueous ammonium chloride solution was added thereto. Ethyl acetate was then added, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.39 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:37])[C:23]4[NH:24][C:25](=[N:28]C(OC(CC)(C)C)=O)[S:26][CH:27]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1>C(O)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)N=c1[nH]c(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=CO
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (2.30 g.) in 98% formic acid (25 ml.) was stirred for 2.5 hours at room temperature. After the reaction, formic acid was distilled off under reduced pressure. The residue was pulverized in acetonitrile (25 ml.), collected by filtration, washed with a small amount of acetonitrile and then dissolved in 5% sodium bicarbonate aqueous solution (14 ml.). The solution was adjusted to pH 6 with acetic acid and subjected to alumina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluate containing the object compound (300 ml.) was adjusted to pH 3 with 10% hydrochloric acid and then washed twice with ethyl acetate (50 ml.). The aqueous layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm & Haas Co.), and the column was washed with water and then eluted with 20% methanol aqueous solution (100 ml.), 50% methanol aqueous solution (100 ml.) and 70% methanol aqueous solution (400 ml.) in turn. The eluates containing the object compound (500 ml.) were collected and then methanol was distilled off at 30° to 35° C. under reduced pressure. The remaining aqueous solution was lyophilized to give pale yellow powder of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.60 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[C:23]2[NH:22][C:21]3[C:16](=[CH:17][C:18]([O:24]C)=[CH:19][CH:20]=3)[C:15]=2[CH2:14][CH:13]([CH3:26])[NH:12]1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[C:23]2[NH:22][C:21]3[C:16](=[CH:17][C:18]([OH:24])=[CH:19][CH:20]=3)[C:15]=2[CH2:14][CH:13]([CH3:26])[NH:12]1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(C)NC31C(=O)Nc2ccc(Cl)cc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC1Cc2c([nH]c3ccc(O)cc23)C2(N1)C(=O)Nc1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 64 (157 mg, 0.428 mmol) in 12 mL DCM was added boron trichloride (1M in dichloromethane) (2.14 mL, 2.14 mmol) cautiously in an ice bath. Additional aliquots of boron trichloride were added after the three, six and eight hours. After the last addition, the reaction was left to stir at room temperature for 18 hours. Upon completion, the reaction was quenched with sat NaHCO3. The mixture was washed with dichloromethane, followed by EtOAc. The organic layers were combined then dried with sodium sulfate, filtered and concentrated in vacuo. The product was isolated by flash column chromatography with the gradient 1-3% MeOH in dichloromethane to provide 65 (100 mg, 66).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([NH2:10])[CH2:12][CH2:13]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN1CCC(N)CC1
Temperature: 23 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of [1-(3-tert-butoxycarbonylamino-propyl)-piperidin-4-yl]-carbamic acid benzyl ester (16.9 g, 43.2 mmol, 1 equiv) in ethanol (200 mL) at 23° C. was added palladium on carbon (2.25 g, 10 wt. %, wet, Degussa type). The reaction vessel was placed under an atmosphere of hydrogen (balloon) and stirred for 14 h. At this time tlc analysis indicated the reaction was incomplete, the mixture was filtered through a pad of Celite, washing with ethanol (100 mL). The resulting solution was treated with fresh palladium catalyst (2.25 g), then placed under an atmosphere of hydrogen (balloon) at 50° C. After 7 h tlc analysis indicates complete consumption of the starting material. The reaction mixture was cooled to 23° C., and then filtered through Celite, washing with ethanol (200 mL). The filtrate was concentrated to give 11.1 g (43.2 mmol, 100%) of the desired compound.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10](OC)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[OH-].[Na+]>ClCCl>[CH:2]1([N:8]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCCC1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1=NN(C2CCCCC2)C(=O)C1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture solution of 39.88 g (0.265 mol) of cyclohexylhydrazine HCl salt in 28.57 mL (0.265 mol) of methyl acetoacetate was heated for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, dichloromethane was added to this mixture and the mixture was neutralized by 2N—NaOH aqueous solution. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was treated with hexane to give crystalline and the crystalline was collected by filtration to give 33.84 g (71%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[CH2:12][S:11][C:10]([NH2:18])=[N:9]2.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[Br:31]N1C(=O)CCC1=O>O.[OH-].[Na+]>[Br:31][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:8]23[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]2[CH2:12][S:11][C:10]([NH2:18])=[N:9]3)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1OC[C@]2(c3ccccc3F)N=C(N)SC[C@H]12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H]1OC[C@]2(c3cc(Br)ccc3F)N=C(N)SC[C@H]12
Temperature: 57.5 °C
Reaction time: 0.5 h

Procedure:
(4aS,5R,7aS)-7a-(2-Fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine* (1.0 g, 3.75 mmol) was dissolved in trifluoroacetic acid (3.5 mL, 45.4 mmol). Sulfuric acid (1.2 mL, 22 mmol) was carefully added dropwise, keeping temperature below 30° C. N-Bromosuccinimide (0.74 g, 4.13 mmol) was added portionwise and the reaction was warmed to 55-60° C. After 30 minutes, the reaction was cooled to room temperature and added dropwise to a cooled solution of sodium hydroxide (3.00 g, 75.1 mmol) in water (25 mL). The solution of reaction mixture in sodium hydroxide solution was extracted with EtOAc (×2), checking the pH to ensure the TFA/H2SO4 had all been neutralised. The organic layer was washed with brine and concentrated to leave a brown solid. The solid was recrystalised from IPA (10 mL): heating to 50° C. for 15 minutes on the rotavap under slight vacuum. The suspension was cooled to room temperature, filtered and washed with IPA (2 mL) and heptane (10 mL). The solid was dried overnight to give the title compound (1.30 g). 1H NMR (400 MHz, CDCl3) δ ppm: 7.55 (dd, J=7.2, 2.7 Hz, 1H), 7.36 (ddd, J=8.7, 4.2, 2.5 Hz, 1H), 6.94 (dd, J=11.6, 8.6 Hz, 1H), 4.55 (dd, J=8.8, 1.3 Hz, 1H), 4.35 (q, J=1.0 Hz, 1H), 3.77 (dd, J=8.8, 2.3 Hz, 1H), 3.07 (dd, J=13.4, 3.5 Hz, 1H), 2.71 (dd, J=13.3, 3.9 Hz, 1H), 2.44-2.53 (m, 1H), 1.37 (d, J=6.1 Hz, 3H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[NH:24][N:25]=[CH:26][C:19]=12.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:8]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H]1CC[C@H](OCCc2ccccc2)CC1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CCOC2CCC(Nc3ncnc4[nH]ncc34)CC2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
A mixture of 219 mg of trans-4-(2-phenyl-ethoxy)-cyclohexylamine, 154 mg of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (R. K. Robins, J. Amer. Chem. Soc., 78, 784-790 (1956)), 10 mL of 2-propanol and 0.174 mL of N,N-diisopropyl-ethylamine was heated to 80° C. for 12 hours. The mixture was cooled and concentrated under reduced pressure and purified by either preparative TLC eluting with 50:50:5 THF:diethyl ether:NH4OH or preparative reverse phase chromatography on delta Pak C (C-18 column) eluting with a gradient of 90:10 to 0:100 of 0.1% TFA in H2O: CH3CN gave 60-92% of (4-phenethyloxy-cyclohexyl)-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine as a white crystalline solid. MS (m+1)=338.32; 1H NMR (400 MHz, CDCl3) 8.43 (s, 1H), 7.92 (s, 1H), 7.3-7.2 (m, 5H), 3.7 (t, 2H), 3.3 (m, 1H), 2.9 (t, 2H), 2.22 (d, 2H), 2.1 (d, 2H), 1.7 (m, 1H), 1.5 (dd, 2H), 1.4 (m, 2H).
Reaction SMILES: C[Si](C[Li])(C)C.[Cl:7][C:8]1[C:9]([O:26][CH2:27][O:28][CH3:29])=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][O:21][CH3:22])=O.[CH3:30]C(C)([O-])C.[K+]>CCCCC.O1CCCC1.CCOCC>[Cl:7][C:8]1[C:9]([O:26][CH2:27][O:28][CH3:29])=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][O:21][CH3:22])=[CH2:30])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[O-]
Reactant: COCOc1ccccc1C(=O)c1cccc(Cl)c1OCOC
Agent: [K+]
Agent: [Li]C[Si](C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(c1ccccc1OCOC)c1cccc(Cl)c1OCOC
Reaction time: 0.67 h
Yield: 230.5 %

Procedure:
A 1.0M solution of trimethylsilylmethyl lithium in pentane (160 ml) was added with stirring to a solution of 50.5 g of 3-chloro-2-methoxymethoxy-2'-methoxymethoxybenzophenone in 500 ml of tetrahydrofuran over a 45 min period. There was a mild exotherm. Analysis by gas-liquid chromatography indicated the reaction was incomplete so another 10 ml of the trimethylsilylmethyl lithium solution was added. After a 20 min reaction period 7.3 g of potassium t-butoxide were added and the reaction was heated to reflux with a heating mantle and held there for 40 min. The mixture was then allowed to cool and was diluted with 1 l of ether. The ethereal solution was extracted with 6-300 ml portions of water and 200 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 50.2 g of the title compound as a pale orange oil. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(O)CCC.C(N(CC)CC)C>ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][C:12]1[N:11]=[C:10]2[NH:9][N:8]=[C:16]([NH2:17])[C:15]2=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NNc1nc(Oc2ccc(F)cc2F)ncc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCO
Product: Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 25 °C
Yield: 59.8 %

Procedure:
N′-[5-Cyano-2-(2,4-difluoro-phenoxy)-pyrimidin-4-yl]-hydrazinecarboxylic acid tert-butyl ester (3.35 g, 9.22 mmol) was dissolved in 60 mL of dichloromethane, and 30 mL of trifluoroacetic acid was added. The reaction mixture was stirred for two and a half hours at room temperature, then concentrated under reduced pressure. 1-Butanol (90 mL) and triethylamine (6.4 mL, 46 mmol) was added to the residue, and the reaction mixture was heated to reflux with stirring for 17 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was taken up in 300 mL and insoluble yellow solid was isolated by filtration, washing with 100 mL of dichloromethane and in vacuo, to give 1.45 g of 6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-ylamine, MS(M+H)=264.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[C:3]([NH:9][S:18]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=2[Cl:10])(=[O:20])=[O:19])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cnc(N)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1

Procedure:
Prepared by the method of Example 1 using 3-bromo-5-methyl-2-pyrazinamine (0.84 g) and 2,3-dichlorobenzenesulphonyl chloride (1.1 g). Yield 0.92 g.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([OH:2])=[O:11])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1ccccc1N
Product: COc1ccc(CNc2ccccc2C(=O)O)cc1

Procedure:
Prepared by a similar procedure as described for preparation 1J, starting from anthranilic acid methyl ester and 4-methoxybenzaldehyde. 13C-NMR (DMSO-d6) δ 169.9, 158.2, 150.6, 134.2, 131.6, 131.0, 128.3, 114.3, 113.9, 111.6, 110.2, 54.9, 45.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[I:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[I:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(I)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc(I)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-iodoaniline to yield 2-[(3-iodophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:48][CH2:49][CH2:50][CH3:51]>CN(C=O)C>[CH2:48]([N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:49][CH2:50][CH3:51]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCCCI
Solvent: CN(C)C=O
Product: CCCCN(CCCN(CCCCCCCCN(CCCN(CCCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
Combine 3.5 gm (0.0053 mol) of the product of Step C of Example 1, 2.7 gm (0.024 mol) of KtBuO, 2.57 ml (0.024 mol) of 1-iodobutane in 10 ml of DMF and allow the mixture to stir for 18 hours. Evaporate the volatiles (0.5 mm at 45° C.), dissolve the residue in 500 ml of EtOAc, water-wash (2× with 100 ml) the organic layer and dry the organic layer over MgSO4. Evaporate off the solvents and subject the residue to flash chromatography (silica gel eluted with 20% EtOAc/hexane to yield 1.32 gm of the title compound. Rf is 0.36 (silica gel plates eluted with 20% EtOAc/hexane).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH3:27])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:29][C:2]([F:1])([F:28])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH3:27])=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1

Procedure:
(2S)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (300 MHz, MeOH) δ 7.72 (d, J=7.3 Hz, 2H), 7.62-7.50 (m, 3H), 7.35 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 3.51 (d, J=11.6 Hz, 1H), 3.34-3.26 (m, 3H), 3.15-3.01 (m, 1H), 2.69 (d, J=11.4 Hz, 1H), 2.53 (t, J=8.9 Hz, 1H), 1.57 (s, 3H), 0.98 (d, J=6.4 Hz, 3H). m/z (ESI, +ve ion) 429.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.12 μM; GK-GKRP EC50 (LC MS/MS)=4.01 μM
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15](=[O:20])[NH:16][CH:17]2[CH2:19][CH2:18]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[NH:7][C:6]=2[CH:14]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:15](=[O:20])[NH:16][CH:17]2[CH2:18][CH2:19]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[NH:7][C:6]=2[CH:14]=1
Reactant: COC(=O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Reaction time: 14 h
Yield: 84.4 %

Procedure:
To a solution of methyl 6-chloro-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylate (2.1 g, 7.2 mmol) in tetrahydrofuran (50 ml) was added dropwise, at 0° C., a solution of lithium hydroxide monohydrate (0.6 g, 14.3 mmol) in water (25 ml). The reaction mixture was stirred at this temperature for 14 h. After removing the tetrahydrofuran under reduced pressure, the aqueous solution was acidified with hydrochloric acid (2 M). The precipitated solid was filtered off with suction. 1.7 g (81% of theory) of 6-chloro-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylic acid were obtained.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[NH:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7]1.[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[N:21]([CH3:35])[C:20]2=[O:36].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[CH3:35][N:21]1[C:20](=[O:36])[C:19]2[C:24](=[C:15]([NH:14][C:11]([CH:9]3[CH2:8][CH2:7][C:6](=[O:5])[NH:10]3)=[O:13])[CH:16]=[CH:17][CH:18]=2)[N:23]=[C:22]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc2c1=O
Reactant: O=C1CCC(C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(NC(=O)C3CCC(=O)N3)cccc2c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionylchloride (83 mg, 0.7 mmol) was added to a solution of 5-oxopyrrolidine-2-carboxylic acid 19 (65 mg, 0.5 mmol) in THF (5 mL) at 0° C. DMF (1 drop) was added and the solution was allowed to warm to room temperature for 3 h then cooled to 0° C. A solution of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 5 (65 mg, 0.2 mmol) and triethylamine (145 mg, 1.44 mmol) in THF (1 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was concentrated to dryness and the crude residue was purified by preparative TLC to give Compound 339. MS (ESI) calcd for C21H17F3N4O3: 430.1. found: 431 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ClN1C(=O)CCC1=O.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:31][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([C:32]([F:33])([F:35])[F:34])[O:8][N:7]=2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(C=NO)ccc1Br
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 35 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
In a solution of 1.27 g of 4-bromo-3-nitrobenzaldoxime in 16 ml of N,N-dimethylformamide, 0.74 g of N-chlorosuccinic acid imide was added, and stirred at 35° C. for 90 minutes. Then, the reaction mixture was cooled with ice, 1.20 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.60 g of triethylamine were added, continued to stir at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was poured in 50 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:2 to 1:4 gradient), and 1.10 g of the aimed product was obtained as yellow crystal.