Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:57])[C:7]([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[S:47][CH:48]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:43])[CH2:19][C:20]([CH2:41]Cl)=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:58].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:57])[C:7]([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[S:47][CH:48]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:43])[CH2:19][C:20]([CH2:41][I:58])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS(=O)[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (2.68 g, 3.18 mmol) in acetone (40 mL) was added sodium iodide (0.715 g, 4.77 mmol). The mixture was stirred at room temperature over 3 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (2.97 g, 3.18 mmol, 100% yield) as a dark red solid. LCMS: (M+H)+: 934.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: BrCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCBr)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2-methoxybenzaldehyde, M.p. 78-79° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br.CC(O)=[O:14]>>[OH:14][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1](=[O:10])[CH:2]=[CH:3]2
Reactant: CC(=O)O
Reactant: O=C1C=Cc2ccccc21
Agent: Br
Product: O=C1C=Cc2cc(O)ccc21

Procedure:
The indenone compound prepared in Step 5 is mixed with HBr/AcOH (1:2), and then the resulting mixture is allowed to reflux for 14 to 16 h with stirring, to obtain the 5-hydroxyindenone of formula 19.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:23])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:21][CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:20][C:19]1[C:14]([C:11]2([OH:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]([CH2:21][CH3:22])=[CH:17][CH:18]=1
Reactant: CCc1ccc(Cl)c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(Cl)c(C2(O)CCNCC2)n1
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
3-Chloro-6-ethyl-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.086 g, 0.25 mmol) was dissolved in TFA (1 mL) and DCM (1 mL). The mixture was stirred for 20 minutes and the solvent removed by evaporation under vacuum and the residues were passed through an SCX cartridge, eluting with 2 M ammonia in methanol to give the title compound (0.052 g). LCMS m/z 243.25 [M+H]+. R.T.=2.45 min (Analytical Method 3).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH2:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:8][C:12](=[O:13])[CH2:11][CH2:10][SH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCS
Reactant: OC1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OC1CCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and hot plate are placed 45.6 grams of cycloheptanol; 16 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 12 hours. At the end of the 12 hour period, the reaction mass is cooled and distilled on a micro distillation apparatus yielding the compound having the structure: ##STR147## as confirmed by GLC, IR, NMR and mass spectral analyses.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:21]([C:23]3[C:27]4=[N:28][C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=[C:26]4[N:25]([CH2:36][CH2:37]I)[CH:24]=3)=[CH:22][C:15]=12>CC#N>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)(=[O:40])=[O:41])[C:21]([C:23]3[C:27]4=[N:28][C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=[C:26]4[N:25]([CH2:36][CH2:37][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:24]=3)=[CH:22][C:15]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCOCC1
Temperature: 60 °C
Yield: 257.1 %

Procedure:
Add morpholine (3.5 equiv., 25.9 mg, 26.1 μmol, 0.30 mmol) and K2CO3 (11.7 mg, 0.085 mmol) to bisazaindole 32 (54 mg, 0.0848 mmol) in CH3CN (6.0 mL). After heating at 60° C. for 30 h, concentrate the reaction medium under vacuum and submit the residue of raw product to flash chromatography on SiO2 (MeOH at 2-4%/CH2Cl2) to obtain 33 (40 mg, 79.2%) as an ivory-colored solid: 1H NMR (CDCl3) δ 8.26 (d, 1H, J=5.4 Hz), 7.72 (d, 2H, J=8.4 Hz), 7.66 (s, 1H), 7.16 (m, 3H), 7.09 (d, 2H, J=8.1 Hz), 4.29 (t, 2H, J=6.6 Hz), 4.05 (s, 3H), 4.01 (s, 3H), 3.73 (m, 4H), 2.86 (t, 2H, J=6.6 Hz), 2.55 (m, 4H), 2.33 (s, 3H), TLC (MeOH at 4%/CH2Cl2, 0.25% of NH3) Rf=0.25, m/z obs.=597.56 (M+1)
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl.O>C(O)(=O)C>[O:1]=[C:2]1[O:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCOC1=C(c2ccccc2)C(CCC(=O)OCC)OC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCCOC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Temperature: 100 °C
Yield: 79.8 %

Procedure:
A mixture of ethyl 3-(5-oxo-4-pentyloxy-3-phenyl-2,5-dihydro-2-furyl)propionate (3 g) and 3N hydrochloric acid (28 ml) in acetic acid (28 ml) was heated at 100° C. for 2 hours with stirring. After cooling the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine successively and dried. Evaporation of the solvent gave a residue which was recrystallized from a mixture of n-hexane and ethyl acetate to give 3-(5-oxo-4-pentyloxy-3-phenyl2,5-dihydro-2-furyl)propionic acid (2.20 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[N:25]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:38]([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:21]=[N:20][N:19]([CH3:38])[CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:27])(=[O:28])[N:25]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cn[nH]c3)cc2OCc2ccccc2)S1(=O)=O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cc(C=Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-{2-benzyloxy-4-[2-(1H-pyrazol-4-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (example 40, step C) (114 mg, 0.224 mmol), MeI (0.05 mL, 0.80 mmol) and K2CO3 (60 mg, 0.43 mmol) in CH3CN (3 mL) is stirred at RT for 2 days. The mixture is partitioned between EtOAc and aq. NaHCO3. The organic phase is dried over MgSO4 and concentrated to afford the crude product.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[CH2:17]([N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH:28]=[C:27]([C:2]2[C:6]3=[N:7][C:8]([C:11]4[O:12][C:13]([CH3:16])=[N:14][N:15]=4)=[CH:9][CH:10]=[C:5]3[O:4][CH:3]=2)[CH:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5)c4)c3n2)o1
Yield: 68 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 68%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.OS([O-])(=O)=O.[K+]>C(OC(C)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Temperature: 2.5 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2 s rotamers, 9H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:23]([CH:26]([CH2:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)C(OCC)=O)([OH:25])=[O:24]>C1CCCCC1>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:6]([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:26](/[C:23]([OH:25])=[O:24])\[CH2:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:8][N:9]=1
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)O
Solvent: C1CCCCC1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1
Temperature: 27.5 °C
Yield: 57.5 %

Procedure:
Methyl 4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate (32 gm) and ethyl 2-carboxy-3-(2-thienyl)propionate (57.15 gm) are added to cyclohexane (292 ml) under stirring at 25-30° C., the contents are heated to reflux (80-85° C.) for 2 hours under dean stark to separate the traces of water. The reaction mass is cooled to 50° C. and then slowly added a freshly prepared catalyst solution of propanoic acid (22.93 ml) in cyclohexane (53 ml) and piperidine (10.66 ml). The resulting mass is heated to reflux (80-85° C.) for 20 hours, and to the reaction mass drop wise was added a 50% NaOH solution (64 gm of NaOH in 256 ml of water) after reflux at 50° C. and then the reaction mass is heated to reflux for 2 hours. The reaction mass is cooled to 60° C., the layers separated, to the aqueous layer was added ethanol (192 ml) and then the pH of the mass is adjusted to 5.0 to 5.1 at 60° C. with 6N HCl solution (66 ml of HCl and 66 ml of water). The resulting mass was cooled to 20-25° C. and stirred for 2 hours. The mass was filtered, washed with water (100 ml) and then dried at 70-75° C. to give 26 gm of crude eprosartan free base (HPLC purity: 98.2%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)[CH:3]=1
Reactant: Brc1cc(I)cc2nnsc12
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cccc(-c2cc(Br)c3snnc3c2)c1
Yield: 82.8 %

Procedure:
A mixture of 7-bromo-5-iodo-1,2,3-benzothiadiazole (20 mg, 0.0586 mmol), 3-fluorophenylboronic acid (9.85 mg, 0.0704 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane complex (2.14 mg, 0.00293 mmol), potassium carbonate (24.3 mg, 0.176 mmol) and 4:1 1,4-dioxane:water (3 mL) was heated to 60° C. for 2 h. The solution was concentrated. Purification by ISCO chromatography (1 to 3% EtOAc:heptane) afforded 15 mg (83%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.13-7.21 (m, 1 H), 7.39 (dt, J=9.7, 2.0 Hz, 1 H), 7.45-7.55 (m, 2 H), 8.04 (d, J=1.5 Hz, 1 H), 8.74 (d, J=1.3 Hz, 1 H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][CH:7]1[CH2:11][CH2:10][C:9](=O)[C@@H:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CO>[NH2:5][C:9]1[CH2:10][CH2:11][C@@H:7]([CH3:6])[C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)[C@H]1C(=O)CCC1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CC[C@H]1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
Ammonium acetate (240.03 g, 3113.9 mmol) was added to a solution of (R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106.0 g, 622.78 mmol) in MeOH (1.2 L). The reaction mixture was stirred at room temperature under nitrogen for 20 hours, after which it was complete as judged by TLC and HPLC. The reaction mixture was concentrated to remove MeOH. The resulting residue was dissolved in DCM, washed twice with H2O, once with brine, dried (Na2SO4), filtered, and concentrated to give (R)-ethyl 2-amino-5-methylcyclopent-1-enecarboxylate (102 g, 97% yield) as an orange oil. LC/MS (APCI+) m/z 170 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9](Cl)[N:8]=2)=[CH:4][C:3]=1[CH:18]1[O:22][CH2:21][CH2:20][O:19]1.BrC1C=CC(OC2N=C(Cl)C=CC=2C#N)=CC=1C1OCCO1.C([O:52][CH2:53][CH2:54][NH:55][C:56]1N=C(OC2C=CC(Br)=C(C=O)C=2)C=CC=1C#N)C1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N:55]([CH2:54][CH2:53][OH:52])[CH3:56])[N:8]=2)=[CH:4][C:3]=1[CH:18]1[O:22][CH2:21][CH2:20][O:19]1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1NCCOCc1ccccc1
Agent: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Solvent: CC#N
Product: CN(CCO)c1nc(Oc2ccc(Br)c(C3OCCO3)c2)ccc1C#N
Temperature: 80 °C
Yield: 36 %

Procedure:
To a solution of compound mixture, 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5, 1 g, 2.6 mmol) in acetonitrile (anhydrous, 30 mL) was added 2-methylamino-ethanol (6, 2.1 mL, 26 mmol). The reaction was heated at 80° C. for 2 hours. After the reaction, all volatile components were evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 10%-80% EtOAc/hexanes gradient, affording 400 mg (36% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.[C:14]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=[O:15]>C1(C)C=CC=CC=1>[CH2:10]([C:4]1[N:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]2[C:3]=1[CH:12]=[CH:17][C:14](=[O:15])[NH:1]2)[CH3:11]
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Solvent: Cc1ccccc1
Product: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Yield: 76.2 %

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (40 g) and (carboxymethylene)triphenylphosphorane (82.5 g) in toluene (1 l) was stirred and heated at reflux for 3 hours. The solution was cooled and the solvent was removed by evaporation. A solution of sodium (20 g) in methanol (800 ml) was added to the residue and the resulting solution was heated at reflux for 4 hours. Methanol was removed by evaporation and water (500 ml) was added. The mixture was acidified to pH 1-2 by addition of concentrated hydrochloric acid. The mixture was then extracted with ethyl acetate (2×500 ml) and ether (1×500) and the extracts were discarded. The aqueous phase was then basified by addition of solid potassium carbonate and the solid which crystallised was collected by filtration and washed with water. The solid was recrystallised from acetone to give 5,7-diethyl-1,6-naphthyridin-2(1H)-one (34.6 g), m.p. 168°-169° C.; NMR (d6 -DMSO): 1.24(dt, 6H), 2.72(q, 2H), 3.0(q,2H), 6.46(d, 1H), 6.9(s, 1H), 8.07(d, 1H); mass spectrum (CI: 203 (M+H)+ ; microanalysis, found: C, 70.9; H, 6.9; N, 13.8%; C12H14N2O requires: C, 71.3; H, 6.98; N, 13.9%.
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1.N([O-])=O.[Na+].[ClH:20]>O>[Cl:20][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(Cl)c2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
In a mixture of 45 ml of hydrochloric acid and 30 ml of water was dissolved 3.35 g (15.0 mmol) of Compound 13 prepared in Example 10, and 1.05 g (15.2 mmol) of sodium nitrite was added to the solution under ice-cooling, followed by stirring for 30 minutes. Then, a solution of 1.80 g (18.2 mmol) of cuprous chloride in 30 ml of hydrochloric acid was added thereto and the temperature of the mixture was raised slowly to room temperature, followed by stirring for one hour. The precipitated crystals were collected by filtration and then washed with water, followed by recrystallization from chloroform/ethanol to give 2.64 g (73%) of Compound 24.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
1-(Bromomethyl)-4-nitrobenzene (1.08 g, 5.00 mmol) was added to a vigorously stirred mixture of tert-butyl piperazine-1-carboxylate (1.02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (I92) (1.523 g, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.32-8.10 (m, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.59 (s, 2H), 3.52-3.39 (m, 4H), 2.43-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 266.1 [M-tBu+2H]+, 222.1 [M-Boc+2H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:7](=[O:8])[O:6][CH2:5][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyltin (1200 g, 3.6 mol), palladium tetrakis triphenylphosphine (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L). The mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100° C. for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated. The resulting solid was purified by silica gel column chromatography (heptane:ethyl acetate, 0→40%) to provide 5-(prop-2-en-1-yl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[OH:15].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[O:15][CH:12]2[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine (18.9 g) in dichloromethane (400 ml) was added in turn sodium hydrogen carbonate (11.3 g) and m-chloroperoxybenzoic acid (23.4 g) with care at 0° C., and which was stirred for 2 hours. Insoluble material was removed by filtration, mother liquor was washed saturated sodium chloride in water (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was dissolved in n-hexane (300 ml) and insoluble material was removed by filtration. Mother liquor was concentrated in vacuo, the remainings were dissolved in ethyl acetate (300 ml) and washed in turn with saturated sodium hydrogen carbonate in water (100 ml×5) and saturated sodium chloride in water (100 ml×2), which was dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (350 ml) eluting in turn with 10%, 20% and 30% ethyl acetate in n-hexane. Fractions, containing desired product, were collected and concentrated in vacuo to give 1-tert-butoxycarbonyl-3,4-epoxypiperidine (13.7 g).