Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][CH:11]2[CH:7]([N:8]=[C:9]([NH:19][CH2:20][CH:21](F)[F:22])[S:10]2)[C@H:6]1[O:24]C(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[F:22][CH2:21][CH2:20][NH:19][C:9]1[S:10][CH:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:24])[CH:7]2[N:8]=1
Reactant: CC(=O)OC[C@H]1OC2SC(NCC(F)F)=NC2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1OC2SC(NCCF)=NC2[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
(5R,6S,7R)-5-(acetoxymethyl)-2-(2,2-difluoroethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (0.209 g, 0.51 mmol) was dissolved in anhydrous MeOH. Solid K2CO3 was added to the solution until it was basic, and the reaction was stirred at room temperature (1.5 h). The reaction was filtered and then concentrated in vacuo. The resulting oil was purified via flash column chromatography with a solvent system of 5:1 DCM and MeOH, providing (5R,6S,7R)-2-(2-fluoroethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (37) (0.106 g, 74% yield),1H NMR (500 MHz, methanol-d4) δ 3.26-3.27 (m, 1H), 3.43-3.46 (m, 1H), 3.51-3.56 (m, 2H), 3.58-3.61 (m, 1H), 3.74 (dd, 1H, J=2.3, 11.9 Hz), 3.93 (t, 1H, J=5.4 Hz), 4.08 (t, 1H, J=6.0 Hz), 6.01 (tt, 1H, J=4.3, 56.4 Hz), 6.34 (d, 1H, J=6.4 Hz). 13C NMR (125 MHz, methanol-d4) δ 58.84, 69.85, 74.23, 75.17, 90.09, 114.19 (t, JC-F=241 Hz), 161.92.
Reaction SMILES: [CH3:1][C@H:2]1[C@:7]2([CH3:15])[CH2:8][C@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH2:11][C:6]2=[CH:5][CH2:4][CH2:3]1.O=O.C([O:22]O)(C)(C)C.O>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:1][CH:2]1[C:7]2([CH3:15])[CH2:8][CH:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH2:11][C:6]2=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: CC(C)(C)OO
Reactant: C=C(C)[C@@H]1CCC2=CCC[C@@H](C)[C@]2(C)C1
Agent: O=O
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C1CCC2=CC(=O)CC(C)C2(C)C1
Temperature: 45 °C
Yield: 34 %

Procedure:
Silica phosphonate chromium (III) resin (48.9 g, PhosphonicS, Ltd.) was placed in a 5 L round bottom flask equipped with a condenser, thermowell, overhead stirrer, and sparge tube. Two (2) L of t-butanol and valencene distillate (68%, 500 g, 1.67 moles, 1 eq) were added, the contents were heated to 45° C., and the heterogeneous suspension was allowed to stir as oxygen was sparged through the solution (ca 1.5 L/min) and nitrogen flushed over the head-space. 70% t-butyl hydroperoxide in water (TBHP, 315 g, 2.45 moles, 1.47 eq) was added to the solution over 2 hrs while the temperature of the reaction was heated and maintained at 60±5° C. The reaction was allowed to stir until >90% of the valencene was consumed, as determined by gas chromatography. The reaction was then allowed to cool to room temperature and the silica catalyst removed by filtration. The flask and resin were washed with 500 mL isopropanol. One (1) L of deionized water was added to the combined organic solution (t-butanol and isopropanol), and the mixture was concentrated under reduced pressure by evaporation to afford an amber colored oil. The oil was dissolved in 3 L of toluene and washed with 3.125 L of 15% sulfuric acid for 15 minutes with vigorous agitation. The aqueous layer was removed and re-extracted with 1 L of toluene. The combined toluene layers were then washed three times with 2.5 L of 1 M sodium hydroxide, twice with 500 mL saturated sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure by evaporation to afford 378 g of viscous amber oil (33% nootkatone by weight, 0.57 moles, 34% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:7][C:8]=1[N:9]([CH3:28])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1
Reactant: CCOC(=O)CCc1ccc(Nc2ccc([N+](=O)[O-])cn2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(N(C)c2ccc([N+](=O)[O-])cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate (3.70 g, 11 mmol) in DMF (60 mL) were added under ice-cooling sodium hydride (60%, 490 mg, 12 mmol) and methyl iodide (0.77 mL, 12 mmol), and the resulting reaction solution was stirred for 2 hours gradually warming up to room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 4.27 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([OH:5])=O.CN1CCOCC1.Cl.[NH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:5]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCCS(C)(=O)=O)ccc2-3)cc1
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (example 127, 35 mg, 0.096 mmol) in DMF (1 mL) was added 4-methylmorpholine (0.064 mL, 0.58 mmol), 2-aminoethylmethylsulfone hydrochloride (27.7 mg, 0.17 mmol), and BOP (77 mg, 0.17 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min). Fractions containing the desired product were combined and dried via centrifugal evaporation to give 2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (8.3 mg, 0.018 mmol, 18.4% yield): product HPLC ret. time=2.54 min. (condition F); LC/MS M+1=468; 1H NMR (400 MHz, 1:1 CD3OD and CDCl3) δ ppm 7.87 (1H, d, J=8.36 Hz), 7.67 (2H, d, J=8.14 Hz), 7.40-7.50 (2H, m), 7.31 (2H, d, J=8.36 Hz), 5.06 (1H, s), 3.73 (2H, t, J=6.49 Hz), 3.19-3.30 (2H, m), 2.94 (3H, s), 2.57-2.70 (2H, m), 1.60-1.77 (2H, m), 0.94 (3H, t, J=7.37 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=O)[NH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:29].P(Cl)(Cl)(Cl)=O.C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:7]1[C:6]2[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[C:12]([Cl:29])=[N:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]2[CH2:9][N:8]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 10 g (0.025 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid, methyl ester, 1 g (0.005 mole) of phosphorus pentachloride and 250 ml of phosphorus oxychloride was refluxed under a drying tube for 44 hrs. Benzene (250 ml) was added and the dark solution was evaporated in vacuo at 50°-60°. Another 250 ml of benzene was added and the solution was again evaporated to dryness at reduced pressure. The residue was dissolved in 250 of methylene chloride and cooled in an ice bath. Ammonia was bubbled into the cold solution for 5 min to give a tan solid. Stirring at room temperature was continued for 15 min. The mixture was filtered and evaporated at reduced pressure to give a brown gum which solidified when triturated with 75 ml of boiling ether. This solid was dissolved in about 50 ml of methylene chloride and filtered over neutral alumina. Eluted first with methylene chloride and then with 30% ethyl acetate in methylene chloride. Evaporation of the ethyl acetate methylene chloride fractions gave a tan solid which was recrystallized from ethyl acetate to give off-white prisms with mp 200°-202°. Uv λ sh 213 μ (ε=44,600) infl 240 (27,500) infl 260 (20,000) infl 300 (1850) ir (CHCl3) 1717 cm-1 (COOCH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:13][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cc(F)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(F)ccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of ethyl 5-fluoro-2-mercaptobenzoate (I) (25.0 g, 124.9 mmol) and 1-fluoro-2-nitrobenzene (13.2 mL, 124.9 mmol) in acetone (700 mL) was added K2CO3 (34.5 g, 249.7 mmol) at ambient temperature. The yellow suspension was heated to reflux (60° C.) for 5 hours. The reaction mixture was quenched with 1N HCl (500 mL), diluted with EtOAc (1000 mL) and filtered through a bed of diatomaceous earth. The aqueous layer was removed, the EtOAc layer was washed with 1N HCl (250 mL×2) and brine (200 mL×1), dried and the solvent removed under reduced pressure. The material was carried forward with no further purification to yield ethyl 5-fluoro-2-(2-nitrophenylthio)benzoate (II) (39.3 g, 95%) as a dark yellow solid. m/z (ES+) M+1=322.1; HPLC tR=0.88 min. 1H NMR (300 MHz, DMSO-d6): δ 1.09 (t, 3H, J=7.2 Hz), 4.16 (q, 2H, J=7.2 Hz), 7.07 (d, 1H, J=7.2 Hz), 7.40-7.75 (m, 5H), 8.20 (d, 1H, J=7.2 Hz).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:23])[NH:7][C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]([CH3:20])[CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:23])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:41])([C:33]([F:34])([F:35])[F:36])[C:37]([F:38])([F:39])[F:40])=[CH:30][CH:31]=4)[CH2:16]3)[CH3:20])=[O:13])=[CH:21][CH:22]=2)[CH2:2][CH2:3]1
Reactant: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCNC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C1
Yield: 14.7 %

Procedure:
A mixture of 4-(3-(cyclopropylmethyl)ureido)-N-methyl-N-(pyrrolidin-3-yl)benzamide (4.74 mmol, 1.5 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.74 mmol, 1.598 g) and potassium carbonate (7.11 mmol, 0.983 g) in acetonitrile (40 mL) was refluxed for 5 hours. The reaction was concentrated under reduced pressure and dichloromethane/methanol was added. The suspension was filtered and the filtrate was concentrated under reduced pressure. Chromatography on silica eluting with a gradient of dichloromethane/methanol gave the title compound (400 mg). MS (ESI) m/z 573.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br-:13].[Br-].O1CCOCC1>O1CCOCC1>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:12]
Reactant: [Br-]
Reactant: CCC(=O)c1ccc(F)c(F)c1
Solvent: C1COCCO1
Product: CC(Br)C(=O)c1ccc(F)c(F)c1
Yield: 98.9 %

Procedure:
To 3',4'-difluoropropiophenone (Alfa Products, Danvers, Mass. 01923) (90.5 g, 0.53 mole) was added a solution of dioxane dibromide (131 4 g, 0.53 mole) in dioxane (500 ml). The reaction was worked up as in Example 1 to yield crude 2-bromo-3',4'-difluoropropiophenone (130.5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:4](=[O:18])[CH:3]=1.[CH3:19][C:20](=[N:22][NH2:23])[CH3:21].CNN>>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:5]2[C:4](=[O:18])[CH:3]=[C:2]([NH:23][N:22]=[C:20]([CH3:21])[CH3:19])[CH:7]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)=NN
Reactant: O=c1cc(Cl)cnn1-c1cccc(C(F)(F)F)c1
Agent: CNN
Product: CC(C)=NNc1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1

Procedure:
Following essentially the same procedure as in example 2, but using an equivalent amount of 5-chloro-2-(3-trifluoromethylphenyl)-pyridazin-3(2H)-one and acetone hydrazone in place of the 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazin-3(2H)-one and methylhydrazine used therein, there is obtained 2-(3-trifluoromethylphenyl)-5-(2-isopropylidenehydrazino)-pyridazin-3(2H)-one, (m.p. 255° to 257° C).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[NH2:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(OC(O)C)C>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1c(Br)cnc2ccccc12
Reactant: NCC1(O)CCCCC1
Agent: CCOC(C)O
Agent: Cl
Solvent: CCN(CC)CC
Product: OC1(CNc2c(Br)cnc3ccccc23)CCCCC1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromo-4-chloroquinoline (12.1 g), 1-aminomethyl-1-cyclohexanol HCl (8.3 g), triethylamine (7.2 g) and 30 ml of ethoxyethanol was stirred at 120° C. for 5 hours and poured into 250 ml of ice water. The solid was filtered and recrystallized from acetone. The yield was 6.5 g, mp 130°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].O1CCCC1.C([Li])(CC)C.CS(O[CH2:61][CH2:62][S:63]([CH3:66])(=[O:65])=[O:64])(=O)=O>CO.O>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:61][CH2:62][S:63]([CH3:66])(=[O:65])=[O:64])[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Agent: [Li]C(C)CC
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCS(C)(=O)=O)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (1.51 g, 2.44 mmol) and tetrahydrofuran (20 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of s-butyl lithium (3.94 mL, 1.3 M in hexane, 5.12 mmol). After 30 minutes, add a solution of 2-methylsulfonylethyl methanesulfonate (0.60 g, 2.93 mmol). Allow to warm to ambient temperature and then heat to reflux. After 48 hours, cool to ambient temperature and add water. Separate the layers. Extract the aqueous layer four times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane to give the title compound: Rf=0.54 (silica gel, 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:31]2[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:31]2[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:19]=[C:20]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:21]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(F)cc(-c2cnc3nc(C(F)(F)F)ccn23)c1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a yellow solid: δH (360 MHz, DMSO) 7.55 (1H, d, J 7), 7.62-7.69 (2H, m), 7.80-7.87 (4H, m), 8.03 (1H, d, J 8), 8.40 (1H, s), 9.47 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:15]([N:20]1[CH2:25][CH2:24][CH:23]2[S:26][C:27](=[O:29])[CH:28]=[C:22]2[CH2:21]1)[C:16]([O:18][CH3:19])=[O:17].CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:3][N:4]([CH3:7])[C:5]([O:29][C:27]1[S:26][C:23]2[CH2:24][CH2:25][N:20]([C@@H:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])[C:16]([O:18][CH3:19])=[O:17])[CH2:21][C:22]=2[CH:28]=1)=[O:6]
Reactant: CN(C)C=O
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Agent: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)N(C)C)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
In an ice bath, sodium hydride (20 mg, 60%) were added to 6 ml of anhydrous N, N-dimethyl formamide, to which 169 mg of (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridine-5(2H,4H,6H)-yl)-acetate (IV-1) was then added. The reaction was naturally warmed to room temperature, stirred for 1 hr, and then cooled to 0° C. 200 μl of N,N-dimethylcarbamoyl chloride was slowly added dropwise. The reaction was naturally warmed to room temperature, and stirred for 3 hrs, and at this time, TLC showed that the raw materials substantially disappeared. The reaction solution was poured into water (30 ml), the aqueous phase was extracted with ethyl acetate (50 ml×3), and the organic phase was dried to obtain a crude product, which was subjected to flash column chromatography (petroleum ether:ethyl acetate=40:3), to obtain (S)-methyl 2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-18) (95 mg). Yield: 45%, mp 96-98° C., ee=93.5% (chiral HPLC analysis conditions were the same as those in Example 10), [α]D20=+34° (c 0.50, MeOH); 1H-NMR (500 MHz, CDCl3) δ 2.73-2.76 (m, 2H), 2.85-2.89 (m, 2H), 2.99 (s, 3H), 3.03 (s, 3H), 3.52 (d, 1H, J=14.3 Hz), 3.63 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.91 (s, 1H), 6.19 (s, 1H), 7.26-7.69 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 25.03, 36.37, 36.88, 48.18, 50.40, 52.12, 67.87, 111.48, 125.38, 127.12, 129.09, 129.37, 129.76, 129.95, 130.56, 133.80, 134.34, 134.68, 151.04, 171.27; ESI-MS m/z 409.2 [M+H]+; HRMS Calcd for C19H22N2O4SCl [M+H]+ m/z 409.0992. found 409.0989.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (5 g, 32.13 mmol) in CH2Cl2 (100 mL) was added with TEA (1.1 mol eq, 4.9 mL) and the mixture was stirred at r.t. for 10 minutes. Then 4-chlorobenzensulfonyl chloride (1 mol eq, 6.81 g) and additional TEA (1.1 mol eq) were added and the solution hated at 50° C. for 5 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The combined organic phases were dried over Na2SO4 and evaporated to reduced pressure. The residue was recrystallized from ethyl ether to afford 2C as white solid (8.6 g, 91% yield). 1HNMR (DMSO, 200 MHz) δ 3.51 (s, 3H), 3.60 (m, 2H), 3.91 (t, 1H), 5.17 (t, 1H), 7.50 (d, 2H, J=8), 7.89 (d, 2H, J=7.8)), 8.35 (bs, 1H).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([C:13]1[CH:44]=[CH:43][C:16]([CH2:17][C:18]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=2)(C(OCC=C)=O)[C:19]([O:21]CC=C)=[O:20])=[CH:15][CH:14]=1)#[N:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([CH:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:44][CH:43]=1)[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=1)([OH:21])=[O:20]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC(Cc2ccc(C#N)cc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 7.5 ml (53.6 mmol) of triethylamine and 1.5 ml (40.6 mmol) of formic acid in 170 ml of dioxane is added to a solution of 7.5 g (16.25 mmol) of diallyl 2-(4-cyanobenzyl)-2-[2-(4-methoxycarbonylphenyl)ethyl]malonate, 0.3 g (1.14 mmol) of triphenylphosphine and 70 mg of palladium acetate in 170 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 2 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The residue is taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three times more with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. 5.48 g (89% of theory, 90% purity) of a colorless solid are obtained.
Reaction SMILES: [N:1]([C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:7][CH2:6][CH2:5][C:4]([N:1]=[N+:2]=[N-:3])([CH3:9])[CH3:8])(=[O:22])=[O:21]
Reactant: CC(C)(CCO)N=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCOS(C)(=O)=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutan-1-ol (3.33 g, 25.8 mmol) and DIEA (9.0 mL, 2 equiv, 51.6 mmol) in anhydrous DCM (200 mL) was added methanesulfonyl chloride (2.99 mL, 1.5 equiv, 38.7 mmol) over 5 min. The reaction was stirred and left at 0° C. for 1.5 h. The reaction mixture was extracted with 1 N HCl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give a colorless liquid. The crude oil was purified on an ISCO purification system with gradient elution from 5-40% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless liquid (4.45 g, 83.4). 1H NMR (CDCl3, 400 MHz): δ 1.36 (s, 6H), 1.93-1.98 (t, J=6.8, 2H), 3.32-4.36 (t, J=6.8, 2H).