Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:23]C(C)([O-])C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:23])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reaction time: 0.17 h

Procedure:
Codeinone (300 g) was added to a stirred suspension of potassium tert-butoxide (153 g) in N,N-dimethylformamide (5 ml) at room temperature. After 10 minutes, methyl trifluoromethanasulphonate (164 mg) was added dropwise to the suspension. The solution was stirred for 5 minutes, diluted with ethyl acetate (30 ml), and then poured into water (50 ml). The aqueous phase was removed, and the organic phase was dried with sodium sulphate and evaporated, producing an orange solid. Analysis by HPLC Against pure thebaine gave a thebaine content of 10%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[N:7][N:8]=1.CCN(C(C)C)C(C)C.[CH:19]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[O:9]=[C:4]1[C:3]([CH2:2][NH:1][C:23]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:24])=[N:8][N:7]=[CH:6][NH:5]1
Reactant: NCc1nnc[nH]c1=O
Reactant: O=C(Cl)C1CCC1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96 mmol) and DIEA (0.829 mL, 4.76 mmol) in anhydrous N,N-DMF (20 mL) and anhydrous pyridine (2 mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL, 3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5 h. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo and was purified by chromatography on silica gel [eluting with 5% MeOH in DCM (200 mL)×10% MeOH in DCM (800 mL)], affording the title compound; 1H NMR (DMSO-d6, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m, 1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d, 2H); 7.97 (br. t, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100) [MH+], HPLC: tR=1.56 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:33]=[CH2:34])=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]>C1C=CC=CC=1.C(O)C.[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:33]([C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]=1[CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate (17.7 g) and tris(triphenylphosphine) rhodium chloride (1.2 g) in benzene (180 ml) and ethanol (180 ml) was hydrogenated for 11 hours. The solvents were removed under vacuum and the residue was crystallized from ethyl acetate/tert butyl methyl ether to afford methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 101.3°-102.08° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:17]O>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH3:17])=[O:9])=[CH:5][CH:6]=1
Reactant: CO
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A 500-mL round bottom flask, with stirrer bar, was charged with p-tolylacetic acid (10.0 g, 66.5 mmol) and methanol (240 mL). Concentrated sulfuric acid (0.1 mL) was added at room temperature. The resulting solution was stirred at 65° C. for 18 h. After this time, the mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.8 g, 100%) as a colorless oil. MW=164.20. 1H NMR (CDCl3, 300 MHz) δ 7.20-7.10 (m, 4H), 3.68 (s, 3H), 3.59 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]2.[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][CH2:2][C:3]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1

Procedure:
heating a mixture of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate in an organic solvent at 35-40° C. for 5 hours to form 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea;
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]=2[N:3]=1.[CH2:19]([O:21][C:22](=O)[O:23]CC)[CH3:20].[Li+].CC([N-]C(C)C)C>C1COCC1>[C:15]([O:14][C:12]([N:5]1[C:4]2[N:3]=[C:2]([CH2:1][C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
The compound was prepared according to the procedure as described in WO 0033838. To a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (1.4 g, 5.6 mmol) and diethylcarbonate (2.5 g, 20 mmol) in THF (10 ml) was added LDA (8 ml of 2M solution in hexane) at −78° C. and stirred at −78° C. for 40 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethylacetate (2×100 ml). Combined organic solution was concentrated and purified on silica gel column to give 1.5 g (83%) yellow oil. NMR (CD3OD) δ 1.25 (t, 3H, J=7.10 Hz), 1.51 (s, 9H), 1.88-1.97 (m, 2H), 2.75 (t, 2H, J=6.59 Hz), 3.74-3.80 (m, 4H), 4.10-4.20 (m, 2H), 7.0 (d, 1H, J=7.61Hz), 7.39 (d, 1H, J=7.47 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:26][S:25][C@@H:12]3[C@H:13]([NH:16][C:17]([CH2:19][N:20]4[N:24]=[N:23][N:22]=[CH:21]4)=[O:18])[C:14](=[O:15])[N:11]3[C:10]=2[C:27]([OH:29])=[O:28])=[N:4][N:3]=1.[N+:30]([O-:33])([OH:32])=[O:31]>CO.C(#N)C>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:26][S:25][C@@H:12]3[C@H:13]([NH:16][C:17]([CH2:19][N:20]4[N:24]=[N:23][N:22]=[CH:21]4)=[O:18])[C:14](=[O:15])[N:11]3[C:10]=2[C:27]([OH:29])=[O:28])=[N:4][N:3]=1.[N+:30]([O-:33])([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Agent: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared by adding to a Cefazolin solution (1.5 g, 3.3 mmoles) in methanol (50 ml) a 65% nitric acid solution (0.250 ml) in acetonitrile (5 ml) and following then the procedure reported in Example 5. Cefazolin nitrate as amorphous solid is obtained. Yield 60%.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CO>CC(C)=O>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
The free base (0.176 g, 0.1635 mmol) was dissolved in acetone (10 mL) and treated with one mole equivalent of L-tartaric acid in methanol (0.1M, 1.60 mL; 0.160 mmol). This mixture was concentrated and treated with dry ether and filtered to give 0.18 g of a tartaric acid salt of the the title compound; mp 150°-153° C.; IR (KBr) 3438, 3064, 2944, 1726, 1662, 1612, 1582, 1486 cm-1 ; MS (FAB) MH+ m/z 1071, (M+Na)+ m/z 1093, (M+K)+ m/z 1109; 1H-NMR (CDCl3) δ 1.112 (s, 2H), 1.218 (s, 3H), 1.705 (s, 3H), 1.804-2.116 (m, 6H), 2.221 (s, 3H), 2.373 (m, H), 2.441 (s, 3H), 2.545 (m, 3H), 3.454-3.697 (m, 4H), 3.794 (d, H), 4.170 (d, H), 4.320 (d, H), 4.445 (m, H), 4.951 (m, 2H), 5.671 (m, 2H), 6.026 (m, H), 6.250 (t, H), 6.287 (s, H), 7.098 (d, NH), 7.200-8.200 (m, 19H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1>C(O)(C)C>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[N:10]=2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccccc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CC(C)O
Product: COc1ccc(-c2nc(=O)c3ccccc3o2)cc1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
6.85 g (50 mmol) of salicylic acid amide are added, dropwise, to 18.1 g of p-methoxybenzoyl chloride and the mixture is heated to 150° C. The mixture is then stirred for 30 minutes at this temperature. After cooling, the honey-like mass is stirred with 100 ml of isopropanol, the precipitated solid filtered off and dried to yield 10.2 g of 2-(4-methoxyphenyl)-4H-1,3-benzoxazin-4-one as a white solid melting at 175-178° C. and having the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.OC1C=CC(CC(O)=O)=CC=1.[NH3:27]>>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[NH2:27]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: N
Agent: O=C(O)Cc1ccc(O)cc1
Product: Nc1cnn(-c2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,5-Dichloro-2-phenyl-pyridazinone (2.41 g), 4-hydroxyphenyl-acetic acid (1.0 g) and 20% aqueous ammonia (20 ml) were heated to 100°-110° C. with stirring in a small autoclave for 4 hours. The reaction mixture was then cooled to room temperature, and the resulting precipitate of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone was isolated by filtration, washed with water and dried. 1.86 g of pure 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone were obtained, m.p. 206°-207° C. The mother liquor and the washings contained 0.15 g of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone. The total amount of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone formed was thus 2.01 g (91%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH3:9]>N1C=CC=CC=1>[CH2:8]([C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:5](=[O:7])[CH3:6])=[CH:12][CH:11]=1)[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(N)cc1
Solvent: c1ccncc1
Product: CCc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
Acetic anhydride (4.3 mL, 45.45 mmol) was added to a mixture of 4-ethylaniline (5.0 g, 41.32 mmol) and pyridine (20 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and an aqueous solution of hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 6.857 g of N-(4-ethyl-phenyl)-acetamide as a brown solid without further purifications.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:21](I)([CH3:23])[CH3:22].O>CN(C=O)C.CCOC(C)=O>[CH:21]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C
Reaction time: 19 h

Procedure:
In a sealed tube, to a suspension of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (566.9 mg, 2.922 mmol) and Cs2CO3 (1.5442 g, 4.739 mmol) in DMF (6 mL), isopropyl iodide (753.3 mg, 4.431 mmol) was added and the reaction was allowed to stir at 100° C. for 19 h. Water was added to dilute the reaction and dissolve all salts that had formed, after which EtOAc was added and the two layers were separated. The organic layer was washed twice with water and once with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The combined aqueous layers were back extracted once with EtOAc, which was combined with the other organic batch. One obtained the title material as yellow oil. It was used without further purification in the next step. 1H NMR (400 MHz, CDCl3): δ=1.33 (s, 12H), 1.51 (d, J=6.8 Hz, 6H), 4.53 (spt, J=6.7 Hz, 1H), 7.75 (s, 1H), 7.80 (s, 1H). MS (AP+): m/z 235.98 (76) [MH+]. HPLC: tR=3.22 min (ZQ3, polar—5 min).
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>C(Cl)Cl>[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: O
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in methylene chloride (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in metylene chloride was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. 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 159.8 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: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5].[CH2:14]1[CH2:19][O:18][CH:17]=[CH:16][CH2:15]1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:19][O:18]2)[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: COCc1cc(O)cc(O)c1C=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Yield: 86.8 %

Procedure:
A solution of 2,4-dihydroxy-6-methoxymethylbenzaldehyde (4.08 g, 22.4 mmol) in dichloromethane (100 mL) was treated with PPTS (100 mg) and DHP (4.06 mL, 44.8 mmol) at room temperature overnight. The reaction was concentrated to dryness. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=3:1) to afford the title compound (5.18 g, 87%). 1H NMR (300 MHz, CD3OD) δ 12.34 (s, 1H), 10.12 (s, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 5.58 (m, 1H), 4.63 (s, 2H), 3.84-3.81 (m, 1H), 3.66-3.62 (m, 1H), 3.40 (s, 3H), 1.95-1.86 (m, 2H), 1.75-1.62 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[BH4-].[Na+].Cl>C1COCC1>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: COC(=O)C1CCC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of methyl 3-oxocyclopentanecarboxylate (9.58 g, 67.5 mmol) in THF (100 ml) was added to a slurry of sodium borohydride (3.8 g, 100 mmol) in THF (100 ml). The mixture was stirred at 23° C. for 2 h, cooled to 0° C. and acidified to pH 6 with 1M hydrochloric acid. The mixture was extracted with EtOAc (2×100 ml) and the organic extracts were washed with water and saturated sodium chloride (100 ml each). The extracts were dried and the solvent was evaporated in vacuo to give the title compound as a colorless liquid, 6.66 g (68% yield), (a mixture of two isomers); ir (liq.) νmax : 3450, 1725 cm-1 : 1Hmr (CDCl3) δ: 4.30 (m, 1H, H-3), 3.70-3.67 (2×s, 3H, OMe), 2.9 (m, 1H, H-1), 2.8 (s, 1 H, OH) and 2.3-1.6 ppm (m, 6H, CH2).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:16][N:15]=[C:10]1[CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCC(c2ccccc2)CC1
Temperature: 70 °C
Yield: 97 %

Procedure:
A mixture of 4-phenylcyclohexanone (28.7 mmol), hydroxylamine hydrochloride (36.0 mmol), and sodium acetate (60.95 mmol) in ethanol and water was heated at 70° C. overnight. Ethanol was removed, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give 1-(hydroxyimino)-4-phenylcyclohexane (97%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].O.O.[Na].[S:12]1([C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[NH:15]1)(=[O:14])=[O:13]>CN(C)C=O.O>[O:17]=[C:16]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[S:12](=[O:14])(=[O:13])[N:15]1[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)OC(=O)CCl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 120 °C
Yield: 86.4 %

Procedure:
23.3 kg (170.6 mol) of isopropyl chloroacetate are added to a solution at 50° C. of 40 kg (165.8 mol) of saccharin sodium dihydrate in 40 l of dimethylformamide. The mixture is heated to 120° C. and maintained for 3 hours at this temperature. The mixture is cooled and diluted with 240 l of water. Finally, the precipitate is centrifuged, washed with cold water and dried, 40.6 kg (86%) of a crystalline white solid, m.p. 112°-7° C. (118°-9° C. from isopropanol), being obtained.
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[CH3:8][S:9][CH3:10]>>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[CH3:8][S+:9]([CH3:5])[CH3:10]
Reactant: COS(=O)(=O)OC
Reactant: CSC
Product: COS(=O)(=O)[O-]
Product: C[S+](C)C

Procedure:
comprising reacting dimethyl sulphate with an excess of dimethyl sulphide thereby to form trimethylsulphonium methyl-sulphate of the formula
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.OS(O)(=O)=O.[CH3:20]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:20])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(O)ccc2c1
Yield: 95 %

Procedure:
To a 1-L round bottomed flash equipped with a nitrogen inlet and magnetic stir bar was added 50 g (0.27 mol) of 6-hydroxy-2-naphthoic acid and 400 mL of methanol. The suspension was treated slowly with 1 mL of con. H2SO4 and stirred at room temperature overnight. The resulting solution was evaporated, taken up in 500 mL of ethyl acetate and washed sequentially with 3×300 ML of saturated NaHCO3, 2×300 mL of water and brine. The pale yellow solution was dried over MgSO4, reduced in volume to about 100 mL and slowly treated with hexane. The resulting crystalline precipitate was collected and dried under a stream of nitrogen to yield 52 g (95%) of the title compound as fine, white plates, mp 196° C.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].C[O:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1>C(Cl)Cl>[CH2:5]([NH:7][C:8](=[O:9])[O-:10])[CH3:6].[OH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Product: CC1c2ccc(O)cc2C2CNCC12
Reaction time: 8 h

Procedure:
BBr3 (1.1 mL, 1.0 M in dichloromethane) was added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.31 g, 1.1 mmol) in CH2Cl2 (10 mL) at 0° C., and stirred overnight. The excess BBr3 was quenched with the dropwise addition of water (2 mL), and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic extract was dried over MgSO4 and concentrated. The subtitle compound was obtained without further purification. MS calculated for C15H19NO3+H: 262, observed: 262.
Reaction SMILES: I[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:18]([O-:23])([N+]([O-])=O)=[O:19].O>C(O)(=O)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:18]([O-:23])=[O:19])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc2c(-c3ccccc3)c(I)oc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 1 h

Procedure:
To a stirred solution of 5.0 g (0.015 mole) of 2-iodo-7-methyl-3-phenylbenzofuran from Example 9 in 100 ml of acetic acid is added dropwise 2.0 g (0.022 mole) of dinitrogen tetroxide in 10 ml of acetic acid. After stirring one hour the mixture is poured into cold water, then extracted with diethyl ether. The ether extracts are washed with water, 10% sodium bisulfite solution, water and saturated sodium chloride solution and dried. Concentration gives a tan powder which is recrystallized from aqueous ethanol to give yellow crystals of 7-methyl-2-nitro-3-phenylbenzofuran, m.p. 123°-126° C. This product is identical to the product of Example 2 according to comparative infrared spectral analysis.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:14]([Br:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:21].[CH2:14]([N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cccnc1-c1ccccc1
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Product: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Product: [Br-]
Yield: 91 %

Procedure:
A suspension of 3-hydroxy-2-phenylpyridine (20 g, 116 mmol) in toluene (250 ml) was heated at reflux for 30 minutes. Benzyl bromide (20 ml) was added and the reaction mixture was heated at reflux for 6 hours then cooled using an ice bath. The solid residue was collected by filtration and washed twice with ether to give crude N-benzyl-3-hydroxy-2-phenylpyridinium bromide (36.5 g, 91%) which was used in the next step without further purification.