Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>>[OH:20][CH2:21][C@@H:22]([NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@H](CO)Cc2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (S)-1-hydroxymethyl-2-phenyl-ethylamine and DIEA to give 2-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].Br[CH2:34][C:35]#[N:36]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][C:35]#[N:36])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: N#CCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=O)[CH:5]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(=O)[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Cl)nc2ncccc12
Yield: 79 %

Procedure:
A solution of 4-isopropyl-1,8-naphthyridin-2(1H)-one (800 mg, 4.3 mmol) and 475 L of POCl3 in toluene were reacted as outlined in Scheme 1 to give the desired 2-chloro-4-isopropyl-1,8-naphthyridine (690 mg, 79%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (d, J=6.74 Hz, 6 H) 3.68 (dq, J=7.03, 6.84 Hz, 1 H) 7.38 (s, 1 H) 7.52 (dd, J=8.35, 4.25 Hz, 1 H) 8.44 (dd, J=8.50, 2.05 Hz, 1 H) 9.09 (dd, 1 H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](=[O:35])[C:29]([C:36]([O:38]C)=O)=[N:28]1>C(Cl)Cl>[F:19][C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](=[O:35])[C:29]([C:36]([N:3]([O:4][CH3:5])[CH3:2])=[O:38])=[N:28]1
Reactant: COC(=O)c1nn(-c2ccc(I)cc2F)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (8.78 g, 90 mmol) and iPr2NEt (15.7 mL, 90 mmol) in CH2Cl2 (100 mL) was added AlMe3 (1.8 M solution in toluene, 50 mL, 90 mmol) slowly at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-(2-fluoro-4-iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (12.1 g, 30 mmol) in CH2Cl2 (100 mL) was added slowly, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and the organic layer was separated. The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (9.96 g, 77% yield) as a white amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.70 (3H, s), 3.90 (3H, s), 7.39 (1H, t, J=8.1 Hz), 7.63-7.67 (2H, m), 7.77 (1H, d, J=2.3 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Br:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[K+].[CH2:13]([OH:15])[CH3:14]>>[F:9][C:6]1[CH:5]=[C:4]([Br:10])[CH:3]=[C:2]([O:15][CH2:13][CH3:14])[C:7]=1[F:8]
Reactant: CCO
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(Br)cc(F)c1F
Reaction time: 3 h

Procedure:
To a 500 ml three neck flask provided with a stirrer, thermometer, and cooling tube were added 25.0 g (118.5 mmol) of 3,4,5-trifluorobromobenzene, 19.9 g (355.5 mmol) of potassium hydroxide, and 20 ml of ethanol, and heated to reflux while being stirred for 3 hours. After finishing of the reaction, unreacted ethanol was distilled off under a reduced pressure, 200 ml of water was added thereto, and it was extracted with 200 ml of diethyl ether. The extract was washed with water (150 ml) thrice and dried over anhydrous magnesium sulfate. The colorless oily product in an amount of 27.8 g which was obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: heptane, Rf=0.36) to obtain 23.3 g of colorless oily 3,4-difluoro-5-ethoxybromobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-chloroindole (4.0 g, 26 mmol) and 4-piperidone hydrochloride hydrate (8.0 g, 52 mmol). The product was isolated as a yellow solid. Yield 3.7 g (61%). mp 181°-185° C. FDMS m/e=234 (M+ of free base).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[Cl:16]C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:16])=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(Cl)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 4-chlorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][Si:16]([CH3:25])([CH3:24])[C:17]1[O:18][CH:19]=[CH:20][C:21]=1[CH:22]=[O:23].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1>[C:26]([O:23][CH:22]([C:21]1[CH:20]=[CH:19][O:18][C:17]=1[Si:16]([CH3:25])([CH3:24])[CH3:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:28])[CH3:27]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: C[Si](C)(C)c1occc1C=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(C)=O)c1ccoc1[Si](C)(C)C
Reaction time: 14 h

Procedure:
Dodecylmagnesium bromide (a 1.0 M solution in tetrahydrofuran; 14.3 ml; 14.3 mmol) was added to a solution 2-trimethylsilyl-3-furaldehyde (1.20 g, 7.1 mmol) in tetrahydrofuran (20 ml). When all the aldehyde was consumed, as monitored by tlc, acetic anhydride (2.02 ml, 21.4 mmol) was added. Stirring was continued at room temperature for 14 hours. The mixture was quenched with water and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column using 2% ethyl ether/hexane to give the titled furan.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13]O)[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23].C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:36]1C=CC=C[CH:37]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13][NH:36][CH3:37])[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23]
Reactant: CC1(C)C(=O)N([C@@H](CCO)c2cccc(F)c2)c2c(F)cccc21
Reactant: c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1cccc(F)c1)N1C(=O)C(C)(C)c2cccc(F)c21
Reaction time: 6 h

Procedure:
7-fluoro-1-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.25 g, 0.76 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.19 g, 0.98 mmol) was added. Stirred for 6 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 25 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 3% methanol saturated with ammonia in chloroform) to give 7-fluoro-1-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a colorless oil (0.16 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.46 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 123 mg (43% over three steps) 7-fluoro-1-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:19]=[N:20]2)=[CH:15][CH:14]=1)=O)(C)(C)C.C[O-].[Na+]>O1CCCC1>[CH3:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][C:18]1[N:19]=[N:20][C:21]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)[CH:22]=2
Reactant: C[C@@H]1CCCN1CCc1cc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2nn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1cc2ccc(-c3ccc[nH]3)cc2nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of the product from Example 187 (0.007 g, 0.017 mmol) in tetrahydrofuran (2 mL), was added NaOMe (0.03 mL, 25% in methanol) and stirred at r.t. for 3 hours. The reaction mixture was then concentrated under reduced pressure, re-dissolved in water (2 mL), extracted with ethyl acetate (2 mL), dried with Na2SO4, and concentrated to afford the product in 76% yield as a yellowish solid. 1H NMR (CD3OD, 300 MHz) δ 8.31 (m, 1H), 8.02 (dd, J=3, 9 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=9 Hz, 1H), 6.89 (m, 1H), 6.71 (m, 1H), 6.18 (m, 1H), 3.33-3.19 (m, 4H), 2.53-2.22 (m, 3H), 1.96-1.87 (m, 1H), 1.77-1.64 (m, 2H), 1.43-1.37 (m, 1H), 1.06 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 307.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)CCCBr
Reactant: COC(=O)c1[nH]c2ccncc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)c2cnccc2n1CCCS(C)(=O)=O
Temperature: 60 °C

Procedure:
A suspension of methyl 3-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 12-c (1000 mg, 3.92 mmol), 1-bromo-3-(methylsulfonyl)propane 12-b (804 mg, 3.92 mmol) and cesium carbonate (1277 mg, 3.92 mmol) in dry DMF (8 ml) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature and poured into iced water. The product was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by column chromatography using a gradient starting from 0% to 10% MeOH/DCM. After evaporation and drying in vacuo, 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.23 (m, 2H) 2.97 (s, 3H) 3.13-3.22 (m, 2H) 3.95 (s, 3H) 4.65 (t, J=7.28 Hz, 2H) 7.75 (dd, J=6.02, 1.00 Hz, 1H) 8.47 (d, J=6.02 Hz, 1H) 8.88 (d, J=1.00 Hz, 1H); m/z=375 (M+H)+, Br pattern.
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][CH2:13][CH2:14][CH3:15])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[CH:6][N:5]=2.NC(N)=[S:18]>C(O)CCC>[NH2:11][C:8]1[N:7]=[CH:6][N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[S:18])[N:3]2[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCn1c(Br)nc2c(N)ncnc21
Reactant: NC(N)=S
Solvent: CCCCO
Product: CCCCn1c(=S)[nH]c2c(N)ncnc21
Yield: 101.1 %

Procedure:
A suspension of 8-bromo-9-butyl-9H-purin-6-ylamine (0.50 g, 1.85 mmol) and thiourea (1.49 g, 19.6 mmol) in n-butanol (10 ml) was heated to reflux for 14 h. Dilution with CH2Cl2 (70 ml), washing with water and concentration afforded 6-amino-9-butyl-7,9-dihydro-purine-8-thione as a white powder (0.42 g, 1.87 mmol, 100%). 1H NMR (DMSO-d6) δ 12.35-12.25 (br. s, 1H), 8.13 (s, 1H), 6.92-6.72 (br. s., 2H), 4.09 (t, J=7.6 Hz, 2H), 1.71 (quint., J=7.5 Hz, 2H), 1.29 (sext., J=7.5 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C([O:26][C:27](=[O:38])[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)C.[OH-].[Na+]>C(Cl)Cl>[CH2:17]([N:11]1[CH2:10][C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:28]([C:27]([OH:38])=[O:26])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(F)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At r.t., trifluoroacetic acid (0.11 ml, 1.34 mmol, 0.1 eq.) followed by N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (4.89 g, 20.2 mmol, 1.5 eq.) were added dropwise to a stirred solution of (3,4-difluoro-phenyl)-propynoic acid ethyl ester (2.83 g, 13.5 mmol) in CH2Cl2 (80 ml). The yellow solution was stirred at r.t. for 18 h. Trifluoroacetic acid (0.034 ml, 0.44 mmol, 0.033 eq.) and N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl) methylamine (1.66 g, 6.73 mmol, 0.5 eq.) were added, and the solution was stirred for 1 h. It was evaporated to dryness, and the residue was dissolved in dioxane (40 ml). An aqueous solution of NaOH (18.7 ml, 37.4 mmol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 18 h, and the low boiling organic solvent was removed under reduced pressure. Water (40 ml) was added, and the aqueous layer separated and washed twice with TBME (50 ml). The organic layers were washed with the same portion of water (15 ml). The combined aqueous layers were acidified by addition of aqueous 3M HCl (12.4 ml). The resulting suspension was stirred for 48 h at r.t. The white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 4.25 g (58%) of IIc as a white solid.
Reaction SMILES: [F:1][C:2]([CH2:5][CH3:6])([F:4])[F:3].[Br-].[Mg+2].[Br-].[Br:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14](N(OC)C)=[O:15]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([C:14](=[O:15])[CH2:6][CH2:5][C:2]([F:4])([F:3])[F:1])[CH:20]=[CH:21][CH:22]=1
Reactant: CCC(F)(F)F
Reactant: CON(C)C(=O)c1cccc(Br)c1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)F)c1cccc(Br)c1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A prepared solution of trifluoromethyl ethane-magnesium bromide (made by refluxing Mg with 1-bromo, 2-trifluoromethyl ethane in THF for 2 hours; 4.6 g=25.82 mmol) in THF was added slowly to a cold (0° C.) solution of 3-bromo-N-methoxy-N-methylbenzamide (3.5 g, 14.3 mmol) in THF. The stirring continued at room temperature for 1 hour, quenched with cold saturated aqueous NH4Cl, acidified with 1 N HCl and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The crude product was purified on silica gel (ISCO) using hexanes/EtOAc (10/1) as the eluting solvent to give 1-(3-Bromo-phenyl)-4,4,4-trifluoro-butan-1-one as a colorless oil (3.1 g, 77% yield). m/e (M−H)− 279, 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.5-2.6 (m, 2 H), 3.3-3.4 (m, 2 H), 7.5 (t, J=7.9 Hz, 1 H), 7.8-7.8 (m, 1 H), 7.9-8.0 (m, 1 H), 8.1 (t, J=1.7 Hz, 1 H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:14].[CH2:15](O)[CH3:16]>>[CH2:1]([CH:8]([CH2:13][CH2:12][Br:14])[C:9]([O:11][CH2:15][CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCC1Cc1ccccc1
Reactant: CCO
Reactant: Br
Product: CCOC(=O)C(CCBr)Cc1ccccc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
In absolute ethanol (78 ml), α-benzyl-γ-butyrolactone (14 g, 80 mmol) was added and then saturated for thirty minutes with gaseous hydrogen bromide, maintaining the temperature below 50° C. The reaction was then heated to 45° C. and stirred at this temperature for 16 hours. The solution was concentrated under reduced pressure and the resulting oil was taken into ethyl acetate (500 ml), washed once with water, and then dried over magnesium sulfate. The solvents were removed in vacuo to yield 15.13 grams of tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19](OCC)=[O:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][CH2:19][OH:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCO
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propanoate (97.5 mg, 0.285 mmol) in THF (1.2 mL) was added lithium tetrahydroborate (14.3 mg, 0.656 mmol) at 0° C. under an atmosphere of nitrogen. The reaction solution was allowed to warm to rt for 2 h. The reaction was quenched with MeOH and concentrated. The residue was purified by flash chromatography (60% ethyl acetate/hexane) to give product. LCMS for C12H12ClFN3O3(M+H)+: m/z=300.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[NH:18][C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[CH2:36]O>C1COCC1>[F:24][C:4]([F:3])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[N:18]([CH2:36][C:27]3[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=3[I:25])[C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Reactant: OCc1cc(C(F)(F)F)ccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil; 5.6 mg; 0.139 mmol) in THF (0.5 mL) at 0° C. under an atmosphere of N2 was added a solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 50 mg; 0.153 mmol) in THF (1 mL) dropwise. The resultant mixture stirred at 0° C. for 15 min prior to dropwise addition of 2-(bromomethyl)-1-iodo-4-trifluoromethyl)benzene (Intermediate 11; 50.7 mg; 0.139 mmol) as a solution in THF (0.5 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with H2O and partitioned between EtOAc (25 mL) and H2O (15 mL). The aqueous layer was re-extracted with EtOAc (3×25 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one as a clear oil. LCMS=611.7 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.91 (s, 2H), 7.89 (s, 1H), 7.52 (s, 1H), 7.29-7.26 (m, 1H), 5.44 (d, J=10.8 Hz, 1H), 4.88 (d, J=16.5 Hz, 1H), 4.62 (d, J=16.5 Hz, 1H), 3.77-3.70 (m, 1H), 2.45 (dd, J=14.1, 5.4 Hz, 1H), 2.06-1.98 (m, 1H), 1.22 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:32])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:29][CH2:30]C)=[N:23][C:24](SC)=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][O-:34].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:32])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:34][CH3:33])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(SC)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-4-ethoxy-2-methylsulfanyl-pyrimidine (250 mg, 0.513 mmol) in methanol (10 mL) was added sodium methoxide (4.1 mL, 0.5M solution in methanol, Aldrich). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The crude residue was taken in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-dimethoxy-pyrimidine (˜200 mg). It was then taken in ethanol (15 mL) and sodium ethoxide (58.1 mg, Fluka) was added. The reaction mixture was left in the fridge overnight then concentrated under reduced pressure. The crude residue was taken in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure. Purification of the crude residue by flash column chromatography (12 g of silica gel, eluting with 20-100% ethyl acetate in hexanes then with 3% methanol in ethyl acetate) gave rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-diethoxy-pyrimidine as an off-white foam (132 mg, 62%). HR-MS (ES, m/z) calculated for C25H27N4O2Cl2 [(M+H)+] 485.1506, observed 485.1508.