Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([N:7]2[C:11]3[C:12]4[O:16][C:15]([CH3:17])=[N:14][C:13]=4[C:18]([F:21])=[C:19]([F:20])[C:10]=3[N:9]([C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])C2=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[K].FC1C2N=COC=2C(NS(C2CC2)(=O)=O)=C(NC2C=CC(I)=CC=2F)C=1F>>[F:21][C:18]1[C:13]2[N:14]=[C:15]([CH3:17])[O:16][C:12]=2[C:11]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[C:10]([NH:9][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:19]=1[F:20]
Reactant: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Agent: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Agent: [K]
Product: Cc1nc2c(F)c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3CC3)c2o1

Procedure:
Compound 1E was prepared from 8-cyclopropanesulfonyl-4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-22a: 55 mg, 0.12 mmol) and potassium trimethylsilonolate (30 mg, 0.18 mmol) using procedures analogous to those described above for Compound 1A to afford 3 mg of the product (5.66% yield). H1NMR (CDCl3, 300 MHz): δ 7.40 (d, 1H), 7.30-7.22 (m, 1H), 6.59 (s, 1H), 6.49 (s, 1H), 6.40-6.30 (m, 1H), 2.70 (s, 3H), 2.66-2.58 (m, 1H), 1.22-1.14 (m, 2H), 1.04-0.94 (m, 2H). LCMS: 82.6%, m/z=523.6 (M+1). HPLC: 99.35%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[OH:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH3:28]>C(#N)C>[CH2:1]([N:3]([CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH3:28])[CH2:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)[OH:6])[CH3:2]
Reactant: CCCSCCCBr
Reactant: CCNCC(O)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCSCCCN(CC)CC(O)c1ccc(C#N)cc1

Procedure:
1.5 g of 4-[2-(ethylamino)-1-hydroxyethyl]-benzonitrile, 2.1 g of potassiumcarbonate, 1.7 g of 1-bromo-3-(propylthio)-propane was mixed in 50 ml acetonitrile and refluxed over night. The mixture was filtered and evaporated and the residue was dissolved in 2 M hydrochloric acid. The acidic waterlayer was washed twice with ether, alkalized with 10 M sodiumhydroxide and extracted with three portions of dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19](Cl)=[O:20].O>CN(C=O)C>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][CH2:18][C:19](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc(F)c(Br)cc2N1
Temperature: 80 °C
Yield: 90.3 %

Procedure:
To a 0° C. mixture of 2-amino-4-bromo-5-fluorophenol (38.0 g, crude from previous step) and K2CO3 (76.0 g, 553 mmol) in DMF (100 mL) was added 2-chloroacetyl chloride (23.0 g, 15.3 mL, 203 mmol) drop-wise. The reaction mixture was heated at 80° C. overnight then cooled to ambient temperature and poured into water (300 mL). The precipitate was collected by filtration, washed with water and dried to give 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 7.13 (m, 2H), 4.62 (s, 2H). The amide proton was not observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[C:14](O)(=O)C.C(=N)N.C(O)CCC.O(C(C)C)C(C)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[N:12][C:11]([SH:13])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NNC(N)=S)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CC(C)OC(C)C
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-n2cnc(S)n2)cc1
Yield: 73 %

Procedure:
A mixture of 10 parts of 2-(4-methoxyphenyl)hydrazinecarbothioamide, 10.6 parts of methanimidamide acetate and 80 parts of 1-butanol is stirred and refluxed for 1 hour. After cooling, water and 2,2'-oxybispropane are added, whereupon the product is precipitated. It is filtered off and dried, yielding 7.6 parts (73%) of 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:15]([CH3:16])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]2[CH3:24])=[N:8][CH:9]=1)#[N:3]>>[CH3:16][CH:15]1[CH2:14][NH:13][CH2:12][CH:11]([CH3:24])[N:10]1[C:7]1[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][N:8]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1c1ccc(C#N)cn1
Agent: Cl
Product: CC1CNCC(C)N1c1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
6N HCl (0.5 mL) was added to tert-butyl 4-(5-cyanopyridin-2-yl)-3,5-dimethylpiperazine-1-carboxylate (120 mg, 0.37 mmol) and the reaction mixture was stirred at 90° C. for 30 min. the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and triturated with ether to afford 6-(2,6-dimethylpiperazin-1-yl)nicotinonitrile (90 mg, crude), which was carried through without further purification. 1H NMR (300 MHz, D2O) δ 8.51 (d, J=2.2 Hz, 1H), 7.93 (dd, J=9.1 Hz, J=2.3 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 4.75 (m, 2H), 3.53-3.49 (m, 2H), 3.41-3.34 (m, 2H), 1.42 (s, 3H), 1.39 (s, 3H).
Reaction SMILES: Cl.CN[O:4][CH3:5].C[Al](C)C.C([C@H:17]1COC(=O)[N:18]1[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26]1)=[O:24])C1C=CC=CC=1>C(Cl)Cl>[CH3:5][O:4][N:18]([CH3:17])[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:26]1)=[O:24]
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (7.82 g, 80.6 mmol) in DCM (130 mL) at RT was added trimethylaluminium (2.0M solution in heptane, 40.3 ml, 80.6 mmol) dropwise and stirring was continued for one hour. To this mixture was added a solution of (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one (19.2 g, 40.3 mmol) in DCM (100 mL) over 10 minutes. Stirring was continued for three hours. The reaction was quenched by an addition of aq. Potassium sodium tartarate solution and extracted with ethyl acetate. The separated organic layer was washed with brine and dried on Na2SO4 and concentrated under vacuo. Its purification by column chromatography (SiO2, EtOAc/H, 15:85) yielded 13 g (90%) of the title compound as a light yellow oil. ES-MS m/e: 361.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[CH3:42][NH2:43].[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:43][CH3:42])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.304 mmol) and magnesium sulfate (92 mg, 0.373 mmol) in THF (4 mL), methylamine (1.52 mL, 3.044 mmol, 2M in THF) is added. The solution is stirred at RT overnight under nitrogen atmosphere and NaBH4 (23 mg, 0.608 mmol) is added. The resulting mixture is stirred for 1 h and the excess reducing agent quenched with water, CH2Cl2 is added and the reaction mixture is poured into an aqueous saturated solution of NaHCO3. The organic layer is separated and the aqueous phase extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5+1% NH4OH ) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.05. MS (LC-MS) [M−H]+=508.1. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 4.53 min.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:23][CH3:24])[C@H:3]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:25](=O)(OC1C=CC([N+]([O-])=O)=CC=1)[O:26]C1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O>[CH3:1][C@@H:2]([CH2:23][CH3:24])[C@H:3]([N:11]1[CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:25]1=[O:26])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](NCCNCc1cccc(C)n1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Yield: 57 %

Procedure:
A solution of the product of Example 32D in N,N-dimethylformamide (60 mL) was treated with bis-(p-nitrophenyl) carbonate (12.6 g, 1.2 equivalents) at 50° C. for 5 hrs. The solvents were evaporated, and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated, and the residue was purified using ethyl acetate:hexanes (2:1) to give 7.3 g (57%) of the title compound.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:16][N:15]=1)=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1.O>[CH:1]([NH:4][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:16][N:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C)nc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of isopropylamine (98 mg, 1.66 mmol) in dioxane (3 mL) was added dropwise a trimethylaluminium (0.83 mL, 2 M solution in toluene, 1.66 mmol) and the resulting solution stirred under argon for 30 min. A solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid ethyl ester (140 mg, 0.41 mmol) in dioxane (3 mL) was then added and the resulting solution stirred under argon for a further 20 h at 85° C. The reaction mixture was cooled and Seignette salt solution (2 mL) and water (2 mL) were added. The reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried, filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 6% methanol in dichloromethane) gave the title compound (138 mg, 95%) as a light yellow solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])[CH3:13]
Reactant: CCC(=O)CC(=O)CC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)CC)C(=O)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
Dissolve heptane-3,5-dione (2.5 g, 19.5 mmol) in dry tetrahydrofuran (10 mL) and add the resulting solution dropwise to a chilled (0° C.) suspension of sodium hydride (0.94 g, 23.4 mmol, 60% dispersion in oil) in tetrahydrofuran (20 mL). Stir at 0° C. for 1 hr., then add bromoacetic acid ethyl ester (2.6 mL, 23.4 mmol) dropwise. Stir for 16 hr. at 0° C. and warm to room temperature. Partition the reaction mixture between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL). Separate the organic layer and wash with saturated aqueous sodium chloride solution (50 mL), dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give 4-oxo-3-propionyl-hexanoic acid ethyl ester as an oil (3.2 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 4.08 (m, 3H), 2.83 (d, 2H), 2.55 (q, 2H), 1.21 (t, 3H), 1.02 (t, 6H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1.[Br:16]/[CH:17]=[C:18]1\[CH2:19][CH2:20][CH2:21][C@@:22]2([CH3:30])[C@H:26]\1[CH2:25][CH:24]=[C:23]2[C@@H:27]([OH:29])[CH3:28].Br[CH2:32][C:33]([NH:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[O:34].[Cl-].[NH4+]>CN(C)C=O.CCCCCC>[Br:16]/[CH:17]=[C:18]1\[CH2:19][CH2:20][CH2:21][C@@:22]2([CH3:30])[C@H:26]\1[CH2:25][CH:24]=[C:23]2[C@@H:27]([O:29][CH2:32][C:33]([NH:35][CH2:36][C:37]([F:42])([F:43])[C:38]([F:41])([F:39])[F:40])=[O:34])[CH3:28]
Reactant: C[C@H](O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Reactant: O=C(CBr)NCC(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C[C@H](OCC(=O)NCC(F)(F)C(F)(F)F)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: -15 °C
Reaction time: 0.07 h

Procedure:
Under a nitrogen atmosphere, a solution of sodium hexamethyldisilazide in tetrahydrofuran (1.1 M, 5.31 ml, 5.84 mmol) was cooled to −15° C., and a solution of (S)-1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanol (Compound 5: 633.7 mg, 2.337 mmol) in dimethylformamide (1 ml) was added thereto over 4 minutes. The resulting mixture was stirred at −15° C. for 7 minutes, and a solution of 2-bromo-N-(2,2,3,3,3-pentafluoropropyl)acetamide (726 mg, 2.688 mmol) in dimethylformamide (1 ml) was added thereto over 5 minutes. After stirring the reaction solution at −5° C. for 30 minutes, aqueous ammonium chloride solution (5 ml) and hexane (20 ml) were added thereto, and the separation of the solution was conducted. The obtained organic layer was sequentially washed with water (5 ml) and saturated brine (4 ml)/water (1 ml), and the solvent was evaporated. The obtained crude product was purified by silica gel column chromatography to obtain 2-[(S)-1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethoxy]-N-(2,2,3,3,3-pentafluoropropyl)acetamide (1.08 g, quantitatively).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[Cl:22][C:23]1[CH:24]=[C:25]([SH:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([S:30][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 19 h
Yield: 74.3 %

Procedure:
A solution containing 2.0 g of (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-phenyl-methanone, 2.0 g of 3,5-dichlorothiophenol and 1.7 g of potassium carbonate in 50 ml of N,N-dimethylformamide was stirred at 60° C. for 19 h. The mixture was partitioned between 100 ml of water and 100 ml of dichloromethane. The organic layer was dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane for the elution to give 2.2 g of [5-(3,5-dichloro-phenylsulfanyl)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanone as a yellow oil. Mass spectrum (ES) m/z 439 [M+H]+, 480 [M+H+CH3CN]+.
Reaction SMILES: ClC1[N:7]=[C:6](C)[C:5](CC)=[C:4](C)[N:3]=1.[CH3:12][C:13]1[C:14](I)=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].FC1C(I)=C(C=CC=1)C(O)=O>>[CH3:12][C:13]1[C:14]([N:7]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]
Reactant: CCc1c(C)nc(Cl)nc1C
Reactant: Cc1cccc(C(=O)O)c1I
Agent: O=C(O)c1cccc(F)c1I
Product: Cc1cccc(C(=O)O)c1-n1cccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 36 substituting 3-methyl-2-iodobenzoic acid for 3-fluoro-2-iodobenzoic acid. 1H NMR (500 MHz, CDCl3): 7.79 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 6.53 (s, 1H), 2.07 (s, 3H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][CH:17]([F:20])[F:16])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
With cooling with ice, 2.7 ml of trifluoromethanesulfonic acid anhydride was added to a chloroform (100 mL) solution of 1 mL of 2,2-difluoroethanol and 2.2 mL of triethylamine, and stirred for 30 minutes. The reaction liquid was diluted with chloroform, and washed with aqueous saturated sodium bicarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.S(=O)(O)[O-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccc(O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3ccccc3c2)cc1
Yield: 70.4 %

Procedure:
A mixture of 1.00 g (6.94 mmol, Aldrich) of 2-naphthol, 1.01 g (9.26 mmol, Aldrich) of 4-aminophenol, and 5.2 g (50 mmol, Aldrich) of sodium bisulfite in 30 ml of H2O was refluxed for 36 hours. The reaction mixture was cooled, added to 50 ml of H2O and extracted with 50 ml of hot ethyl acetate. The organic layer was separated, washed with an additional 50 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (15×5.0 cm, 1:4 EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 1.15 g (71%) of title compound as pale purple flakes, m.p. 134°-135° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:32][O:33][C:34]1[C:35]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:44]=2[CH2:53]Br)=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=1>C1COCC1.CC(N(C)C)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:53][C:44]3[CH:45]=[C:46]([C:49]([F:50])([F:51])[F:52])[CH:47]=[CH:48][C:43]=3[C:35]3[CH:36]=[C:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.08 h

Procedure:
((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one) (46.2 mg, 0.148 mmol) was placed in a dry flask and DMA (3 mL) was added. NaHMDS (296 μL of a 1M solution in THF, 0.296 mmol) was added and the reaction was stirred for 5 min. At this time, 2′-(bromomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl methyl ether (80.0 mg, 0.207 mmol) was added by cannula in DMA (2 mL). After 30 min, the reaction was quenched with saturated NH4Cl (2 mL). The mixture was diluted with EtOAc (40 mL). The organic layer was washed with water (15 mL), and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.27 (25% EtOAc/hexanes). LCMS=620.2 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 6.90-7.88 (m, 9H), 4.04-5.05 (m, 3H), 3.25-3.74 (m, 4H), 2.88 (m, 1H), 1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6](F)[C:5]([Br:13])=[CH:4][CH:3]=1.F[C:15]1C2C(=O)OC(=O)NC=2C=CC=1.CC1C2C(=O)OC(=O)NC=2C=CC=1>>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH3:15])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1F
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Agent: Cc1cccc2[nH]c(=O)oc(=O)c12
Product: CNC(=O)c1c(N)ccc(Br)c1C

Procedure:
Prepared analogously to Compound 27D replacing 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 27E) with 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 29E). 1H NMR (CDCl3, 500 MHz) δ 2.32 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 4.0 (br.s, 2H), 5.81 (br.s, 1H), 6.42 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[CH2:38][O:39][C:40](=[O:50])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][O:46][N+:47]([O-:49])=[O:48])=[C:19](\[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)/[C:20]([O:22][C@@H:23]([CH3:31])[C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[CH2:38][O:39][C:40](=[O:50])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][O:46][N+:47]([O-:49])=[O:48])=[C:19](\[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)/[C:20]([O:22][C@@H:23]([CH3:31])[C:24]([OH:26])=[O:25])=[O:21])=[CH:16][CH:17]=1)(=[O:11])=[O:10]
Reactant: C[C@H](OC(=O)/C(=C(\COC(=O)CCCCCO[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](OC(=O)/C(=C(\COC(=O)CCCCCO[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1)C(=O)O

Procedure:
The titled compound (0.25 g) was obtained as a white powder after a TFA treatment of the (1S)-2-tert-butoxy-1-methyl-2-oxoethyl (2Z)-3-[4-(methylsulfonyl)phenyl]-4-{[6-(nitrooxy)hexanoyl]oxy}-2-phenylbut-2-enoate as prepared above. 1H NMR (500 MHz, Acetone-d6): δ 7.80 (d, 2 H), 7.48 (d, 2 H), 7.17–7.09 (m, 5 H), 5.34 (s, 2 H), 5.25 (m, 1 H), 4.50 (t, 2 H), 3.08 (s, 3 H), 2.25 (t, 2 H), 1.69 (m, 2 H), 1.55 (d, 3 H), 1.49 (m, 2 H), 1.32 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[F:12][C:13]1([F:25])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH2:24])=[CH:21][C:15]=2[O:14]1.C(=O)(O)[O-].[Na+]>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][C:20]2[CH:19]=[CH:18][C:16]3[O:17][C:13]([F:25])([F:12])[O:14][C:15]=3[CH:21]=2)[CH:7]=1
Reactant: NCCc1ccc2c(c1)OC(F)(F)O2
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc3c(c2)OC(F)(F)O3)n1
Yield: 79 %

Procedure:
To a solution of 4,6-dichloro-2-methoxy-pyrimidine (0.606 g, 3.38 mmol, Intermediate (4)] and 2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethylamine hydrochloride (0.884 g, 3.72 mmol, Intermediate (62)]) in EtOH (11 mL) is added sodium bicarbonate (0.85 g, 10.14 mmol) and heated to reflux for 4 hours. The reaction mixture is filtered and filtrate is concentrated, residue solid is washed with small amount of EtOH to yield (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,2-difluoro-benzo[1,3]dioxol-5yl)-ethyl]-amine [0.918 g, 79%, Intermediate (63)] as a solid. LC/MS: MS: 344 (M+H).