Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:9]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C1([O:28][C:29](=O)[NH:30][C:31]2[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[N:32]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>O.C(#N)C>[CH3:38][O:37][C:35]1[CH:34]=[C:33]([O:39][CH3:40])[N:32]=[C:31]([NH:30][C:29](=[O:28])[NH:19][S:18]([C:10]2[CH:9]=[C:8]([NH:7][NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])(=[O:20])=[O:21])[N:36]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(NNC(=O)C(C)C)cc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC(=O)c1ccc(NNC(=O)C(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
0.8 g (2.5 mmol) of methyl 4-(2-isobutyrylhydrazino)-2-sulfamoylbenzoate and 0.77 g (2.8 mmol) of phenyl-N-(4,6-dimethoxypyrimidin-2-yl)carbamate are initially introduced into 25 ml of acetonitrile. 0.83 g (5.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added dropwise at 0° C. and the mixture is stirred at this temperature for 2 hours. It is poured into water and the pH is brought to 2-3 with 2N HCl. The aqueous phase is extracted three times with CH2Cl2. After the CH2Cl2 phase has been washed with 2N HCl and water, it is dried and evaporated. The residue is triturated with diethyl ether. Filtration with suction and drying gives 0.8 g (64% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyl]-4-(2-isobutyrylhydrazino)benzoate of melting point 169°-171° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[S:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CCOP(=O)(CS)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (569 mg, 1.57 mmol), potassium carbonate (303 mg, 2.36 mmol), diethyl sulfhydrylmethylphosphonate (405 mg, 2.20 mmol) and 2-butanone (5 ml) is heated under reflux for 5 hours. The reaction mixture is then filtered, and the filtrate is concentrated to dryness and purified by prep. TLC to give diethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylthiomethylphosphonate. NMR (CDCl3)δ5.87 (m, 4H, OCH2CH3), 6.90 (d, 2H, 14 Hz, SCH2 --P) and 8.63 ppm (t, 6H, OCH2CH3).
Reaction SMILES: [CH3:1][C:2]1[N:6](C2CCCCO2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.Cl>C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccc(CC#N)cc2)c(C(F)(F)F)nn1C1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(CC#N)cc1
Reaction time: 1 h

Procedure:
To {4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl}-acetonitrile (Example 8B) (35 mg, 0.1 mmol, 1.0 equiv) in ethyl acetate (1 ml) was added HCl in ethyl acetate (1 ml) and the mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the title compound was purified by column chromatography (SiO2) eluting with a linear gradient (0→30% ethyl acetate-petrol) 16 mg (60%); LCMS (PS-A) Rt 2.85 min [M+H]+266.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]=[CH:10][C@@H:11]([C@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])O)[OH:14])[OH:12]>[Cl-].[Cl-].[Zn+2]>[CH2:19]1[O:20][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][C@H:15]([C@H:13]([OH:14])[C@@H:11]([OH:12])[CH:10]=[O:9])[C@@H:17]1[OH:18]
Reactant: O=Cc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C[C@H](O)[C@@H](O)[C@H]1OC(c2ccccc2)OC[C@H]1O
Reaction time: 0.5 h

Procedure:
A portion of ZnCl2 (23 kg, 171 mol) was placed into a reactor, taking measures to exclude moisture. Benzaldehyde (70 L, 680 mol) was poured into the reactor, and the mixture was stirred for about 30 minutes using a powerful mechanical stirrer. After initial dissolution of zinc chloride, a thick slurry of a benzaldehyde-ZnCl2 complex forms. Anhydrous D-galactose (30 kg, 164 mol) and more benzaldehyde (60 L, 570 mol) were added to the warm slurry, and the mixture was allowed to react at RT for 24 hours with vigorous stirring. The precipitate was filtered off and washed portionwise with benzaldehyde (10-15 L total) and then with acetone, to give, after air-drying, 6-7 kg of unreacted D-galactose, probably as the monohydrate. The combined filtrate and benzaldehyde washings were diluted with ether (70 L) and petroleum ether (80 L), and the mixture was extracted with ice-cold water (140 L) . The organic layer was washed 3 times with ice water (70 L each time), and the combined aqueous layers were neutralized by rapid addition of a solution of potassium carbonate (38 kg of anhydrous carbonate in approximately 45-50 L of water). The resulting thick suspension of zinc salts was filtered, and the precipitate was washed thoroughly with water until 500-600 L of filtrate were collected. After extraction with chloroform (70 L) and with petroleum ether (70 L), the filtrate, containing 4,6-O-benzylidene-D-galactose (2) and a mixture of KCl and KHCO3, and having a pH of about 8.7, was used directly for the following oxidation.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31][CH3:32])=[O:30])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C(OCC)(=O)C>CO.O1CCCC1.[Pd]>[CH3:32][O:31][C:29]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])[C:26]([CH3:28])([CH3:27])[CH2:25]2)=[O:30]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Yield: 91.4 %

Procedure:
A mixture of methyl 2-(3-(benzyloxycarbonyl)-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (10.2 g, 23.7 mmol, 1.0 eq.), 2.04 g Pd/C in methanol/tetrahydrofuran (V/V=1/1, 102 mL) was treated with H2 at room temperature overnight. Thin layer chromatography (petroleum ether:ethyl acetate=3:1) showed the reaction was complete. The mixture was separated by filtration and the filtrate was concentrated in vacuo to give 7.35 g of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid as a white solid, yield: 91.2%. MS (ESI+APCI) M+1=340.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[CH3:2].[Br:14]Br>CCOCC>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([Br:14])[CH2:7]1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)CC1CCC(=O)CC1
Solvent: CCOCC
Product: CCOC(=O)CC1CCC(=O)C(Br)C1

Procedure:
74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. of anhydrous ether were placed in a 3 l. three-necked flask, provided with a thermometer, nitrogen inlet, dropping funnel, condenser and stirrer. The solution was cooled to -10° by means of a dry ice-acetone bath, and 64.0 g. of bromine was added dropwise over a period of 30-40 minutes. The resulting colorless solution was washed three times with 100 ml. of water, then two times with 125 ml. of cold saturated sodium bicarbonate solution followed by 100 ml. of water. The combined aqueous solutions were extracted twice with 150 ml. of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, and the ether was removed by distillation from a steam bath at atmospheric pressure to give a residue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester, weighing 105 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].N#N>O.O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:31]3[CH2:33][CH2:32]3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)C1CC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc2c(cn1)c(C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
To a flask were added 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3a, 2 g, 3.83 mmol), cyclopropylboronic acid (0.560 g, 6.52 mmol)), potassium carbonate (1.3 g, 9.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (0.157 g, 0.192 mmol), dioxane (10 ml), and water (5 ml). The mixture was Vac/N2 purged 6 times and heated at 60° C. After 5 h, the reaction was treated further with cyclopropylboronic acid (0.560 g, 6.52 mmol)), potassium carbonate (1.3 g, 9.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.157 g, 0.192 mmol), then degassed, and then heated at 80° C. overnight. The mixture was diluted with DCM and water and then filtered through celite. The organic phase was separated and concentrated to afford a dark residue, which was purified on silica gel (40 g, 0-20% ethyl acetate/hexanes) to afford 6-chloro-3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.4 g, 84% yield) as a white foam. MS ESI calc'd. for C28H22Cl1N3[M+1]+ 436, found 436.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][OH:6])[CH3:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH3:7])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20.8 g (0.20 mol) of 2-ethoxypropanol are added slowly during 20 minutes with stirring to a mixture of 43.3 g (0.227 mol) of toluene-p-sulphonylchloride and 20 ml of dry pryridine. The temperature of the reaction mixture is kept at 20° with external cooling. After stirring for 2 hours at 20°, the mixture is poured into ice-water and extracted with ether. The ether layer is washed with 2N sulphuric acid, with water and with saturated sodium hydrogencarbonate solution. After drying over sodium sulphate, filtration and evaporation in vacuo, 2-ethoxypropyl toluene-p-sulphonate is obtained as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O.ClCCl>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc(F)cc2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 140.3 %

Procedure:
Triethylamine (6 mL) and a solution of 4.0 g of 4-methoxybenzoyl chloride (supplied from Tokyo Chemical Industry) in 40 mL of chloroform were added to a solution of 6.0 g of 4-fluorophenol (supplied from Tokyo Chemical Industry) in 60 mL of chloroform, and stirred at 55° C. for one hour. Then 100 mL of dichloromethane, 200 mL of water and 25 mL of an aqueous solution of 1 N sodium hydroxide were added to the reaction solution, and the mixture was separated into two liquid phases. The organic layer was dried on sodium sulfate anhydrate and subsequently concentrated, to yield 8.1 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:9][CH:10]([CH3:26])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12].Cl[CH2:28][CH2:29][C@@H:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.O>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][C:41]=1[O:44][CH3:45])[O:37][C@@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][CH2:28][N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:26])[CH3:9])[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(O[C@H](CCCl)c2ccccc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of potassium carbonate (321 mg, 2.32 mmol), sodium iodide (522 mg, 3.48 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (570 mg, 2.32 mmol) and 4-{[(1R)-3-chloro-1-phenylpropyl]oxy)-1,2-dimethoxybenzene (712 mg, 2.32 mmol) in DMF (5.00 mL) was stirred at 100° C. for 3 h, at which time TLC indicated that the reaction was complete. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Preparatory TLC [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the product (970 mg, 90.1%) as a thick oil.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:36]([O:35][C:5]([CH3:34])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:40])=[O:3])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3cccc(C(F)(F)F)c3)C(=O)N2C)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3cccc(C(F)(F)F)c3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated. The residue is diluted with 1N HCl, extracted with CH2Cl2, dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.51-7.38 (m, 4H), 7.04 (d, 2H, J=8.8 Hz), 6.69 (d, 2H, J=8.8 Hz), 4.46, 4.34 (ABq, 2H, J=14.9 Hz), 3.94 (t, 2H, J=5.7 Hz), 3.68-3.60 (m, 1H), 3.57-3.52 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (t, 1H, J=8.8 Hz), 2.98, 2.92 (ABq, 2H, J=14.4 Hz), 2.83 (s, 3H), 2.25-2.18 (m, 1H), 1.91-1.83 (m, 1H), 1.59-1.52 (m, 2H), 1.45 (s, 3H), 1.39-1.30 (m, 2H), 0.91 (t, 3H, J=7.2 Hz). MS [EI+] 537 (M+H)+, [EI−] 535 (M−H)+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:38])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[C:6]([CH2:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)([CH3:38])[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 157F (1.06 g, 2.00 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.25 (m, 2 H) 0.25 (m, 2 H) 0.46 (m, 2 H) 0.80 (m, 1 H) 1.57 (s, 3 H) 2.15 (m, 1 H) 2.32 (m, 1 H) 6.99 (m, 2 H) 7.44 (d, J=8.82 Hz, 1 H) 7.54 (m, 1 H) 7.77 (d, J=4.04 Hz, 2 H) 8.15 (d, J=7.72 Hz, 1 H) 13.55 (s, 1 H). MS (ESI+) m/z-438 (M+H)+, 455 (M+NH4)+.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)(Cl)[Cl:20]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:20][C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: CCOC(=O)C(C)(Cl)C(=O)OCC
Yield: 98 %

Procedure:
Diethyl methylmalonate (1.74 g, 10 mmol), 1.38 g (10 mmol) of potassium carbonate, 0.12 g of tetra-n-butylammonium bromide, and 5 mL of carbon tetrachloride were mixed at 70° C. for 3 h. Gas chromatographic analysis of the mixture showed complete conversion of the diethyl methylmalonate to give 2.04 g of diethyl α-chloro-α-methylmalonate (98% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:44]=[CH:43][C:9]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]5[CH:31]=[CH:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)=[CH:19][C:14]=4[N:13]=[C:12]3[CH2:32][C:33]3([C:38]([O:40]CC)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:8][CH:7]=2)=[CH:2]1.C1COCC1.[Li+].[OH-]>CO>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]5[CH:31]=[CH:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)=[CH:19][C:14]=4[N:13]=[C:12]3[CH2:32][C:33]3([C:38]([OH:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:43][CH:44]=2)=[CH:2]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccoc3)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccoc3)cc2)CCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 20 mL vial were added ethyl 1-((1-(4-(furan-3-yl)benzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (60 mg, 0.1 mmol), THF (1.3 mL) and MeOH (1.3 mL) followed by LiOH (1.4 mL, 1 M). The reaction mixture was heated at 80° C. for 1.5 h. The mixture was cooled to RT and concentrated to dryness. Water (5 mL) was added and the pH was adjusted to ˜5-6 using 1 M HCl. To the mixture was added DCM (5 mL) and the mixture was stirred for 1 h at RT. The organic layer was separated then concentrated to dryness. The resulting residue was purified using FCC or reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C35H31N3O4, 557.23; m/z found, 558.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=8.5, 1H), 8.10 (d, J=8.5, 1H), 7.84 (d, J=8.1, 1H), 7.77-7.69 (m, 3H), 7.58-7.54 (m, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J=8.1, 2H), 7.35-7.34 (m, 1H), 7.16 (d, J=8.8, 1H), 7.04-7.01 (m, 3H), 6.65 (s, 1H), 5.42 (s, 2H), 5.35 (s, 2H), 3.12 (s, 2H), 2.32-2.26 (m, 2H), 1.73-1.68 (m, 2H), 1.65-1.52 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.C(O)(=O)C.[Br:17]Br.C([O-])(O)=O.[Na+]>O>[Br:17][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: c1ccc(Nc2nccs2)nc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc(Nc2ccccn2)s1
Reaction time: 0.25 h

Procedure:
To a flask containing pyridin-2-yl-thiazol-2-yl-amine (5-2, 3.92 g, 0.0221 mol) was added acetic acid. Bromine (1.14 mL, 0.0221 mol) was then added dropwise to the stirred solution at ambient temperature. The reaction was stirred for 15 min, resulting in an orange-white precipitate. At 15 min, 100 mL H2O were added and solid NaHCO3 introduced, causing a large amount of foaming. The product was obtained as a tan colored precipitate, which was washed with 1.5 L H2O and dried under high vacuum overnight. 1H NMR (DMSO-d6): δ11.53 (bs, 1H), 8.31 (d, 1H, J=3.3 Hz), 7.73 (t, 1H, J=7.6 Hz), 7.45 (s, 1H), 7.05 (d, 1H, J=8.4 Hz), 6.96 (t, 1H, J=5.5 Hz). Mp: 210-212° C. (dec). [M+H]+=255.9.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC.[OH-].[Na+]>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(C)CCCC(C)O
Agent: O=[Cr](=O)([O-])Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)CCCC(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
A mixture of 1.27 g (9.76 mmoles) of 6-methyl-2-heptanol (purchased from Aldrich Chemical Co., Milwaukee, Wis.) and 9.26 g (42.9 mmoles) of pyridinium chlorochromate (purchased from Aldrich Chemical Co., Milwaukee, Wis.) in 35 mL of dichloromethane was stirred at room temperature for 3.5 hours. At that point, the mixture was diluted with 150 mL of ether and 200 mL of 1M aqueous sodium hydroxide. After separating the layers, the organic layer was washed in successive order with 9:1 (volume/volume) 1M aqueous sodium hydroxide: saturated brine (2×100 mL), 10% aqueous sodium chloride (1×100 mL), 3:1 (volume/volume) 2M aqueous hydrochloric acid: saturated brine (3×100 mL), saturated aqueous sodium bicarbonate (1×100 mL), and saturated brine (1×100 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 1.214 g (97% yield) of the named ketone. The identity and purity of this known compound were ascertained by IR and proton NMR analysis.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.Cl.[OH:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:18][OH:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccc(Br)nc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of (6-bromopyridin-3-yl)(phenyl)methanone, 4-b, (5.2 g, 20 mmol) in 100 ml of 95% ethanol was treated with N-hydroxylamine hydrochloride (4.2 g, 60 mmol) and sodium carbonate (6.36 g, 60 mmol). The resulting mixture was heated at reflux for 3 hours, cooled to room temperature, and concentrated under vacuum. The residue was taken into ethyl acetate (100 mL) followed by washing with water and brine (50 mL each). The organic layer was dried over sodium sulfate and concentrated. The resulting solid was recrystallized in ethyl acetate/petroleum ether to provide the product, 4-c, (2.7 g, 50%). 1H NMR (CD3OD, 300 MHz,): δ 8.34 (s, 1H), 7.78 (m, 1H), 7.32 (m, 7H).