Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH2:31][CH:32]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:25]1([CH2:31][CH2:32][N:16]2[CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CCN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
A mixture of 50 mg (0.16 mmol) 3-(SR)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A) and 37 mg (0.31 mmol) of phenylacetaldehyde and 100 mg 4 A powdered molecular sieves in 3 mL of MeOH was treated with 18 mg (0.28 mmol) of sodium cyanoborohydride and 2 drops of HOAc and stirred at rt for 18 h. The mixture was filtered onto a pad of Celite; the pad and flask were rinsed well with MeOH (25 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 25 mL of EtOAc and 15 mL of sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 15 g of silica gel using 2:1 v/v hexanes/EtOAc afforded 32 mg (48%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.66-2.04 (6H), 2.42-3.13 (15H), 7.20-7.37 (15H). Mass Spectrum (NH3 -CI): 427 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:20]3([S:36][CH2:35][CH2:34][S:33]3)[C:19]1=2>C1(C)C(C)=CC=CC=1>[C:14]([O:13][CH:6]1[C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:26]2[CH:27]1[C:18](=[O:17])[C:19]1[C:20]3([S:36][CH2:35][CH2:34][S:33]3)[CH2:21][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:23][C:24]=1[C:25]2=[O:28])(=[O:16])[CH3:15]
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: COC(=O)C1CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Solvent: Cc1ccccc1C
Product: COC(=O)C1CC2=C(C(=O)C3C(OC(C)=O)c4ccccc4C(OC(C)=O)C3C2=O)C2(C1)SCCS2
Yield: 62 %

Procedure:
A solution of 0.757 g (3.4 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 0.970 g (3.1 mmol) of methyl rac-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate [prepared as described in Example 2(A)] in 100 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 1 hour. The mixture was evaporated to dryness and the resulting brown oil was triturated with 10 ml of diethyl ether, cooled and filtered to give 1.02 g (61.5%) of methyl rac-1',2',3',4',5',5a',6',11',11a',12'-decahydro-6',11'-diacetoxy-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a pale yellow solid of melting point 174°-175° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][N:12](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:11]#[N:12])[C:3]=2[CH:10]=[CH:9]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccnc2[nH]ccc12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.1 g, 20 mmol), zinc cyanide (1.4 g, 12 mmol), zinc (130 mg, 2.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (370 mg, 0.40 mmol), 1,1′-bis(diphenylphosphino)ferrocene (440 mg, 0.80 mmol) and N,N-dimethylacetamide (20 mL) was stirred at 120° C. for 1.5 hr under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (2.60 g, 91%) as a red-brown solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C:11]#[C:12][CH2:13][C@@H:14]([OH:16])[CH3:15].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]I)[CH3:18]>O1CCCC1>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:16][C@@H:14]([CH3:15])[CH2:13][C:12]#[C:11][CH2:10][O:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][O:3]1)[CH3:18]
Reactant: CCOC(CI)OCC
Reactant: C[C@H](O)CC#CCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(CO[C@@H](C)CC#CCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 9.8 g, 240 mmol) was added portion-wise to a 0° C. solution of (2S)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-yn-2-ol (synthesized as described by G. V. M. Sharma and K. Veera Babu, Tetrahedron: Asymmetry 2007, 18, 2175-2184) (27.0 g, 136 mmol) in tetrahydrofuran (130 mL), at a rate such that the reaction temperature remained below 5° C. After 5 minutes, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 3.5 hours, whereupon it was again cooled to 0° C. A solution of 1,1-diethoxy-2-iodoethane (49.9 g, 204 mmol) in tetrahydrofuran (5 mL) was added drop-wise over 30 minutes, at a rate that maintained the reaction temperature below 10° C. After removal of the cooling bath, the reaction mixture was stirred at room temperature for 30 minutes, and then placed in a 50° C. oil bath for 90 minutes, at which time additional 1,1-diethoxy-2-iodoethane (3.3 g, 14 mmol) was added, as a solution in tetrahydrofuran (5 mL). Heating was continued for 1 hour, at which time the reaction mixture was cooled in an ice bath and quenched with a mixture of saturated aqueous ammonium chloride solution (210 mL) and saturated aqueous sodium chloride solution (210 mL). The resulting mixture was extracted with tert-butyl methyl ether (3×200 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in hexanes) afforded the product as a yellow oil. Yield: 22.8 g, 72.5 mmol, 53%. 1H NMR (500 MHz, CDCl3), characteristic peaks: δ 4.80 (t, J=3.5 Hz, 1H), 4.59 (t, J=5.2 Hz, 1H), 4.28 (dt, half of ABX2 pattern, J=15.3, 2.1 Hz, 1H), 4.20 (dt, half of ABX2 pattern, J=15.3, 2.1 Hz, 1H), 3.81-3.87 (m, 1H), 2.48-2.56 (m, 1H), 2.28-2.36 (m, 1H), 1.78-1.88 (m, 1H), 1.69-1.77 (m, 1H), 1.25 (d, J=6.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]=3[F:38])=[C:7]([CH:23]3[CH2:25][CH2:24]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH:16]=2)=[CH:4][CH:3]=1.CC[N:41]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[Cl-]>CN(C=O)C.O>[NH2:41][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:15]1[CH:16]=[C:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=3[F:11])[C:6]([S:26][C:27]3[C:28]([F:38])=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:7]2[CH:23]2[CH2:24][CH2:25]2)[CH:13]=[N:14]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(N)=O)c3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 0.17 h
Yield: 10.3 %

Procedure:
To a stirred solution of indole 1 (Example 16, Step 2; 150 mg, 0.26 mmol) in DMF (3 mL) under inert atmosphere were added EDCI.HCl (36 mg, 0.40 mmol), HOBt (61.5 mg, 0.40 mmol), NMM (0.07 mL, 0.67 mmol) at RT and stirred for 10 min. To this, NH4Cl (17.1 mg, 0.32 mmol) was added at RT and stirred for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and dried under reduced pressure to obtain the crude. This was purified (silica gel; 2% MeOH/CH2Cl2) to afford compound 2 (15 mg, 10%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.81 (s, 1H), 7.60 (dt, J=8.0, 1.6 Hz, 1H), 7.29 (br s, 1H), 7.22-7.11 (m, 3H), 6.84 (dt, J=8.0, 1.6 Hz, 1H), 6.78 (br s, 1H), 4.33 (q, 2H), 4.20 (t, J=6.4 Hz, 2H), 2.08-2.02 (m, 4H), 1.82-1.77 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.88 (m, 2H), 0.86-0.80 (m, 2H); MS: m/z 559.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:10])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Product: Cc1nc(NC(=O)Nc2ccc(F)cc2)sc1C(=O)NCc1ccccc1
Yield: 83 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use 4-fluorophenyl isocyanate in place of phenyl isocyanate to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 83% yield; m.p.>300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.03 (s, 1H), 8.47 (t, J=6.0 Hz, 1H), 7.49-7.05 (m, 10H), 4.35 (d, J=5.7 Hz, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.2, 140.2, 128.7, 127.7, 127.2, 121.1, 121.0, 120.5, 116.1, 115.9, 115.8, 43.0, 39.1; MS (ES+) m/z 385.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].[OH-].[Na+].Cl>CC(N(C)C)=O.O>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=1)([CH3:36])[CH3:35])[CH3:34]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (80 mg, obtained in Example 172) and ethyl 2-bromoisobutyrate (0.2 mL) were dissolved in dimethylacetamide (2 mL). Powdered sodium hydroxide (54 mg) was added to this solution and the mixture was allowed to stir at r.t. for 12 hours. The mixture was poured into water and ice and was acidified to pH 3 with 2N HCl. The aqueous phase was extracted with ethyl acetate two times and the organic extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate:hexanes=4:1) to provide the title compound 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid ethyl ester as a colorless foam (113 mg). MS (m/e, ISP neg. ion)=514.1 [M−H+].
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-:15].[Na+].[Na+].CN1CCCC1=O>O>[CH3:1][O:2][CH:3]([OH:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(Cl)C(=O)Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(O)C(=O)Nc1ccccc1
Yield: 70 %

Procedure:
In a 250 ml flask, 10 g (0.05 mol) of 2-methoxy-chloroacetanilide (prepared from chloroacetyl chloride and 2-methoxyaniline) and 6 g (0.55 mol) of sodium carbonate are heated at 100° C. in a solvent mixture of 100 ml of N-methylpyrrolidone and 70 ml of water. A GC check after a reaction time of 6 hours reveals a yield of 70% of 2-methoxy-hydroxyacetanilide and 5.5% of 2-methoxydiglycolanilide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: COc1ccnc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccnc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 2-methyl-4-methoxypyridine (2.03 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 12.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.99 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(4-methoxypyridin-2-yl)propan-2-one (2.35 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.Cl[Sn]Cl>C(Cl)Cl.CCOC(C)=O>[CH3:15][N:14]([CH3:16])[S:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CNC
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-[(dimethylamino)sulfonyl]aniline to generate the title compound. The 3-[(dimethylamino)sulfonyl]aniline was prepared by sequential treatment of commercial 3-nitrobenzenesulfonyl chloride with Me2NH in CH2Cl2 containing (i-Pr)2NEt followed by reduction with SnCl2 in EtOAc at 20° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH:17]1([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cnc(C2CC2)c(-c2ccccc2)c1
Yield: 17.5 %

Procedure:
In a schlenck tube, a mixture of 2-chloro-5-nitro-3-phenylpyridine (described in Intermediate 3 (step B)) (1.43 mmol, 0.4 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.59 mmol, 0.29 ml), PdCl2dppf.DCM (0.14 mmol, 0.12 g), Cs2CO3 (4.3 mmol, 1.4 g) in a dioxane/water 4:1 mixture (6.5 ml) was heated at 100° C. for 16 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 2-cyclopropyl-5-nitro-3-phenylpyridine (0.06 g, 17% of yield) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]([O-])=[O:10].[Na+]>>[Cl:1][C:2]1[C:3](=[O:8])[CH:4]=[CH:5][C:6](=[N:9][OH:10])[CH:7]=1
Reactant: Oc1ccccc1Cl
Reactant: O=N[O-]
Agent: [Na+]
Product: O=C1C=CC(=NO)C=C1Cl

Procedure:
2-Chloro-1,4-benzoquinone-4-oxime was prepared by reaction of 2-chlorophenol with sodium nitrite under acidic conditions by the method described by T. Ishikawa et al. in J. Org. Chem. 1996, 61, page 2778.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:19][CH:18]2[C:14]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)([N:15]([C:20](=[S:30])[NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:16][CH2:17]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+]>[Zn].O>[C:22]([NH:21][C:20]([NH:15][C:14]1([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH:18]([CH2:17][OH:16])[CH2:19][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:13]1)=[S:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2cccs2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cccs2)C1
Temperature: 40 °C
Reaction time: 7 h
Yield: 32 %

Procedure:
Acetic acid (104 mL) is added to tert-butyl-1-(benzoylcarbamothioyl)-6a-(2-thienyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate followed by powdered zinc (17.1 g, 261 mmol) and the resulting suspension is vigorously stirred at 40° C. for 7 hours followed by an additional hour at 45-50° C. The reaction is concentrated under reduced pressure. To the crude reaction mixture is added diatomaceous earth and water, followed by a saturated solution of sodium bicarbonate. The mixture is filtered and washed with ethyl acetate. The filtrate is extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (3.8 g, 32%). ES/MS (m/e): 460 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[F-].[Cs+].Cl.[NH2:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1B(O)O.COCCOC>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.O.CCOC(C)=O>[NH2:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(I)ccc1Br
Reactant: N#Cc1ccc(B(O)O)c(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2ccc(C#N)cc2N)ccc1Br
Temperature: 100 °C
Reaction time: 36 h

Procedure:
To a mixture of the product from Step 1, -bromo-4-iodo-2-methoxybenzene (750 mg, 2.4 mmol), CsF (1.09 g, 7.2 mmol), (2-amino-4-cyanophenyl)boronic acid hydrochloride (390 mg, 2.4 mmol), and Pd(PPh3)4 (277 mg, 0.24 mmol) was added DME (15 mL) under nitrogen. It was then heated to 100° C. After 36 hours, EtOAc and water were added to the resulting thick red suspension. The organic layer was washed with brine, dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified on silica (gradient elution, 3-50% EtOAc/hexanes) to yield the title compound as a red oil. LRMS (M+H)+=303.1.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9](CC3C=CC=CC=3F)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C([Sn](CCCC)(CCCC)C1N(COCC[Si](C)(C)C)N=NC=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:11]1[C:3]2[CH:2]=[N:7][C:6]([NH2:8])=[N:5][C:4]=2[NH:9][N:10]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3ccccc3F)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnnn1COCC[Si](C)(C)C
Solvent: CN(C)C=O
Product: Nc1ncc2nn[nH]c2n1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 7-chloro-3-(2-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (145 mg, 0.50 mmol), tributyl 1-(2-(trimethylsilyl)ethoxymethyl)-1H-triazol-5-ylstannane (336 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) in DMF (2 mL) was shaken at 80° C. for 17 h then purified directly by chromatography [SiO2; iso-hexane:EtOAc (2:1)] to give 3-(2-fluorobenzyl)-7-(1-(2-trimethylsilyl)ethoxymethyl)-1H-triazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine as a colourless oil. This material was dissolved in MeOH (1 mL), treated with a solution of HCl (0.5 mL, 4-M in dioxane), stirred for 17 h, concentrated in vacuo and the residue triturated with Et2O to give the title compound (16 mg, 10%) as an off-white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:15][CH:14]=[CH:13][C@@H:12]([OH:16])[C@@H:11]1[OH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:20]([O:16][C@H:12]1[C@H:11]([O:17][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][CH:14]=[CH:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 40 °C
Yield: 60 %

Procedure:
6-O-tert-butyldimethylsilyl-D-glucal (11.5 mmol) was dissolved in dichloromethane (30 mL). Sodium hydroxide (23 mmol) followed by tetrabutylammonium bromide (5 mg) and benzyl bromide (27 mmol) were added and the reaction mixture was stirred at 40° C. After reaction was completed the reaction mixture was cooled down, solids were filtered off, filtrate was diluted with dichloromethane (100 mL), washed with water until neutral and dried over anhydrous sodium sulfate. Drying agent and solvents were removed and product was separated using column chromatography (SilicaGel 60) and hexanes:ethyl acetate as eluents. 3,4-di-O-benzyl-6-O-tert-butyldimethylsilyl-D-glucal (6.9 mmol, yield 60%) was obtained. [α]D−6.6 (c=1, chloroform).