Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[N:42]1(C(Cl)=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:25])[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)N3CCOCC3)CC2)cc1

Procedure:
The title compound, MS: m/e=613.2 (M+H+), [α]58920=−10.99 (c=0.4369, chloroform), was prepared in accordance with the general method of example 102 (part1) and example 38 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and 4-morpholine carbonyl chloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3-fluorobenzoyl chloride (0.45 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-benzamide as a white solid (0.7 g, 77%): mp, 215-217° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.2 min. (99%); 1H NMR (DMSO-d6): δ 2.07-2.12 (m, 1H), 2.54-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.39-7.84 (m, 7H), 9.26 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.40, 48.86, 114.29, 118.49, 121.92, 123.50, 127.15, 130.62, 131.52, 133.09, 134.82, 136.31, 138.97, 163.69, 165.31, 166.94, 167.51, 169.83, 172.74. Anal Calcd for C21H16FN3O5: C, 61.61; H, 3.94; N, 10.26; F, 4.64. Found: C, 61.36; H, 3.84; N, 10.00; F, 4.74.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[S:6][CH:7]=1.[N+:18]([CH:21]([CH3:23])[CH3:22])([O-:20])=[O:19].C[O-].[Na+].[C:27](O)(=[O:29])C>CO>[CH3:27][O:29][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[S:6][CH:7]=[CH:3][CH:4]=2)[C:21]([CH3:23])([N+:18]([O-:20])=[O:19])[CH3:22])=[CH:17][CH:16]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1csc(C=CC(=O)c2ccccc2)c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)CC(c2cccs2)C(C)(C)[N+](=O)[O-])cc1

Procedure:
168 g of 4-methoxy-3-(2-thienyl)-acrylophenone are heated to the boiling point together with 267 g of 2-nitropropane and 400 ml of absolute methanol. A solution of 43 g of sodium methylate in absolute methanol is added within 60 minutes. The resulting mixture is still refluxed during 3 hours. After cooling 43 g of glacial acetic acid are added to the reaction mixture, which is then evaporated to dryness. The residue is taken up with 1500 ml of dichloromethane. This solution is twice washed with 500 ml of water each time, dried over sodium sulfate and evaporated to dryness. The residue crystallises from ethanol and yields 4'-methoxy-4-methyl-4-nitro-3-(2-thienyl)-valerophenone of melting point 90° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3](=[O:20])[CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=1.[CH3:23][Mg+].[Br-].O.Cl>C1COCC1.CCOC(C)=O>[OH:20][C:3]([CH3:23])([C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=1
Reactant: CC(C)(C)C(=O)CNc1cc(C(=O)O)nn1-c1ccccc1
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(C)(O)CNc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
200 mg (0.664 mmol) 5-(3,3-Dimethyl-2-oxo-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid are dissolved in 10 ml dry THF under argon and cooled to 0° C. in an ice bath. 0.664 mmol (1 eq) of MeMgBr (3.0M solution in Et2O) are added within 5 minutes and the resulting mixture is allowed to reach RT overnight. 20 ml of water and EtOAc are added, then the pH is adjusted to 3-4 by addition of 10% HCl solution and the phases are separated. The organic phase is dried over Na2SO4 and the solvent removed to yield 110 mg (51%) of 5-(2-Hydroxy-2,3,3-trimethyl-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)[N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35]([Cl:38])(=[O:37])[CH3:36].Cl.CCO>C(Cl)Cl>[ClH:38].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([O:24][C:35](=[O:37])[CH3:36])[CH2:20]3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2nc(-c3cccc(CN4CCC(O)C4)c3)n[nH]2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(-c3cccc(CN4CCC(OC(C)=O)C4)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of (RS)-1-{3-[5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-pyrrolidin-3-ol hydrochloride (1:1) (mixture of tautomers) (50 mg, 0.13 mmol) in CH2Cl2 (5 ml) was treated with triethylamine (26 mg, 0.26 mmol 2 eq.) and stirred for 30 min. at r.t. Acetyl chloride (11 mg, 0.13 mmol, 1 eq.) was added and stirring was continued for 1.5 hrs. After removal of the solvent the residue was chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4. The resulting product was dissolved in ethanol at r.t. and an excess 1.45 N HCl/EtOH solution (0.1 ml, 0.14 mmol) was added. After 30 min. stirring the solvent was evaporated and the residue dried under high vacuum at 40° C. overnight affording the title compound (53 mg, 0.12 mmol, 96% yield) as a colorless solid. MS: m/e=393.2 (M+H+)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14](=[CH:20][C:21]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([OH:29])=O)[C:22]=3[CH3:30])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][NH2:36])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][NH:36][C:27]([C:23]1[C:22]([CH3:30])=[C:21]([CH:20]=[C:14]2[C:13]3[C:17](=[CH:18][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:11][CH:12]=3)[NH:16][C:15]2=[O:19])[NH:25][C:24]=1[CH3:26])=[O:29])[CH3:32]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c(C)c1C(=O)O
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c1C
Reaction time: 2 h

Procedure:
To a solution of N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide (80 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (53 mg, 0.32 mmol) in ethanol (8 ml) is added 4 drops of piperidine. It is stirred at 80° C. for 20 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol to give crude 5-(6-benzoylamino-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. This carboxylic acid (20 mg, 0.050 mmol) is then dissolved in DMF (1 ml). To this reaction is also added N, N-diethylethylenediamine (17 mg, 0.15 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and HATU (23 mg, 0.061 mmol). It is stirred for 2 hours and concentrated. The desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 1.24 (t, 6H, J=7.2 Hz), 2.43 (s, 3H), 2.47 (s, 3H), 3.20-3.24 (m, 6H), 3.57 (q, 2H, J=5.4 Hz), 7.38 (d, 1H, J=6.6 Hz), 7.53 (t, 2H, J=7.2 Hz), 7.56 (s, 1H), 7.58-7.61 (m, 2H), 7.73-7.77 (m, 2H), 7.96 (d, 2H, J=7.8 Hz), 9.32 (s, 1H), 10.27 (s, 1H), 10.97 (s, 1H), 13.60 (s, 1H); LC-MS: 500.2 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[N:21][N:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>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].COCCOC>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([C:19]4[N:18]([CH3:17])[CH:22]=[N:21][N:20]=4)=[CH:29][CH:28]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Cn1cnnc1-c1ccc(N)cc1
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc(-c4nncn4C)cc3)n2)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-(2-chloropyrimidin-4-yl)-N,N-dimethylaniline (50 mg, 0.2 mmol) [obtained from 4-(dimethylamino)phenylboronic acid and 2,4-dicholorpyrimidine by following procedure B], 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (45 mg, 0.25 mmol), Davephos (3 mg, 0.006 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), NaO′Bu (30 mg, 0.28 mmol) and DME (1.0 mL) was placed in a sealed tube and heated to 140° C. in a microwave for 30 min. The reaction mixture was cooled, filtered through a pad of Celite, washed with ethyl acetate and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford 4-(4-(dimethylamino)phenyl)-N-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-2-amine. 1H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 9.06 (s, 1H), 8.47 (d, 1H), 8.12-8.08 (m, 4H), 8.78 (d, 2H), 7.38 (d, 1H), 6.84 (d, 2H), 3.88 (s, 3H), 3.03 (s, 6H). MS (ESI) 372 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH2:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH:43][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Indazole-3-carboxylic acid (30 mg; 0.182 mmol), DCC (56 mg, 0.273 mmol) and DMAP (2 mg) were dissolved in DCM:DMF (1:1, 4 ml). 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine (46 mg, 0.182 mmol) was added and the reaction mixture was stirred for overnight at RT. DCM (30 ml) was added and organic layer washed with water (3×15 ml). Combined organic phases were dried over Na2SO4, evaporated and purified by chromatography (silica column, eluent: 1% MeOH/DCM) to give 25 mg (34%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.00 (t, 2H), 3.63 (q, 2H), 6.37 (d, 1H), 7.02 (d, 1H), 7.23 (t, 1H), 7.41 (t, 1H), 7.60 (d, 1H), 7.61 (d, 2H), 7.85 (d, 1H), 8.16 (d, 1H), 8.54 (d, 1H), 13.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1C=O.[OH:15]O>OS(O)(=O)=O.CO.O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[OH:15]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(OC)c1OC

Procedure:
A solution of 2,3,4-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) and 30 wt/v % hydrogen peroxide (0.672 mL, 6.52 mmol) in conc. H2SO4 (0.102 mL) and MeOH (10.19 mL) was stirred overnight at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 50% EtOAc in hexanes over 2088 mL) to afford 2,3,4-trimethoxyphenol, as a colorless oil. Rf=0.93 (50% EtOAc/hexanes). LCMS calc.=185.1; found=185.2 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 6.62 (d, J=9.0 Hz, 1 H); 6.55 (d, J=8.9 Hz, 1 H); 5.49 (s, 1 H); 3.94 (s, 3 H); 3.89 (s, 3 H); 3.80 (s, 3 H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][N:24]1[C:28]([CH2:29]Cl)=[N:27][CH:26]=[N:25]1.O>CN(C=O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([O:20][CH2:29][C:28]4[N:24]([CH3:23])[N:25]=[CH:26][N:27]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=[C:10]3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Reactant: Cn1ncnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nnn(-c3ccccc3)c2nc1OCc1ncnn1C
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of 3-phenyl-5-oxo-6-methoxycarbonyl-4H-1,2,3-triazolo[4,5-b]pyridine (0.10 g, 0.37 mmol) and sodium hydride (55% in oil, 0.018 g, 0.40 mmol) in dry DMF (2 ml) was stirred at room temperature under nitrogen until all effervescence had ceased. A solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.065 g, 0.50 mmol) in dry DMF (0.5 ml) was added and the mixture was stirred for 4 days. Water was added and the aqueous solution was extracted with dichloromethane. The extracts were dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography on silica gel, eluting with 5% methanol-dichloromethane, gave the alkylation product which was washed with hot ethyl acetate to give 3-phenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-methoxycarbonyl-1,2,3-triazolo[4,5-b]pyridine (0.036 g, 27%) as an off-white, crystalline solid, m.p. 188-190° C. Found: C, 55.97; H, 4.17; N, 26.93. C17H15N7O3 requires C, 55.89; H, 4.14; N, 26.84%. δH (360 MHz; CDCl3) 3.96 (3H, s), 4.08 (3H, s), 5.76 (2H, s), 7.50 (1H, t, J=7.5), 7.63 (2H, dd, J=7.5 and 7.5), 7.89 (1H, s), 8.23 (2H, d, J=7.5) and 8.96 (1H, s); m/z (ES+) 366 (M+H+).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]=[CH:6]2)[O:4][CH2:3][CH2:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C=CC(O)=CC=1)O>C(#N)C>[O:1]1[CH2:2][CH2:3][O:4][C:5]21[CH2:9][C@@H:8]1[CH2:7][C@@H:6]2[CH2:12][CH:11]1[C:10]([O:14][CH3:15])=[O:13]
Reactant: C1=CC2(CC1)OCCO2
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: COC(=O)C1C[C@H]2C[C@H]1CC21OCCO1

Procedure:
A mixture of 1,4-dioxaspiro[4.4]non-6-ene (5 g), methyl acrylate (10.24 g), and hydroquinone (0.13 g) was heated in an autoclave at 100° C. in acetonitrile (12 mL) for three days. After cooling, the solvent was removed, and residue was purified by flash chromatography on silica gel eluting with 4:1 hexane/ethyl acetate to give the title compound as a mixture of two 5-isomers.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Sn](C)(C)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>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>[Cl:8][C:7]1[C:2]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Clc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 82 %

Procedure:
66.7 g (0.451 mol) of 2,3-dichloropyridine and 115 g (0.451 mol) of trimethyl(p-tolyl)tin were dissolved in 1 L of toluene, after which 52.1 g (0.045 mol) of Pd(PPh3)4 was added, and the mixture was heated to reflux for 6˜7 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and to the concentration residue was added 700 mL of distilled water, followed by stirring. The organic layer was separated, treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 82% yield.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4]1/[CH:5]([O:12][CH3:13])[N:6]2[C@H:9]([O:10]/1)[CH2:8][C:7]2=[O:11].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(OCC)C.C(OCC)(=O)C>[CH3:13][O:12][CH:5]1[N:6]2[C@H:9]([O:10]/[C:4]/1=[CH:3]\[CH2:2][O:1][C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][C:7]2=[O:11]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC1/C(=C/CO)O[C@@H]2CC(=O)N12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC1/C(=C/COC(=O)Cc2ccccc2)O[C@@H]2CC(=O)N12
Reaction time: 15 h
Yield: 69.2 %

Procedure:
(Z)-(5R)-3-(2-Hydroxyethylidene)-2-methoxy-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (15 mg.) was dissolved in dry diethyl ether (2 ml.) and the solution was stirred and ice-cooled with exclusion of moisture while phenylacetyl chloride (30 mg.) followed by dry pyridine (15 mg.) were added. The mixture was kept at 4° with exclusion of moisture for 15 hours. The mixture was diluted with ethyl acetate (30 ml.) and was washed with 5% sodium chloride solution (10 ml.) and saturated sodium chloride solution (10 ml.). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield a yellow gum. Chromatography of the gum on silica gel (10 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) gave the title compound as a colourless gum (17 mg.). [α]D22 =+45.6° (c=1.0, CHCl3). νmax (CHCl3): 1798 (β-lactam C=O), 1730 (ester C=O), 1710 (sh.) (olefinic C=C)cm-1. δ (CDCl3): 2.96 (d, J 16 Hz, 1H, C(6)H), 3.34 (dd, J 16, J' 2 Hz, 1H, C(6)H), 3.36 (s, 3H, OCH3), 3.56 (s, 2H, CH2Ar), 4.60-4.90 (complex, 3H, CH2O and olefinic H), 5.25 (s, 1H, C(2)H), 5.52 (d, J 2 Hz, 1H, C(5)H), 7.22 (s, 5H, Ar-H). m/e: 234 (2%), 229 (C13H11NO3, 13%), 168 (19), 118 (12), 99 (22), 91 (100).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[S:9]([CH2:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[H][H]>[Pd].C1COCC1.C(O)C>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][CH:2]2[S:9]([CH2:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(-c2ccoc2)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1c(CS(=O)(=O)C2CC3CCC2CC3)ccc(-c2ccoc2)c1OC
Yield: 11.1 %

Procedure:
A mixture of methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 170, 0.26 g) and palladium on carbon (10%, 0.01 g) in THF (15 ml) and ethanol (10 ml) was stirred in an atmosphere of hydrogen (balloon) for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate in cyclohexane with a gradient of 10-50% to give methyl 6-(bicyclo[2.2.2]octane-2-ylsulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (0.029 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]([O:41][CH2:42][C:43]3[S:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38][S:37]2(=[O:53])=[O:52])=[CH:32][CH:31]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[C:24]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH:40]([O:41][CH2:42][C:43]3[S:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38][S:37]2(=[O:53])=[O:52])=[CH:34][CH:35]=1)(=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1ccc(N2C(OCc3ccc(C(=O)OC)s3)CCS2(=O)=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(N2C(OCc3ccc(C(=O)OC)s3)CCS2(=O)=O)cc1
Yield: 101.2 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (44 mg, 0.104 mmol) was added to a solution of the alcohol 14 (42 mg, 0.087 mmol) in CH2Cl2 (2 mL) at 23° C. After stirring for 16 h the reaction mixture with CH2Cl2 and filtered. The filtrate was concentrated in vacuo and purification of the residue by flash column chromatography (silica gel, 1:1 hex/EtOAc) gave 41 mg (98%) of the ketone 16.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:16]C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClC1C=CC=CC=1Cl>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:2]2[CH:7]=[C:6]([P:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:26]3[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=3)=[O:16])[N:5]=[CH:4][N:3]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(P(=O)(c2ccccc2)c2ccccc2)ncn1

Procedure:
To a stirred, refluxing mixture of 5.00 g 4,6-dichloropyrimidine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 17.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6.5 hours and then allowed to cool. The cooled mixture was added to 750 ml of n-hexane, and the white solid that formed was separated by filtration, washed with n-hexane, recrystallized from 150 ml of toluene, and dried at 100° C./0.1 mm (13 Pa) to give 13.64 g of 4,6-bis(diphenylphosphinyl)pyrimidine as cream-colored crystals, mp 213°-215° C. Anal. Calcd for C28H22N2O2P2 : C, 70.00; H, 4.62; N, 5.83; P, 12.89. Found: C, 69.80; H, 4.65; N, 5.65; P, 12.89.