Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([OH:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH2:21]([N:23]([CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:30]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH3:31].[CH3:19][N:2]([CH3:1])[CH2:3][CH:4]([OH:18])[CH:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCCC(=O)[O-]

Procedure:
A solution of 3-dimethylamino-1,1-diphenyl-propan-2-ol (2.55 g.), 4-diethylaminobutyric acid hydrochloride (1.95 g.) and dicyclohexylcarbodiimide (2.1 g.) in dichloromethane (50 ml.) was stirred at room temperature for 5 days. Dicyclohexylurea was filtered off and the filtrate concentrated. The residue was dissolved in dilute hydrochloric acid and ether. The acid extract was basified; isolation through ether in the normal manner gave an oil which was chromatographed as alumina (200 g.). Elution with progressively graded mixtures of light petroleum and ether gave the 4-diethylaminobutyrate of 3-dimethylamino-1,1-diphenyl-propan-2-ol isolated as the dihydrochloride (41%) as a glass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]([CH3:21])[C:10]=1[CH2:22]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]([CH3:21])[C:10]=1[CH2:22][Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(CC(F)(F)F)cc(=O)c(OCc2ccccc2)c1CO
Solvent: CC#N
Product: Cn1c(CC(F)(F)F)cc(=O)c(OCc2ccccc2)c1CCl
Reaction time: 0.17 h

Procedure:
To a suspension of 3-benzyloxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.34 g, 1.04 mmol) in acetonitrile (15 mL), was added thionyl chloride (0.38 mL, 5.19 mmol) at room temperature. A clear solution resulted and the reaction was completed within 10 min. The reaction mixture was evaporated to dryness to give the crude 3-benzyloxy-2-chloromethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil, which was taken up in ethanol (15 mL) to give a clear solution. Sodium borohydride (430 mg, 11.4 mmol) was added to the solution portionwise. The reaction mixture was stirred for another 10 min, and the progress of the reaction was monitored by TLC (methanol/dichloromethane, 1/10 v/v as eluant). There was still some unreacted chloride derivative present at this time. Additional sodium borohydride (360 mg, 9.5 mmol) was added in several portions. The reaction mixture was stirred for another 10 min. The reaction mixture was purified by column chromatography on silica gel (methanol/dichloromethane, 1/20 v/v as eluant) to give 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil (0.20 g, 61% for the two combined steps, HPLC Method 1 (Example 24), RT=15.1 min, HPLC purity (peak percent area): 92% at λ=280 nm). This material, 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.20 g, 0.64 mmol) was taken up in methanol (25 mL) to give a clear solution. To the solution was added Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 90 mg). The hydrogenation reaction was conducted under a hydrogen pressure of 50 psi. The reaction was completed in 30 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was evaporated to give the first crop of 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a solid product (free base, 74 mg, 52% yield), HPLC Method 1 (Example 24), RT=9.9 min, HPLC purity (peak percent area): 96.4% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 6.25 (s, 1H), 3.94 (q, J=11 Hz, 2H), 3.57 (s, 3H), 2.32 (s, 3H). MS-ESI (m/z) 222.2 ([M+1]+, 100%), 202.3, 153.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:30]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]([Br:30])[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (5.0 g, 15.2 mmol) and sodium bicarbonate (19.2 g, 228 mmol) in dichloromethane (150 mL) at 0° C., a solution of bromine in dichloromethane (0.5 M, 32 mL, 16 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexane-ethyl acetate gradient to provide the titled product.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:33]=3[F:32])[OH:36])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COc1cccc(F)c1C=O
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(O)c1c(F)cccc1OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (158 mg, 0.33 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.4 mL, 0.8 mmol) via dropwise addition. The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-fluoro-6-methoxy-benzaldehyde (96.6 mg, 0.63 mmol) at −30° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2-fluoro-6-methoxyphenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (110 mg) as yellow syrup in 60% yield. ESMS m/z: 549 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.ClCCCl>[CH:16]([C:10]1[CH:15]=[CH:14][C:13]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are added to a round flask, which is fitted with a stirrer, thermometer, condenser and dropping funnel. The mixture is cooled to 0° C., and 127 g of propionic acid chloride are allowed to drop in at 0°-5° C. within 3/4 hour. After the addition, the temperature is allowed to rise to +18° C. and then 157 g of cumene are added within 2 hours at 30° C. The mixture is left to stand for 12 hours and the product is then poured into a mixture of 800 g of ice, 130 ml of water and 130 ml of concentrated hydrochloric acid. The aqueous phase is separated and extracted with two 250 ml portions of dichloroethane. The combined organic phases are washed with three 200 ml portions of 2% sodium hydroxide and with 250 ml of water. The solvent is removed by evaporation under a vacuum and the residue (244 g) is distilled over a 10 cm column. There are obtained 192.1 g of p-isopropyl-propiophenone (yield: 83.2% of theory). B.p.=76°-77° C./0.15 mmHg; nD20 =1.5150; d420 =0.9645.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])/[CH:9]=[CH:12]/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccncc1)c1cc(Br)ccc1O
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (50 g, 0.23 mol) in EtOH (285 mL) and H2O (15 mL) was added isonicotinaldehyde (25 g, 0.23 mol) and NaOH (84 g, 0.23 mol). The reaction mixture was stirred overnight. EtOH was added to the mixture and filtered to give a solid residue. The residue was dissolved in water and acidified by 1 M HCl to give a solid. The solid was collected by filtration to give (E)-1-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (30 g, 40%).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:5]3[S:12][C:2]([CH3:1])=[CH:3][C:4]=3[C:9](=[O:10])[O:8][C:7]2=[O:11])=[CH:16][CH:17]=1
Reactant: Cc1cc2c(=O)oc(=O)[nH]c2s1
Reactant: Fc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)oc(=O)n(Cc3ccc(F)cc3)c2s1
Temperature: 0 °C
Yield: 41.2 %

Procedure:
step 3—Sodium hydride (1.5 g of a 60% dispersion in mineral oil, 37.5 mmol) was suspended in DMF (50 mL) in a 250 mL round-bottom flask equipped with a stir bar, and cooled to 0° C. and maintained under a nitrogen atmosphere. A solution of 61a (4.6 g, 25 mmol) dissolved in DMF (50 mL) was added dropwise through a septum. The flask was removed from the ice bath and the mixture was stirred at RT for 30 m. The reaction was cooled to 10° C. and 1-bromomethyl-4-fluoro-benzene (3.74 mL, 30 mmol) was added through the septum. The flask was removed from the ice bath and the mixture was stirred at RT for 2 h. The reaction was poured into ice and 1N HCl, extracted twice with EtOAc, dried (Na2SO4), filtered and concentrated. A solid was precipitated from the EtOAc by addition of Et2O and hexanes to afford 3.0 g (41%) of 1-(4-fluoro-benzyl)-6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (61b): ms 2[M+Na]=605.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCO
Reactant: Cc1ccc(Cl)cc1C(=O)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)ccc1C
Temperature: 0 °C

Procedure:
A mixture of 5-chloro-2-methylbenzoic acid (3.00 g, 17.5 mmol) in ethanol (30 mL) was cooled to 0° C. with an ice bath and thionyl chloride (12.5 mL, 105.5 mmol) was added dropwise, over 30 minutes. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath, and heated to 70° C. overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The solids obtained were then redissolved in diethyl ether (50 mL) and washed with 1 N sodium hydroxide (50 mL), brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to afford ethyl 5-chloro-2-methylbenzoate as a clear oil: 1H NMR (500 MHz, CDC13) δ 7.88 (d, J=2.5 Hz, 1H), 7.34 (dd, J=8.5, 2.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 4.36 (q, J=7.5 Hz, 2H), 2.56 (s, 3H), 1.39 (t, J=7.5 Hz, 3H); ESI MS m/z 199 [M+H]+.
Reaction SMILES: Br[C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([O:20][CH3:21])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:8]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:2]=2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 130 °C
Yield: 58.9 %

Procedure:
2-Bromo-4-methoxy-3-(4-nitro-phenoxy)-benzaldehyde (19.4 g, 55.1 mmoles) is dissolved in dry DMF (450 mL) under nitrogen atmosphere. Sodium carbonate (7.0 g, 66.11 mmoles) and palladium acetate (1.15 g, 5.1 mmoles) are added to the solution. The reaction mixture is heated at 130° C. for 18 hours. The crude is filtered and the mother liquor is poured in water. Precipitation occurs. The suspended solid is filtered, washed with water and dried under vacuum overnight to afford a pale brown solid (8.8 g).
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:59][C:60]1[CH:65]=[C:64](I)[CH:63]=[CH:62][C:61]=1[CH3:67]>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:64]2[CH:63]=[CH:62][C:61]([CH3:67])=[C:60]([F:59])[CH:65]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(I)cc1F
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Cc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1F
Yield: 67 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 2-fluoro-4-iodo-1-methylbenzene in 67% yield.
Reaction SMILES: [C:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:21].Cl>CN(C)C=O>[CH3:21][NH:17][S:14]([C:5]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:1](=[O:3])[CH3:2])(=[O:15])=[O:16]
Reactant: CI
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Temperature: 25 °C
Reaction time: 66 h
Yield: 62 %

Procedure:
To a mixture of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (300 mg, 1.02 mmol) and sodium hydride (53 mg, 1.32 mmol) in 10 mL of N,N-dimethylformamide, iodomethane (70 μL, 1.12 mmol) was added. The mixture was stirred at room temperature for 66 hours. The mixture was acidified with 1 N aq. HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), gave the desired product (185 mg, 59%). EI-MS (m/z) 307.3, 309.3 (M−).
Reaction SMILES: [F:1][C:2]([F:20])([C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]C)=[O:17])[NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29].[OH-].[Na+].Cl>CC(C)=O.O>[CH2:28]([N:9]1[C:10]([C:16]([OH:18])=[O:17])=[C:11]([C:12]([F:14])([F:15])[F:13])[C:7]([C:2]([F:1])([F:20])[C:3]([F:5])([F:6])[F:4])=[N:8]1)[CH3:29]
Reactant: CCI
Reactant: COC(=O)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.23 g (0.72 mmol) of methyl 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate and 0.3 g (2.2 mmol) of potassium carbonate are suspended in 7.0 ml of acetone and admixed with 0.12 ml of iodoethane (1.4 mmol). The reaction mixture is stirred overnight at room temperature. 1.1 ml (2.2 mmol) of 2N sodium hydroxide solution are added to the suspension. The solution is then stirred overnight at room temperature. The reaction mixture is diluted with water and adjusted to pH 2-3 with 1M hydrochloric acid. The aqueous reaction solution is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure on a rotary evaporator. This gives 0.22 g of 1-ethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (91%) as a colourless solid.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][N:11]2[C@@H:15]([CH3:16])[C@@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=3)[O:13][C:12]2=[O:28])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[C:29]([O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[C:44](B(O)O)[C:45]([O:48][CH3:49])=[N:46][CH:47]=2)=[C:38]([CH3:53])[CH:37]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:27][C:19]1[CH:18]=[C:17]([C@H:14]2[O:13][C:12](=[O:28])[N:11]([CH2:10][C:3]3[C:2]([C:44]4[CH:43]=[C:42]([C:39]5[CH:40]=[CH:41][C:36]([C:34]([O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:35])=[CH:37][C:38]=5[CH3:53])[CH:47]=[N:46][C:45]=4[O:48][CH3:49])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=3)[C@H:15]2[CH3:16])[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of (4S,5R)-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 10, 150 mg, 0.312 mmol) in THF (3.0 mL) was added {5-[4-(tert-butoxycarbonyl)-2-methylphenyl]-2-methoxypyridin-3-yl}boronic acid (INTERMEDIATE 32, 129 mg, 0.375 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (10.2 mg, 0.016 mmol), and aqueous potassium carbonate (0.468 mL, 2.0 M). The mixture was degassed, flushed with nitrogen and heated to 90° C. for 45 minutes, then allowed to stir at room temperature overnight. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was purified by column chromatography to afford tert-butyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfanyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (192 mg, 0.275 mmol). LCMS (M+H)+: 699.1
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:12]1[CH2:16][CH:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:14][C:13]1=[O:27])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:15]2[O:14][C:13](=[O:27])[N:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH2:16]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(OCC2CN(C(C)CO[Si](C)(C)C(C)(C)C)C(=O)O2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(OCC2CN(C(C)CO)C(=O)O2)cc1
Yield: 96 %

Procedure:
A procedure similar to that described in Preparation 5(b) was repeated, except that 1.26 g of 3-(2-t-butyldimethylsilyloxy-1-methylethyl)-5-(4-methoxyphenoxymethyl)oxazolidin-2-one (polar isomer), obtained as described in Preparation 76, 9.6 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) and 10 ml of anhydrous tetrahydrofuran were used, to give 0.86 g of the title compound, melting at 62° C. to 67° C., from the polar diastereomer.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:13]1C3.Cl>C(Cl)(Cl)Cl.C(O)C>[ClH:11].[NH2:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC(=O)c1cccc(Cl)c1
Temperature: 55 °C
Yield: 239.4 %

Procedure:
2-Bromo-1-(3-chlorophenyl)ethanone (2.0 g, 8.57 mmol) was added to a solution of hexamethylenetetramine (1.201 g, 8.57 mmol) in CHCl3 (60 mL), and the resulting mixture was heated at 55° C. for 1 hour. The mixture was cooled to room temperature, and the white precipitate was collected by filtration, washed with CHCl3, and dried in vacuo to afford 3.1 g. This white solid was suspended in a mixture of ethanol (50 mL) and hydrochloric acid (0.25 mL, 8.30 mmol) and heated at 105° C. for 1.5 hours. The mixture was cooled to 0° C., filtered and washed by ethanol (30 mL). The organic phase was concentrated to afford an HCl salt of the title compound (1.74 g) as a pale yellow solid. LC-MS (ES) m/z=170 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C@H:11]([C:15]([N:17]2[CH2:37][CH2:36][CH2:35][C@H:18]2[C:19]([NH:21][CH:22]([CH:32]([CH3:34])[CH3:33])[C:23](=[O:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:46][NH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CN1CCOCC1>CN(C=O)C>[CH3:46][N:47]([CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[C:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C@H:11]([C:15]([N:17]2[CH2:37][CH2:36][CH2:35][C@H:18]2[C:19]([NH:21][CH:22]([CH:32]([CH3:34])[CH3:33])[C:23](=[O:31])[C:24]([F:29])([F:30])[C:25]([F:27])([F:26])[F:28])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)=[O:2]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Reactant: CNCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)N(C)CCN2CCOCC2)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Yield: 56.6 %

Procedure:
The acid of Example 13 (b) (0.36 g, 0.64 mmol) was activated with oxalyl chloride (0.07 mL, 0.83 mmol) and DMF (3 drops) and coupled with 4-[2-(methylamino)ethyl]-morpholine (92 mg, 0.64 mmol) using NMM (0.14 mL, 1.28 mmol) according to the method described in Example 5 (h). Purification by flash chromatography (75:25 acetone:EtOAc) gave 0.25 g (57%) of the title compound (7:1 L-L-L:L-L-D) as an off-white foam. TLC: Rf 0.19 (3:1 acetone:EtOAc). 1H NMR (partial): δ7.88-7.82 and 7.52-7.46 (pr m, 4H, aryl), 7.42 (br d, J=7.6 Hz, 1H, NH), 6.84 (br d, J=8.8 Hz, 1H, NH), 5.02-4.96 (m, 1H, CH), 4.85 (dd, J=8.6, 7.0 Hz, 1H, CH), 4.72 (dd, J=8.0, 2.0 Hz, 1/8H, CH of Pro), 4.6 (dd, J=8.1, 2.9 Hz, 7/8H, CH of Pro), 1.14-0.82 (m, 12H, 4×CH3). 19F NMR: δ−82.12 (s, CF3, major isomer), −82.15 (s, CF3, minor isomer), −121.52 and −122.70 (AB quartet, J=294 Hz, CF2, minor isomer), −121.54 and −122.58 (AB quartet, J=294 Hz, CF2, major isomer). MS (DCI/CH4): m/z (rel intensity) 691 (26), 690 (MH+, 100), 374 (62), 317 (18), 113 (22), 100 (43), 84 (36), 83 (23). HRMS (C32H45F5N5O6) (MH+): calcd, 690.3290; obsd, 690.3274.