Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][C:3]([F:13])([F:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O-:5].[CH2:14]([O:16][C:17](=[O:22])[CH:18](Br)[CH2:19][CH3:20])[CH3:15]>CN(C)C=O>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([O:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([F:12])([F:13])[F:2])[CH2:19][CH3:20])[CH3:15]
Reactant: CCOC(=O)C(Br)CC
Reactant: [O-]C(c1ccccc1)C(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)OC(c1ccccc1)C(F)(F)F
Reaction time: 96 h

Procedure:
10.3 g of the sodium-2,2,2-trifluoro-1-phenylethanolate, obtained according to the process of Step A, are transferred into a three-neck flask with 50 ml dimethylformamide. After complete mixing, there is slowly added while cooling with an ice-bath a cooled mixture of 9.4 g ethyl-2-bromobutyrate and 35 ml dimethylformamide. The reaction is strongly exothermic and external cooling is applied so that the temperature of the reaction mixture does not go over 20°. The stirring and the cooling of the mixture are kept for four days.
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1N2CN3CN(C2)CN1C3.C(O)(=[O:26])C.Cl>C(Cl)(Cl)(Cl)Cl.O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:26]
Reactant: CC(=O)O
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cccc(OC=C(Cl)Cl)c1

Procedure:
3(2,2-Dichlorovinyloxy)benzyl bromide (2.5 g) was carefully added to a stirred solution of hexamethylene tetramine (2.1 g) in carbon tetrachloride (20 ml) at the ambient temperature. After 5 minutes the precipitate was collected by filtration and washed with acetone. The solid thus obtained was added to aqueous acetic acid solution (50% by weight, 16 ml) and the mixture refluxed for 1 hour. A mixture of water (16 ml) and concentrated hydrochloric acid (4.5 ml) was then added and the mixture refluxed for a further 15 minutes. After cooling the mixture was extracted with chloroform, the extracts washed with water (twice), dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure to yield a residue of substantially pure 3(2,2-dichlorovinyloxy)benzaldehyde, identification of which was confirmed by infra-red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[CH3:22].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[CH3:22])[NH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]2=[O:19]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(C)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2cc(C)c(OC)cc2c1=O
Temperature: 220 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Diethyl 2-[(4-methoxy-3-methyl-phenylamino)-methylene]-malonate (73.9 g) was dissolved in diphenyl ether (200 ml) to prepare a solution which was then stirred at 220° C. for 2 hr. The reaction solution was cooled to room temperature, hexane was then added to the reaction solution, and the precipitated crystal was collected by filtration to give ethyl 6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (25.5 g, yield 35%).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:26]([O-])([OH:28])=[O:27].[N+]([O-])([O-])=O.[Na+].O>C(O)(=O)C>[C:7]1([C:6]2[C:5]3[CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:4]=3[O:3][C:2]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12
Reactant: O=[N+]([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
A solution of 6 g. (0.018 mole) of the product of step E in hot acetic acid is treated with 6 ml. of 70 percent nitric acid while the solution is maintained at about 80° C. Sodium nitrate (2.7 g., 2 equivalents) is added gradually, and the mixture is heated on a steam bath for 45 minutes. The mixture is then poured into 500 ml. of water. The solid is filtered, recrystallized twice from acetone, then from an ethyl acetate-hexane mixture to provide yellow crystals of 3,5-diphenyl-2-nitrobenzofuran-7-carboxylic acid, m.p. 207°-209° C.
Reaction SMILES: C([N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19]#[N:20])[N:11]=1)(=O)C.[OH-].[Na+]>CO>[NH:6]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19]#[N:20])[N:11]=1)[C:5]([NH2:23])=[NH:4]
Reactant: CNC(=NC#N)NCCSCc1csc(NC(N)=NC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-(2-acetylguanidino)-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (13.6 mg.), methanol (1 ml.) and 0.2 N aqueous sodium hydroxide solution (2 ml.) was stirred at room temperature for 20 minutes. This resulted in complete conversion to 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole, identical with the free base of the product obtained in Example 3. The free base had a m.p. 159°-162° C. on recrystallization from aqueous dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([Cl:26])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Product: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1

Procedure:
1.2 g of ((3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid in 15 mL thionylchloride was stirred 30 min. at 60° C. The solvent was removed to give 1.3 g desired product. (M+H)+: 334
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:29])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.060 g, 28%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.50 mmol) and methylamine (0.155 g, 5.0 mmol). mp 194-196° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)[CH2:17][C@@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19].O>CS(C)=O>[CH3:19][C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16][N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5]
Reactant: CC(C)=CCC[C@@H](C)CCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC[C@@H](C)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
This example illustrates a synthesis of 1-(3-(R)-methyl-7-methyl-6,7-oxidooctyl)-3,7-dimethylxanthine (inventive compound no. 1588R). Sodium hydride(95%) (631 mg, 25 mmol) was added to a solution of theobromine (4.14 g, 23 mmol) in dimethylsulfoxide (75 mL). After 20 minutes of stirring, (R)(-)Citronellyl bromide (5.0 g, 22.8 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 500 mL of water and extracted with dichloromethane (3×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% petroleum ether/ethyl acetate eluant, yielding 5.9 g (81.5% yield) 1-(3-(R)-methyl-7-methyloct-6-enyl)-3,7-dimethylxanthine (inventive compound no. 1596R) as a yellowish oil. A solution of 1-(3-(R)-methyl-7-methyloct-6-enyl)-3,7-dimethylxanthine (318 mg, 1 mmol) and m-chloroperoxybenzoic acid (0.52 g; 1.5 mmol) (50% by wt) in dichloromethane (7 mL) was stirred for 5 hours. The reaction mixture was diluted with 40 mL of dichloromethane and washed successively with 20% aqueous sodium sulphite solution (10 mL), saturated sodium bicarbonate solution (10 mL), water and brine solutions. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 5% petroleum ether/ethyl acetate eluant, yielding 0.253 g (76% yield) of 1-(3-(R)-methyl-7-methyl-6,7-oxidooctyl)-3,7-dimethylxanthine.
Reaction SMILES: [CH3:1]I.[Mg].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])=[O:6].[NH4+].[Cl-]>C(OCC)C>[F:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:5]([OH:6])([CH3:1])[CH3:4]
Reactant: CI
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(C)(C)O)c(F)c1
Yield: 80.9 %

Procedure:
17.75 g (0.125 mole) methyliodide are dissolved in diethylether and the resulting solution is added dropwise with stirring to 3.04 g magnesium chips in 15 ml anhydrous ether. The mixture is then heated under reflux for 30 minutes, followed by the dropwise addition with stirring of a solution of 16.82 g (0.1 mole) 2-fluoro-4-methoxy-acetophenone in diethylether. After heating under reflux for 2 hours, the reaction mixture is cooled, poured onto ice and the corresponding deposit dissolved by addition of aqueous NH4Cl solution. The ether phase is separated off, the aqueous phase is extracted with ether, the combined ether phases are washed with aqueous solutions of NaHSO3, NaHCO3 and then with pure water, dried over Na2SO4 and the ether removed. Distillation of the residual oil in a high vacuum gives 14.9 g 2-(2-fluoro-4-methoxyphenyl)-2-propanol.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]1>C(O)C.[Pd]>[CH2:29]([O:28][C:26]([CH:25]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:24][CH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C(=O)CCc1c[nH]c2ccccc12
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1c[nH]c2ccccc12)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of L-alanyl-L-proline (0.35 g) and ethyl 4-(3-indolyl)-2-oxobutyrate (1.0 g) in 30 ml of ethanol was hydrogenated with 10% Pd on carbon in the presence of 3.2 g of powdered molecular sieves (4A) under 40 lbs of hydrogen pressure. After the reaction was complete the slurry was filtered and the filtrate concentrated to dryness. The residual oil was dissolved in 5 ml of methanol and chromatographed on a Sephadex LH-20 column to yield 0.67 g of crude product as an orange oil. A portion of the crude (0.3 g) was purified by solution in water and extraction with ether. Product was recovered by dilution of the aqueous phase with an equal volume of saturated NaCl solution and extraction with ethyl acetate to yield 80 mg of (N-[1-ethoxycarbonyl-3-(3-indolyl)propyl]-L-alanyl-L-proline as a yellow oil. Mass spectral analysis showed peaks at 559 for the di-silylated product and at 631 for the tri-silylated product.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:34](=[O:35])[N:14]2[C:15]([C:31]([OH:33])=[O:32])=[C:16]([CH2:19]OC(=O)C(C3C=CC=CC=3)O)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[SH:36][C:37]1[N:41]([CH3:42])[N:40]=[N:39][N:38]=1.C(=O)([O-])O.[Na+:47]>O>[Na+:47].[C:1]([NH:11][C@@H:12]1[C:34](=[O:35])[N:14]2[C:15]([C:31]([O-:33])=[O:32])=[C:16]([CH2:19][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: Cn1nnnc1S
Reactant: O=C(O)C1=C(COC(=O)C(O)c2ccccc2)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
In water (5 ml) was dissolved 7β-(D-mandelamido)-3-mandelyloxymethyl-3-cephem-4-carboxylic acid (0.50 g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.17 g). The solution was stirred at 60° C. for 30 minutes. After cooling in the air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2, elution being carried out with water and a solvent mixture of water and methanol. The fractions containing the desired product were pooled, concentrated and lyophilized. The procedure provided 7β-(D-mandelamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (0.34 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17]
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1C1CCC1
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CCC1
Yield: 80.7 %

Procedure:
A solution of 8-bromo-2-chloro-3-cyclobutylquinazolin-4(3H)-one (294.7 mg, 0.94 mmol), tert-butylamine (Aldrich; 1.5 mL, 14.27 mmol), and NMP (0.5 mL) was heated in a sealed microwave vial at 120° C. for 30 min. The reaction mixture was then partitioned between EtOAc (60 mL) and water (40 mL). The organic layer was separated and sequentially washed water (40 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(tert-butylamino)-3-cyclobutylquinazolin-4(3H)-one (266 mg, 0.759 mmol, 81% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (1H, dd, J=7.6, 1.2 Hz), 7.84 (1H, dd, J=7.8, 1.4 Hz), 6.98 (1H, t, J=7.8 Hz), 5.88 (1H, s), 4.47-4.60 (1H, m), 2.54-2.64 (2H, m), 2.06-2.20 (2H, m), 1.56-1.66 (2H, m), 1.52 (9H, s). m/z (ESI, +ve) 349.9/352.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH:10]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccsc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48).
Reaction SMILES: Cl[O-:2].[Na+].[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])C)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC(C)=O>[O:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:2])=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1

Procedure:
In each case a 5.25% sodium hypochlorite solution (85.1 g.: 0.060 mole) was added slowly in portions to a solution of 3.18 g. (0.0150 mole) the p-phenoxyacetophenone sample while heating from 40° to 100° C. The resulting solution was concentrated at 100° C., producing a crystalline precipitate. Acetone was then added to consume excess sodium hypochlorite followed by boiling, acidification with some excess concentrated hydrochloric acid (10 ml of 12N), stirring, filtration, water wash and then drying at 70° C./under vacuum for about 1 hr. The p-phenoxybenzoic acid obtained from the p-phenoxyacetephenone produced in the presence of hydrogen fluoride was white with a melting point of 159°-162° C. In contrast, the p-phenoxybenzoic acid produced in the presence of aluminum trichloride had a yellow (or light beige) discoloration and a strongly depressed melting point of 137°-149° C., indicating presence of considerable impurities.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10](O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=[C:12]2[CH:14]=[CH:15][S:16][C:11]=12
Reactant: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Yield: 88 %

Procedure:
A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6 g) in phosphorus oxychloride (50 mL) is refluxed for 3 hours. After the excess amount of phosphorus oxychloride is removed under vacuum, the residue is treated with ethyl acetate (20 mL) and NaOH (2N, 20 mL). The mixture is then extracted with ethyl acetate (3×20 mL). The combined organic layers are washed with brine and dried over MgSO4. Evaporation of the solvent affords 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (1.5 g, 88% yield) as a white solid, m.p. 119-121° C.
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)C(=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1>CC(O)=O>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)ccc32)cc1
Reactant: NCC(=O)O
Agent: N#N
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CNC(=O)c3cc(Cl)ccc32)cc1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (34 g, 0.45 mol) was added to 6-chloro-1-(4-methoxybenzyl)-1H-benzo[d][1,3]oxazine-2,4-dione (280 g) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 8 h. Solvent was removed on the rotary evaporator at 50-60° C. To the thick syrupy crude product was added heptane (1 L) and H2O (1 L) followed by the addition of NaHCO3 to adjust the pH to ˜8-9. The mixture gave a solid along with organic and aqueous layers. The organic and aqueous layers were decanted and the solid was slurried with 500 mL of 5% NaHCO3 solution. NaHCO3 layer was decant and sticky solid was suspended in 700 mL EtOAc and 300 mL of dichloromethane (DCM). The mixture was stirred for 20 min, filtered and the filter cake was washed with 1 L of DCM. The filtrate was concentrated and residue was pass through 330 g silica gel plug using 25/75 to 75/25 EtOAC/heptane (total of 8 L). Clean fractions were combined to give 58 g of pure product. An additional 13 g of ˜70% pure product was obtained from less pure fractions. Yield was 47% over two steps. 1H NMR (300 MHz, DMSO-d6) δ 3.45 (m, 1H), 3.6 (s, 3H), 3.8 (m, 1H), 4.8 (d, 1H), 5.3 (d, 1H), 6.8 (d, 2 H), 7.1 (d, 2H), 7.7-7.5 (m, 3H), 8.9 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:12][C:13]([F:23])([F:22])[C:14]([C:18]([F:21])([F:20])[F:19])([OH:17])[CH2:15]O.Cl.C1(C)C=CC=CC=1>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]([C:18]([F:19])([F:21])[F:20])([OH:17])[CH2:15][O:9][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
Under ice cooling, a solution of 54 g of p-toluene sulfonate in 140 g of pyridine was added dropwise to a mixture of 93 g of the 61 wt % IPE solution of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol prepared in Reference Synthesis Example and 140 g of pyridine. Stirring was continued for 48 hours at room temperature. The reaction solution was ice cooled and poured into a mixture of 678 g of 20 wt % hydrochloric acid aqueous solution and 100 g of ice to quench the reaction. Toluene, 500 g, was added to the reaction solution, which was separated into layers. The organic layer was washed with water, concentrated, and recrystallized from heptane, obtaining 74 g of 3,3,3-trifluoro-1-(p-toluene-sulfonyloxy)-2-trifluoromethylpropan-2-ol (yield 74%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].CCN=C=NCCCN(C)C.Cl.[CH2:57]([N:59]([CH2:64][CH3:65])[CH2:60][CH2:61][NH:62][CH3:63])[CH3:58]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:57]([N:59]([CH2:64][CH3:65])[CH2:60][CH2:61][N:62]([CH3:63])[C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1)[CH3:58]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CCN(CC)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
Into a 10-mL round bottom flask, was placed a solution of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (5 mL), EDC.HCl (63.75 mg, 0.33 mmol, 2.00 equiv), 4-dimethylaminopyridine (40.5 mg, 0.33 mmol, 2.00 equiv), N1,N1-diethyl-N2-methylethane-1,2-diamine (64.8 mg, 0.56 mmol, 3.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×70 mL of NH4Cl (aq). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 47.8 mg (34%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.36 (s, 1H), 9.57 (t, 1H), 9.28 (s, 1H), 8.90 (d, J=5.1 Hz, 1H), 8.30 (m, 2H), 7.98 (d, J=7.2 Hz, 2H), 7.84 (d, J=4.8 Hz, 1H), 7.65 (m, 7H), 7.28 (d, J=8.4 Hz, 1H), 4.66 (d, J=6.0 Hz, 2H), 3.82 (m, 2H), 3.31 (m, 9H), 2.97 (s, 4H), 1.71 (m, 6H), 1.24 (m, 6H). MS (ES, m/z): 715 [M+H]+.