Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C@@H:6](O)[CH3:7])[CH3:2].O=S(Cl)[Cl:12]>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH2:1]([O:3][C:4](=[O:9])[C@H:5]([Cl:12])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C[C@H](C)O
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cl)CC
Yield: 65 %

Procedure:
0.24 moles (S)-(+)-3-hydroxy-butyric acid ethyl ester in 100 ml benzene are added to 0.07 moles anhydrous ZnCl2 while agitating and while excluding moisture. Subsequently, 0.72 moles SOCl2 are added, and the product is agitated at room temperature for two days. Then the reaction mixture is treated with saturated NaHClO3 solution. After separating off the aqueous phase, it is dried with Na2SO4. The solvent is distilled off, and the residue is fractionally distilled. One obtains (R)-(-)-chlorobutyric acid ethyl ester with a yield of 65 percent.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(OC(C)(C)C)=O)CC1.[CH:30]1([C:33]2[C:34]([O:47][CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][C:51]([CH3:56])([CH3:55])[CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([O:40]C(C)(C)C)=[O:39])[CH2:32][CH2:31]1>>[CH:30]1([C:33]2[C:34]([O:47][CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][C:51]([CH3:56])([CH3:55])[CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([OH:40])=[O:39])[CH2:32][CH2:31]1
Reactant: CC1(C)CCCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)C1
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCCC(COc2cc(F)c(C(=O)O)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 158 step 4, and making variations as required to replace tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as a colorless solid (0.46 g, 22%): MS (ES−) m/z 319.3 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[C:7]#[N:8].B.C1COCC1>C1COCC1>[NH2:8][CH2:7][C:6]1[CH:9]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=1[I:10]
Reactant: N#Cc1cc(O)ccc1I
Agent: B
Solvent: C1CCOC1
Product: NCc1cc(O)ccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.1 %

Procedure:
To a solution of 5-Hydroxy-2-iodo-benzonitrile (245 mg, 1 mmol) in THF (3 mL) is added BH3.THF (6 mL, 1 M solution in THF) under N2. The mixture is then allowed to stir at room temperature for 24 hours. The reaction is then quenched with 6N HCl. THF is then removed and the aqueous layer is then neutralized with ammonium hydroxide to pH 9. The mixture is then extracted with CHCl3/MeOH (9:1). The organic layer dried and evaporated and the residue is chromatographed to provide the desired product (80 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[Cl:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH2:16]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]pyridine from Example 5A (6.65 g, 25.1 mmol) in ethanol (120 mL) was added zinc powder (8.22 g, 126 mmol), and the mixture was heated to 60° C. A solution of ammonium chloride (2.67 g, 50.3 mmol) in water (24 mL) was added dropwise, and the reaction was stirred for additional 2 h at this temperature. The mixture was filtered through Celite®, and the solvent was removed in vacuo. The residue was triturated with water, and the precipitate was collected by suction filtration, washed with water and dried to yield 4.97 g (84%) of the aniline.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[O:17]1[C:21]2([CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:24]2([OH:27])[CH2:25][CH2:26][C:21]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:22][CH2:23]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(C(F)(F)F)c2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a round bottom flask was added n-BuLi (3.84 mL, 9.60 mmol) at −78° C. under argon. THF (10 mL) was added followed by addition of 1-bromo-3-(trifluoromethyl)benzene (0.884 mL, 6.40 mmol) in THF (1 mL). The reaction mixture was stirred for 30 minutes at −78° C. A solution of 1,4-dioxaspiro[4.5]decan-8-one (1.00 g, 6.40 mmol) in THF (5 mL) was then added dropwise to the reaction mixture at −70° C. The reaction was stirred for 1 h at −70° C., and then quenched by the addition of 1 N HCl. The reaction mixture was extracted with EtOAc and the organic portions were separated and combined. The organic layer was dried over Na2SO4, filtered, and concentrated to give Intermediate 3A (1.87 g, 6.19 mmol, 97.0% yield). LCMS=325 [M+Na], RT=1.89 minutes (Method B).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2.[Cl-].[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:13][CH2:14][CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CCOC(=O)CNCC(OCC)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(OCC)OCC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The compound obtained in Step 1 (504 mg) was suspended in methylene chloride (20 ml) and to the suspension were added triethylamine (336 ml) and then 6-chloronaphthalene-2-sulfonyl chloride (600 mg) under cooling with ice. After stirring the mixture overnight at room temperature, saturated sodium chloride solution was added and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1–4:1) to obtain the title compound (750 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20]Cl)[CH2:17][C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+].[I-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16](=[O:22])[CH2:17][CH:18]([CH2:20][C:23]#[N:24])[CH2:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=C1CC(CCl)CN1c1ccc(OCc2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Yield: 36.8 %

Procedure:
123 mg (0.39 mmol) (RS)-1-(4-benzyloxy-phenyl)-4-chloromethyl-pyrrolidin-2-one is dissolved in 2.5 ml N,N-dimethylformamide. After addition of 29 mg (0.58 mmol) sodium cyanide and 6 mg (0.04 mmol) sodium iodide, the mixture is hold at 120° C. for 15 min. Dilution with water and extraction with ethyl acetate yields 44 mg (37%) of a brownish solid. MS: m/e=307.3 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[F-].[Cs+].Cl[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:17][N:18]2[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:14][CH:13]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:17][N:18]3[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])=[CH:14][CH:13]=2)=[CH:2]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1ccoc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccoc3)ccc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 12 %

Procedure:
457 mg of furan-3-boronic acid, 1.24 g of caesium fluoride, 13 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 100° C. for 23 hours. A further 457 mg of furan-3-boronic acid, 1.24 g of caesium fluoride, 13 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added and refluxing is continued for 7 hours. The mixture is then allowed to return to about 19° C. over 16 hours and then filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is rinsed with 50 cm3 of tetrahydrofuran and 50 cm3 of distilled water. The resulting residue is taken up in 75 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 130 mg of N-[6-(furan-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of an orange-coloured oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:21][C:20]=3[CH3:35])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:40])[O:4][N:3]=1.Cl.O1CCOCC1>O1CCCC1.CO>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][OH:28])=[CH:21][C:20]=3[CH3:35])[CH2:36][CH:37]([CH3:39])[CH3:38])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:5]([CH3:40])[O:4][N:3]=1
Reactant: Cc1cc(OCCOC2CCCCO2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(OCCO)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(2-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)benzenesulfonamide (51.2 mg, 0.089 mmol) in tetrahydrofuran (THF) (4 mL) stirred at room temperature was added a solution of 4M HCl in dioxane (4 mL, 16.00 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by Open Access Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product, 27 mg as colourless oil which solidified. LCMS (M+1) 489, RT 1.14 mins.
Reaction SMILES: O.C[O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([O:14]C)=[C:6]([CH3:16])[C:5]=1[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(#N)C>[CH3:13][O:12][C:8]1[C:7](=[O:14])[C:6]([CH3:16])=[C:5]([CH:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:4](=[O:3])[C:9]=1[O:10][CH3:11]
Reactant: COc1c(C)c(C(CCCCCCO)c2ccccc2)c(OC)c(OC)c1OC
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(C(CCCCCCO)c2ccccc2)=C(C)C1=O
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
A solvent mixture of acetonitrile (12 ml) and water (6 ml) was added to 2.01 g (5.0 mmole) of 7-(2,3,4,5-tetramethoxy-6-methylphenyl)-7-phenylheptanol and 2.51 g (5×3 mmole) of 2,6-pyridinecarboxylic acid, and a cooled solution of 8.22 g (5×3 mmole) of ceric ammonium nitrate in 50% aqueous acetonitrile (16 ml) was added dropwise to the mixture over the 20 minutes period under ice-cooling. After stirring was continued for another 20 minutes under ice-cooling, the insoluble matter was filtered out, and the acetonitrile was distilled off under reduced pressure. Isopropyl ether was added to the residue to carry out extraction. The isopropyl ether layer was separated out, washed with aqeuous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column to elute with isopropyl ether/ethyl acetate to give 1.56 g (84%) of 7-(5,6-dimethoxy-3-methyl-1,4-benzoquinon -2-yl)-7-phenylheptanol. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound No. 57 was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[Cl:17][CH2:18][C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[C:19]([CH2:18][Cl:17])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a yellow solution of 2-amino-5-chlorobenzophenone (6.93 g, 30.0 mmol) in ethanol (150 ml) was added ethyl 4-chloroacetoacetate (5.3 ml, 39.0 mmol) followed by ytterbium triflate (1.6 g, 3.0 mmol). The mixture was stirred at room temperature for 48 hours, at which time a voluminous white suspension was noted. The mixture was filtered, and the precipitate washed with ethanol, then diethyl ether, to provide ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate as a white powder (93%). 1H NMR (CDCl3; 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.71 (dd, 1H, J=8.9, 2.3 Hz); 7.59 (d, 1H, J=1.95 Hz); 7.54 (m, 3H); 7.38-7.30 (m, 2H); 5.0 (s, 2H); 4.05 (q, 2H, J=7.0 Hz); 0.92 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 360.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CCc1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1cccc[n+]1[O-]
Yield: 80.6 %

Procedure:
tert-Butyl 3-(2-pyridyl)propanoate (1.0 g, 5.0 mmol) was dissolved in ethyl acetate (5 ml), and 3-chloroperbenzoic acid (ca. 70%, 1.3 g, 5.2 mmol) was added thereto. The reaction mixture was subjected to a silica gel (50 g) column chromatography and eluted with ethyl acetate-ethanol (5:1, v/v) to give the titled compound (0.9 g, 80%). 1H-NMR (CDCl3) δ: 1.41 (9H, s), 2.76 (2H, t, J=7.1 Hz), 3.17 (2H, t, J=7.1 Hz), 7.15-7.32 (3H, m), 8.24 (1H, d, J=5.7 Hz).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([I:16])[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[I:16][C:14]1[CH:13]=[N:12][N:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(n2cc(I)cn2)CC1
Temperature: 65 °C
Yield: 98.6 %

Procedure:
The mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-iodo-1H-pyrazole (20.0 g, 59.8 mmol), pyridinium p-toluenesulfonate (30.1 g, 120 mmol) in acetone (300 mL) and H2O (300 mL) was heated at 65° C. for 16 h. The reaction mixture was partitioned between EtOAc (200 mL) and H2O (100 mL), and the layers were separated. The aqueous layer was re-extracted with EtOAc (3×100 mL), and the combined organic fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in 17.1 g (98% yield) of the title compound as a white solid. The material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=7.54 (s, 1H), 7.52 (s, 1H), 4.62 (tt, J=4.0, 10.1 Hz, 1H), 2.64-2.38 (m, 6H), 2.36-2.24 (m, 2H). MS (ES+): m/z=291.00 [MH+]. HPLC: tR=3.37 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH2:19][OH:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][S:15][C:11]=3[C:10]=2[F:21])[CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][S:15][C:11]=3[C:10]=2[F:21])[CH2:3]1
Reactant: Cc1nsc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nsc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of {6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-methyl-1,2-benzothiazol-5-yl}methanol (Intermediate 157, 0.18 g, 0.6 mmol) in DCM/CH3CN mixture (3 mL, 1:1 v/v) was added NMO (0.12 g, 0.7 mmol) followed TPAP (0.04, 0.2 mmol) and mixture stirred for 2 h at room temperature. The reaction mixture filtered through silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give title compound as a yellow crystalline solid. Yield: 0.12 g (67%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1CO>C(Cl)Cl>[Br:5][CH2:1][C:27]1[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:26]=1[I:25]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(I)c(CBr)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (Intermediate 10, 1.13 g; 3.74 mmol) in CH2Cl2 (25 mL) at 0° C. under N2. The reaction was stirred at room temperature for 48 h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-25% EtOAc/hexanes gradient) to afford 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear oil. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1 H), 7.73 (d, J=1.8 Hz, 1 H), 7.26 (dd, J=8.3, 1.8 Hz, 1 H), 4.64 (s, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.021 g) in methylene chloride (1 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 hour and 10 minutes. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 7 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.013 g of 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]3[C:34]=2[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]3[CH3:38])[CH:23]=[CH:24][CH:25]=1>C1COCC1>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:27][CH:28]=[C:29]3[C:34]=2[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]3[CH3:38])[CH:23]=[CH:24][CH:25]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Tetra-n-butylammonium fluoride solution (1.0M, 24.8 mL, 24.8 mmol) was added to a suspension of 5-(3-fluorophenyl)-1,3-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.00 g, 2.48 mmol) in THF (7 mL), and the mixture was stirred at 60° C. for 2 hours, then cooled to room temperature and stirred for 4 hours. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The mixture was washed with water (3×25 mL) and brine (1×25 mL). The organic phase was dried over magnesium sulfate and the solvent was evaporated under vacuum to afford the title compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O.C(OP(OCCCCCCCC(C)C)OCCCCCCCC(C)C)CCCCCCC(C)C>[C:1]([O:9][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCCc1ccccc1
Agent: CC(C)CCCCCCCOP(OCCCCCCCC(C)C)OCCCCCCCC(C)C
Agent: CS(=O)(=O)O
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A 2-L, 4-neck round bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 671.7 g (5.50 mol, 1.00 equiv) of benzoic acid, 806.3 g (6.60 mol, 1.20 equiv) of 2-phenylethyl alcohol, 5.30 g (0.43% w/w, 1.0 mol %) of methanesulfonic acid (MSA) and 1.25 g (0.1% w/w) of triisodecylphosphite (TDP). The system was heated gently with slow stirring (<50 rpm) until the benzoic acid dissolved. The air was removed with three cycles of evacuation/nitrogen fill using a mechanical vacuum pump (50-100 torr). The rate of stirring was increased to ca. 200 rpm, the nitrogen sparge was set at 0.2 scfh, and the reaction mixture was heated to 140° C. After a 1-h hold, the temperature was increased to 150° C, and held for 1 h. The temperature was increased to 160° C. and the nitrogen sparge was increased to 0.5 scfh. After a 1-h hold, the reaction mixture was cooled to room temperature and sampled for analysis. The acid number was 8.1 mg KOH/g (97.3% conversion of benzoic acid, corrected for MSA), the APHA color was 66, and the excess 2-phenylethyl alcohol was 7.9% by GLC. To the reaction mixture at 25° C. was added 213 g of 10% w/w aqueous sodium carbonate solution. The batch was heated to 50° C. and stirred for 15 min. The stirring was stopped and the batch was allowed to settle for 30 min. The bottom aqueous layer was removed from the flask with a pipette, and 2-phenylethyl alcohol was removed by vacuum distillation at 180-190° C. (20 torr) for 1 h with a nitrogen sweep of 0.5 scfh. The reaction mixture was cooled to ca. 70° C. and sampled for analysis. The residual 2-phenylethyl alcohol was 0.17% by GLC, the acid number was 0.10 mg KOH/g, and the APHA color was 95. Treatment with activated carbon and filtration as usual (see Example 1) gave 1100 g (88%) of 2-phenylethyl benzoate. The APHA color was 72, the acid number was 0.11 mg KOH/g, the saponification number was 242 mg KOH/g, the residual sulfur was <10 ppm, and the residual phosphorous was <10 ppm.