Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:26].[O:28]1[CH:33]=[CH:32][CH2:31][CH2:30][CH2:29]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:27][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:26]
Reactant: C1=COCCC1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OC5CCCCO5)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Reaction time: 7 h

Procedure:
8.4 g of 11β-fluoro-7α-(5-bromopentyl)-3-hydroxyestra-1,3,5(10)-trien-17-one in 90 ml of tetrahydrofuran are allowed to react at room temperature with 9.0 ml of 3,4-dihydropyran and 805 mg of p-toluenesulphonic acid hydrate. After 7 h, 1 ml of triethylamine is added, and the mixture is diluted with ethyl acetate, washed with saturated sodium chloride solution until neutral and dried over sodium sulphate. Chromatography on silica gel using a hexane-ethyl acetate gradient affords 7.6 g of 11β-fluoro-7α-(5-bromopentyl)-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one as a foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:36]6[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1ccc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.35 mmol, 1 eq), 1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.058 g, 0.42 mmol, 1.2 eq), HOBT (0.08 g, 0.069 mmol, 1.7 eq), EDC.HCl (0.073 g, 0.014 mmol, 1.8 eq), in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and the final purification was done by preparative HPLC. Yield: 0.06 g (45%) 1H NMR (400 MHz, DMSO-d6): δ 1.18-1.20 (m, 4H), 2.29 (s, 3H), 2.81-2.82 (d, 3H, J=4.64 Hz), 3.73 (s, 3H), 3.96 (s, 3H), 6.06-6.07 (d, 1H, J=2.4 Hz), 7.12 (s, 1H), 7.32-7.34 (dd, 1H, J=8.4, 1.6 Hz), 7.38.-7.42 (t, 2H, J=8.8 Hz), 7.48.-7.49 (d, 2H, J=2.34 Hz), 7.59 (s, 1H), 7.71-7.73 (d, 1H, J=8.4 Hz), 7.97-7.97-8.01 (m, 2H), 8.47-8.48 (d, 1H, J=4.8 Hz), 8.69 (s, 1H). LCMS: (ES+) m/z=553.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [CH:1](/[Sn](CCCC)(CCCC)CCCC)=[CH:2]/[CH3:3].[O:17]([CH2:24][C:25]([NH:27][CH:28]1[C:56](=[O:57])[N:30]2[C:31]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:32](OS(F)(=O)=O)[CH2:33][S:34][C@H:29]12)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:17]([CH2:24][C:25]([NH:27][CH:28]1[C:56](=[O:57])[N:30]2[C:31]([C:40]([O:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:32](/[CH:1]=[CH:2]\[CH3:3])[CH2:33][S:34][C@H:29]12)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)F)CS[C@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.05 h
Yield: 92.9 %

Procedure:
A solution of palladium (II) acetate (3.6 mg, 0.016 mmole, 0.1 eq.) in dichloromethane (2 mL) was treated with Z-1-propenyl tri-n-butylstannane (66.2 mg, 0.2 mmole, 1.2 eq.) under an inert atmosphere and allowed to stir for 3 minutes. The resulting dark suspension was then treated with diphenylmethyl 7-phenoxyacetamido-3-[(fluorosulfonyl)oxy]-3-cephem-4-carboxylate (100.0 mg, 0.16 mmole, 1.0 eq.) in one portion and the reaction mixture was allowed to stir for 10 minutes. The reaction mixture was diluted with additional dichloromethane and washed with water (1×10 mL). The organic fraction was dried over magnesium sulfate and purified by flash filtration through a pad of silica gel (W. R. Grace, 951W) first with dichloromethane (50 mL) to remove the residual stannane and then with 10% ethyl acetate in dichloromethane (50 mL) which upon concentration furnished 80.4 mg (89%) of the title compound as a pale yellow solid. The product was then recrystallized from isopropyl alcohol to afford 62.3 mg (69%) of a white solid, mp. 103°-104° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([Se:19][CH3:20])[N:3]=1>CCOC(C)=O.C1CCCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([Se:19][CH3:20])[N:3]=1
Reactant: C[Se]c1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C[Se]c1nc(N)nc2c1ncn2[C@@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
The procedure was the same as that used for the synthesis of 7a except that 500 mg (0.0015 mol) of 2 was used and the yield from the EtOAc-cyclohexane mixture was 200 mg (39%) of product, mp 167°-170°. For analysis the sample was dried in vacuo over Drierite for 1 hr. at the temperature of refluxing toluene: mp unchanged; uv λmax (pH 1) 334 nm ( ε 14 400); uv λmax (MeOH) 313 nm ( ε 15 800); uv λmax (pH 11) 316 nm ( ε 15 500).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].N1C=CC=CC=1.[C:13]([C:21]1[CH:22]=[CH:23]C(C)=[C:25]([N:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:28](=[O:30])[CH3:29])[CH:26]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[C:40]([O:43]CC)(=[O:42])[CH3:41]>O>[C:13]([C:21]1[CH:22]=[CH:23][C:41]([C:40]([OH:43])=[O:42])=[C:25]([N:27]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:28](=[O:30])[CH3:29])[CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C(=O)O
Temperature: 25 °C

Procedure:
Potassium permanganate 0.24 g was added to a mixed solution of pyridine 5.0 mL and water 5.0 mL of N-(5-benzoyl-2-methylphenyl)-N-(4-fluorophenyl)acetamide 0.52 g at room temperature, and it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, potassium permanganate 0.24 g was added to it, it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, potassium permanganate 0.24 g was added to it, it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, furthermore, potassium permanganate 0.24 g was added to it, and it was heated and refluxed for 30 minutes. After the reaction mixture was cooled, ethyl acetate was added to it, it was adjusted to pH2.3 with 6.0 mol/L hydrochloric acid, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2] to give 4-benzoyl-2-(N-(4-fluorophenyl)acetamido)benzoic acid 0.39 g of white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]3[S:11][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:13][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]3[S:11](=[O:25])[CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:13][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc2c1nc1n2CC(c2ccccn2)S1
Product: Cc1cccc2c1nc1n2CC(c2ccccn2)S1=O
Yield: 75.3 %

Procedure:
In a manner analogous to Example 4 2,3-dihydro-8-methyl-2-(2-pyridyl)thiazolo[3.2-a]-benzimidazole (1.04 g) was reacted with m-chloroperoxybenzoic acid (0.85 g) to give the title compound (0.83 g. 80%) mp 182° C decomp.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.[CH3:13][NH:14]N.CC(O)=O>CC(O)(C)C>[CH3:13][N:14]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:2]1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CNN
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Cn1ncc2c1CCCC2=O
Yield: 44.4 %

Procedure:
To a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (55 g crude, 300 mmol) in t-BuOH (400 ml) was added methylhydrazine solution (35 g, 40% aqueous solution, 304 mmol) and AcOH (20 ml) at room temperature. The resulting mixture was heated to reflux for 3 h under nitrogen protection. After cooling, the mixture was concentrated in vacuo and the residue was purified by column chromatograph on silica gel (petroleum ether/ethyl acetate=1/1 v/v %) to give 1-methyl-6,7-dihydro-1H-indazol-4(5H)-one (20 g, two steps: 44%). MS-ESI (m/z): 151 (M+1)+ (Acq Method: 0-60AB_2 min; Rt: 0.90 min)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][CH:13]1[CH2:15][O:14]1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH:13]1[CH2:15][O:14]1
Reactant: BrCC1CO1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCC2CO2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 113.3 %

Procedure:
To a solution of compound NaH (416.2 mg, 17.34 mmol) in DMF (10 mL) was added 3-bromophenol (1.0 g, 5.78 mmol) at 20° C. After addition the solution was stirred for 5 minutes at this temperature before the addition of 2-(bromomethyl)oxirane (1.2 g, 8.67 mmol). The reaction mixture was stirred for 16 h at 20° C. Once complete the reaction mixture was treated with water (50 mL) and extracted with EA (2×20 mL) and the organic layers combined and washed with NaHCO3, brine (30 mL), dried over Na2SO4 and concentrated to give the compound 2-((3-bromophenoxy)methyl)oxirane (1.5 g, crude) as colorless oil which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[O:12]=[C:10]([N:29]1[CH2:28][CH2:27][CH2:26][CH2:24]1)[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)butanoic acid (1.5 g, 7.38 mmol), HATU (3.37 g, 8.86 mmol) and pyrrolidine (1.303 mL, 14.76 mmol) in DCM (50 mL) was added Et3N (2.057 mL, 14.76 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.6 g, 85%). 1H NMR (500 MHz, CDCl3) δ 0.88-1.04 (m, 3 H) 1.38-1.48 (m, 9 H) 1.52-1.64 (m, 1 H) 1.69-1.79 (m, 1 H) 1.82-1.92 (m, 2 H) 1.92-2.02 (m, 2 H) 3.36-3.47 (m, 2 H) 3.53 (dt, J=12.08, 7.14 Hz, 1 H) 3.65 (dt, J=10.01, 6.47 Hz, 1 H) 4.30-4.43 (m, 1 H) 5.37 (d, J=8.30 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:3]([N:18]2[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26])=[N:4][C:5]([N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH2:10][C:9]2([CH3:17])[CH3:16])=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)CCC.[F-].[Cs+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:19]1([CH3:26])[CH2:20][CH2:21][CH2:22][C:23]([CH3:25])([CH3:24])[N:18]1[C:3]1[C:2]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:7][CH:6]=[C:5]([N:8]2[C:9]([CH3:16])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]2([CH3:15])[CH3:14])[N:4]=1
Reactant: CC1(C)CCCC(C)(C)N1c1ccc(Br)c(N2C(C)(C)CCCC2(C)C)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC1(C)CCCC(C)(C)N1c1ccc(-c2ccccn2)c(N2C(C)(C)CCCC2(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3-Bromo-2,6-bis(2,2,6,6-tetramethylpiperidin-1-yl)pyridine (0.4 g, 0.92 mmol), 2-(tributylstannyl)pyridine (0.4 g, 1.10 mmol), Pd(PPh3)4 (0.053 g, 0.046 mmol), and Cesium fluoride (0.28 g, 1.83 mmol) in Toluene (30 ml) was stirred under reflux for 2 days. After cooling down to room temperature the reaction was quenched with saturated CsF aqueous solution (100 mL). The product was extracted with ethylacetate. The product was purified by column chromatography on silica gel and obtained as white solide (Rf=0.5 in Ethylacetate:hexane=1:4, Yield=50 mg (12.5%))
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21][CH3:22])[C:17]([CH:23]=[N:24][OH:25])=[N:16]1>FC(F)(F)C(O)=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21]([CH3:22])=[O:1])[C:17]([CH:23]=[N:24][OH:25])=[N:16]1
Reactant: OO
Reactant: CSc1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(C)=O)c(C=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
30% Hydrogen peroxide solution (0.32 ml) was added to a solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carboxaldehyde oxime (0.8 g) in trifluoroacetic acid at 20° C. The reaction solution was partitioned between water and dichloromethane and the organic layer dried (magnesium sulfate), evaporated and flash-chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (3:1) to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (0.29 g), m.p.210-214° C. Compound 30 and 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfonyl-1H-pyrazole-3-carboxaldehyde oxime (0.2 g), m.p.211-212° C. Compound 31.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[CH:23]1[O:45][C@@H:44]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:24]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)C.C(OCC)(=O)C>C[Si](C)(C)N[Si](C)(C)C.C(#N)C.ClCCl>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:23]2[O:45][C@@H:44]([CH2:46][O:47][C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@@H:34]([O:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:24]2[O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:4]([NH2:11])[N:3]=1
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1nc(F)nc2nc[nH]c12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of a 2-fluoroadenine (107.8 mg, 0.70 mmol) and ammonium sulfate (5.3 mg) in 1,1,1,3,3,3-hexamethyldisilazane (HMDS) (10 ml) is refluxed under argon for 7 h. More ammonium sulfate (4.6 mg) is added, and reflux is continued for 24 h. After cooling the reaction mixture to room temperature, the HMDS is removed in vacuo, and the residue is co-evaporated with anhydrous toluene (3×3 ml). To this material is added 1-O-acetyl-2,3,5-tri-O-benzoyl-L-lyxofuranose (212 mg, 0.42 mmol) dissolved in anhydrous acetonitrile (7 ml). The resulting suspension is chilled to −10° C. before being treated dropwise over 5 min with 2.1 ml of 1.0 M stannic chloride (SnCl4) in dichloromethane. The now clear reaction solution is warmed to 0° C. over 15 min and then stirred at room temperature. After 3 h, the solution is added dropwise to ice-cold saturated NaHCO3 (100 ml) and stirred 10 min at 5° C. Ethyl acetate (75 ml) is added, and the separated aqueous layer is extracted with more ethyl acetate (2×50 ml). The combined organics are washed with brine (50 ml), dried (MgSO4), and evaporated to a solid. Column chromatography on 20 g silica gel (95:5 chloroform-methanol) gave 1 a as a white solid after ethanol crystallization.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][C@H:59]([C:64](O)=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][C@H:59]([C:64]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:65])[CH2:60][CH:61]([CH3:62])[CH3:63])=[O:57])([CH3:53])([CH3:54])[CH3:52]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 56 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-leucine. Yield 56%. [α]D =-2.7° (c=0.86, tetrahydrofuran).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:27](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH4+].[OH-]>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([NH2:27])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nnc2ccc3c(cc(C(N)=O)n3Cc3ccccc3)n12

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.0096 g, 0.031 mmol, from Step 4) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.022 mL, 0.12 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.021 g, 0.056 mmol). The reaction was stirred for 2 minutes before 28% NH4OH was added (0.1 mL). The mixture was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (5 mg, 50%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]([C:35]1[CH:40]=[CH:39][C:38]([B:41]2[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]2)=[C:37]([CH3:50])[CH:36]=1)([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([O:30]COC)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[C:15]([CH3:34])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>ClCCl>[CH2:8]([C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([C:22]([F:25])([F:23])[F:24])([OH:30])[C:26]([F:28])([F:27])[F:29])=[C:15]([CH3:34])[CH:14]=1)([C:35]1[CH:40]=[CH:39][C:38]([B:41]2[O:45][C:44]([CH3:46])([CH3:47])[C:43]([CH3:48])([CH3:49])[O:42]2)=[C:37]([CH3:50])[CH:36]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.8 %

Procedure:
Trifluoroacetic acid (0.8 mL) was added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 284 mg, 0.464 mmol) in dichloromethane (4 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for six hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target product as a colorless oil (142 mg, 54%).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].COCCOC>O>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@@:8]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])[CH:18]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)c1
Yield: 10 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 3-cyanophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (10% yield) as an off-white solid. MS (ISP): m/z=340.2 [M+H]+.