Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([CH3:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:24])[CH2:16][C@@:15]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:25])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:24])[CH2:16]2)[C@:19]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([CH3:22])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Product: C[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A solution of 3α-hydroxy-2β-methyl-5α-pregnane-11,20-dione (1.04g.) in dry methanol (150ml) was stirred at 0°-5° during the dropwise addition of a solution of bromine (0.16ml) in dry methanol (20ml) over a period of 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to a white foam; purification by preparative t.l.c. (ethyl acetate: benzene 1:2.5) gave the title compound (510mg.), m.p. 140° dec.; [α]D + 133° (c 0.95).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: BrCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 100 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved together with N-bromosuccinimide (2.32, 13.0 mmol) and benzoyl peroxide (0.15 g, 0.62 mml) in 31 g of chlorobenzene. The mixture was heated up to 85° C. to give a pale yellow solution that slowly turned red. The solution was maintained at 85° C. for two hours to give a red solution of 6-bromomethyl-quinoxaline. The solution was then cooled down to room temperature with the formation of a precipitate mainly composed of succinimide. The solution was then mixed with an equal volume (˜31 ml) of pentane to ease the precipitation of succinimides (NHS as well as any unreacted NBS). After filtration, the orange solid obtained (1.4 g) was extracted few times with pentane (4 times, 50 ml each) to recover any remaining 6-bromomethyl-quinoxaline. The extracts were combined with the yellow solution of bromomethyl-quinoxaline and vacuum dried to give a yellow solid (1.92 g) that was suspended in an alkaline solution prepared by dissolving 2.0 g of sodium hydroxide pellets in 30 g of water. The catalyst (5% Pd/C) was added to the alkaline mixture (0.2 g) and the suspension was heated up to 85-95° C. and sparged with air for 48 hours. The black suspension was filtered to give an amber solution that was neutralized with dilute sulfuric acid to give a yellow powder (1.28 g, 85% yield) that precipitated from solution (6-quinoxaline-carboxylic acid).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C1(C)C=CC=CC=1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in toluene (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in toluene was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 162.9 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]2[CH2:14][C:15]3[C:16]([O:24][CH3:25])=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[C:20]=3[O:21][C:11]=2[C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:23][O:22][C:19]1[C:20]2[O:21][C:11]3[C:10](=[O:26])[N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[CH2:13][C:12]=3[CH2:14][C:15]=2[C:16]([O:24][CH3:25])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC2=C(Oc3c(OC)ccc(OC)c3C2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Yield: 244.9 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (1.4 g, 1.39 mmol) and lithium hydroxide monohydrate (0.18 g, 4.26 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (30 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (1.23 g, 89.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:25])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N+:21]([O-:31])[CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:25])[CH:4]=1
Reactant: COc1ccn(-c2nc(C)c(C(=O)NCc3cccnc3)s2)c(=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3ccc[n+]([O-])c3)s2)c(=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
To a stirred solution of 2-(4-methoxy-2-oxopyridin-1(2H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.28 mmol) in anhydrous dichloromethane (10 mL) was added m-chloroperoxy benzoic acid (0.072 g, 0.42 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours, diluted with dichloromethane (100 mL), washed with saturated bicarbonate solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane to afford the title compound as a colorless solid in 34% yield (0.035 g): mp 255-257° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.8 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 8.09 (d, J=6.3 Hz, 1H), 7.37-7.23 (m, 2H), 6.33 (dd, J=8.1, 2.7 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.34 (d, J=5.7 Hz, 2H), 3.81 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.6, 162.2, 161.7, 154.1, 151.0, 139.3, 138.1, 137.7, 131.9, 126.7, 124.9, 123.0, 104.2, 96.5, 56.8, 42.1, 17.5; MS (ES+) m/z 373.3 (M+1), 395.2 (M+23).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[S:5][CH:6]=[C:7]([C:9]#[CH:10])[CH:8]=1.C(OC)(OC)OC>CO.OS(O)(=O)=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1
Reactant: C#Cc1csc(C(OC)OC)c1
Agent: O=S(=O)(O)O
Solvent: COC(OC)OC
Solvent: CO
Product: CCc1csc(C(OC)OC)c1

Procedure:
2-Dimethoxymethyl-4-ethynylthiophene (15 g, 0.082 mol) was mixed with 1.5 g Pd[C] in 200 mL of methanol and hydrogenated for 4 hr at 44-31 psi. The mixture was filtered through glass fiber paper and concentrated. The residue (11.6 g) was dissolved in 60 mL of methanol and treated with trimethyl orthoformate (19 g, 0.18 mol) and H2SO4 (6 drops) in a flask equipped with a reflux condenser and drying tube. The mixture was heated at reflux for 70 min, cooled, and poured into 200 mL of saturated aqueous NaHCO3. The suspension was extracted with 200 mL of CH2Cl2, and the organic was filtered through 1 PS paper and concentrated at aspirator pressure. The 16 g of residue was dissolved in 200 mL of hexanes and applied to 150 g of silica gel (topped with Na2SO4 and equilibrated with hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([N:38]2[C:42]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:41](=[O:48])[NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:45]4[CH2:44][CH2:43][C:42]5([N:38]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:39][NH:40][C:41]5=[O:48])[CH2:47][CH2:46]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as in General Procedure 10 to give the title compound. LCMS: m/z=661.03 (M+H+); retention time=0.86 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][NH:30][CH2:31]2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]2[CH:32]([CH2:31][N:30]([CH2:11][C:9]3[S:8][C:6]4[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[C:5]=4[N:10]=3)[CH2:29]2)[CH2:33]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (57 mg, 0.20 mmol) in 1,2-dichloroethane (2 mL) was added hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (46 mg, 0.22 mmol). The mixture was stirred at RT for 5 min before sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added. The resulting solution was stirred at RT for 1 h. The crude reaction mixture was partitioned between DCM and brine. The organic layer was isolated, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (83 mg, 86%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:14][C:15]([OH:19])([C:17]#[CH:18])[CH3:16]>COCCOC.[Cu]I.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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:18]#[C:17][C:15]([CH3:16])([OH:19])[CH3:14]
Reactant: C#CC(C)(C)O
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1nccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,3-thiazole (6.0 g, 37 mmol) and CuI (1.3 g, 7.3 mmol) were combined in DME (150 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (25 mL, 180 mmol) and PdCl2(PPh3)2 (2.5 g, 3.7 mmol) were added and 2-methyl-3-butyne-2-ol (4.6 g, 55 mmol) was added dropwise. After stirring at ambient temperature for 16 h, GC/MS showed the reaction was not complete. The reaction was heated to reflux for 2 h. The mixture was filtered through Celite.™., the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (600 mL), washed with water (600 mL), brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 7:3 hexane:ethyl acetate to afford 4-(2-thiazolyl)-2-methyl-3-butyn-2-ol contaminated with 2,7-dimethyl-but-3,5-diyne-2,7-diol. (The dimer of 2-methyl-3-butyne-2-ol) The product was crystallized from boiling hexane to afford 2-methyl-4-(1,3-thiazol-2-yl)-3-butyn-2-ol (2.18 g, 36% yield) as off white crystals that were contaminated with a small amount of 2,7-dimethyl-but-3,5-diyne-2,7-diol. M.p. 69-70° C. 1H NMR (CDCl3, 300 MHz) Δ7.80 (d, J=3.0 Hz, 1H), 7.34 (d, J=3.0 Hz, 1H), 4.40 (s, 1H), 1.65 (s, 6H). MS (ESI) 168.1 (M++H).
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.[CH3:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:48]2[N:44]([CH3:43])[N:45]=[CH:46][N:47]=2)=[CH:28][CH:27]=1
Reactant: Cn1cncn1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cn1ncnc1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Yield: 89 %

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-methyl-1H-1,2,4-triazole. (0.22 g, 89% yield). M/e+ 324.1 for C17H14ClN5 (M+H)+; 1H-NMR (300 MHz, DMSO-d6, δ) 8.26 (d, J=6.9 Hz, 1H), 7.74-7.70 (m, 3H), 7.65-7.61 (m, 1H), 7.54-7.51 (m, 2H), 7.33-7.28 (m, 1H), 6.93 (td, J=6.8, 1.2 Hz, 1H), 4.68 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:17]#[N:18])[C:3]=2[CH:4]=[N:5]1
Reactant: Brc1cccc2c1cnn2C1CCCCO1
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1cnn2C1CCCCO1
Temperature: 85 °C
Yield: 75 %

Procedure:
To a mixture of 196 (0.57 g, 2.05 mmol), Zn(CN)2 (264 mg, 2.25 mmol) in NMP (6 mL) under an argon atmosphere was added (Ph3P)4Pd(0) (356 mg, 0.31 mmol). The mixture was heated at 85° C. overnight, cooled, and partitioned between EtOAc (300 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with 1% MeOH/DCM to afford 430 mg (75%) of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (198) as yellow solid: MS (ESI) m/z=228 [M+1]+.
Reaction SMILES: [CH3:1][CH:2](C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[C:14]([CH2:19][CH:20]1[C:25](=[O:26])[CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]1)([O:16]CC)=O.O1C2C=CCCC2CC1=O>C1(C)C=CC=CC=1>[C:27]1([C:23]2[CH2:22][CH2:21][C@H:20]3[CH2:19][C:14](=[O:16])[O:26][C@H:25]3[CH:24]=2)[CH:28]=[CH:29][CH:30]=[CH:2][CH:1]=1
Reactant: CCCCC1=CC(=O)C(CC(=O)OCC)CC1
Reactant: CC(C)[O-]
Agent: O=C1CC2CCC=CC2O1
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: O=C1C[C@@H]2CCC(c3ccccc3)=C[C@@H]2O1
Yield: 83.7 %

Procedure:
The reaction of 7.12 g (34.8 mmoles) of aluminum isopropoxide in 100 ml of toluene with 1.5 g (5.8 mmoles) of 6-(carbethoxymethyl)-3-n-butyl-2-cyclohexen-1-one was conducted in a similar manner to the synthesis of 3a,4,5,7a-tetrahydro-2(3H)-benzofuranone described in Example I. The crude material was purified by crystallization from hexane to yield 1.04 g (84%) of cis 6-phenyl-3a,4,5,7a-tetrahydro-2(3H)-benzofuranone, mp 90°-92° C. NMR and IR confirm the structure of the compound.
Reaction SMILES: [C@@H:1]12[O:6][C@@H:5]1[CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]2>CC(OC)(C)C>[OH:6][C@H:1]1[CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: COC(=O)C1C[C@@H]2O[C@@H]2C1
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1CC[C@H](O)C1

Procedure:
A solution of methyl (1S,5R)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (8 g, 56.3 mmol) in MTBE (100 ml) was hydrogenated at 3 atm on Parr shaker for 12 hrs. Filtered through celite evaporated followed by chromatagraphy on a 50 g silica gel Biotage Snap cartridge with 10-50% 6:3:1 Hexane-MTBE-MeCN/Hexane to give title compound. 1H NMR (500 MHz, CDCl3) δ 1.63-1.74 (m, 3H), δ 1.78 (s, br, 1H), δ 1.82-2.07 (m, 4H), δ 2.11-2.19 (m, 1H), δ 3.09 (m, 1H), δ 3.70 (s, 3H), δ 4.48 (m, 1H)
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOCC>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH2:16][C:17](=[O:19])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH2:1][C:8]=2[CH:13]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Solvent: CCOCC
Product: COc1ccc2c(c1)Cc1ccccc1C(=O)C2
Reaction time: 0.25 h

Procedure:
Finely powdered 2-benzyl-4-methoxyphenylacetic acid (3.26 g, 12.72 mmol) was added to well-stirred polyphosphoric acid (165 g) at 100-110° C. After 15 min, the reaction was poured onto ice (330 g). Et2O (330 mL) was added, and the mixture was stirred briskly for 15 min. The layers were separated, and the aqueous layer was extracted with Et2O (330 mL). The combined organic layers were washed with 5% NaHCO3 (2×80 mL) then with brine (80 mL), dried (MgSO4), and concentrated. The residue was reconcentrated from toluene, then was chromatographed (silica gel, 20% EtOAc/hexanes). The title compound was obtained as a yellow solid (1.44 g, 48%): TLC Rf (20% EtOAc/hexanes) 0.46; 1H NMR (250 MHz, CDCl3) δ 8.07-8.15 (m, 1H), 7.39-7.49 (m, 1H), 7.25-7.48 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.71 (dd, J=8.3, 2.6 Hz, 1H), 4.21 (s, 2H), 4.11 (s, 2H), 3.77 (s, 3H); FTIR (CCl4) 1680, 1501, 1282, 1270 cm-1 ; MS (ES) m/e 261 (M+Na)+, 256.0 (M+NH4)+, 239.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:20]([O:22][C@H:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1)[CH3:21].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:31](=[O:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([O:22][CH2:20][CH3:21])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][CH:34]=1
Reactant: CCCCCCCNCc1cccc(OC)c1OC
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of N-(2,3-dimethoxybenzyl)-N-heptylamine (1.46 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (100 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.57 g (58%) of a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)Cl.[NH2:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20].[Br:24][CH2:25][C:26](Br)=[O:27]>O>[Br:24][CH2:25][C:26]([NH:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20])=[O:27]
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSc1cc(C)nc(SC)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Triethylamine (274 mg, 2.71 mmol) was added to a chloroform (10 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (492 mg, 2.46 mmol), and bromoacetyl bromide (521 mg, 2.58 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in this order, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 25 g, eluent—hexane:acetone=7:1→5:1→3:1) to obtain 100 mg (yield 13%) of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as a colorless crystal (melting point: 171 to 172° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH2:13][OH:14])[CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Si:29]([O:14][CH2:13][C:11]1[CH:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of (5-morpholino-2-nitrophenyl)methanol (3.0 g, 12.6 mmol), triethylamine (2.54 g, 25.2 mmol) and 4-dimethylaminopyridine (0.2 g) in dichloromethane (100 mL) was added tert-butylchlorodimethylsilane (2.83 g, 18.9 mmol). After the addition was over, the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed by saturated sodium bicarbonate, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 4-(3-((tert-butyldimethylsilyloxy)methyl)-4-nitrophenyl)morpholine (4.0 g, yield 90.9%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH2:8][CH2:9][N:10]=[C:11]1[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH:12]1[CH3:18].C(N(CC)CC)C>CCCCCC>[CH3:18][C:12]1[CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[C:11]=1[N:10]([CH2:9][CH2:8][O:7][CH3:6])[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: COCCN=C1C(C)CCCC1C
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COCCN(C(=O)CCl)C1=C(C)CCCC1C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
Over a period of 3 hours and at 20°-30° C. 37.5 g of chloroacetylchloride are added dropwise while stirring to a solution of 57 g of N-(2-methoxy-ethyl)-2,6-dimethylcyclohexylideneamine in 200 ml of hexane. Afterwards during 2 hours 48 ml of triethylamine are added dropwise in the course of which the temperature of the mixture rises to ca. 50° C. Subsequently the mixture is heated under reflux for 30 minutes and poured onto ice. The organic layer is washed with water and dried over sodium sulfate. The solvent is distilled off and the residue is fractionally distilled: 54.5 g of N-(2,6-dimethyl-1-cyclohexene-1-yl)-N-(2-methoxyethyl)-α-chloro-acetamide are obtained, b.p. 136°-139° C./0.1 Torr.