Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[CH:20]=[N:19][NH:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[CH:20]=[N:19][NH:18][C:13]3=2)[N:8]=1
Reactant: Oc1nc2ccc3cn[nH]c3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Finely powdered potassium nitrate (0.11 g, 1 mmol) was added to a stirred solution of 7,8-dihydroxy-1H-pyrazolo[3,4-f]quinoxaline (0.2 g, 1 mmol) in 2 ml of conc. sulfuric acid at room temperature. The solution was stirred for 1 h at this temperature and then poured into 50 ml of ice/water. After 30 min the precipitated solid was isolated by filtration and washed with water. Recrystallization from N,N-dimethylformamide/water afforded 0.13 g (53%) of the nitro compound; m.p.>300° C.; IR (KBr): 3300-2500, 1705 cm-1 ; 1H-NMR (DMSO-d6): 7.83 (s, 1H, ArH), 8.37 (s, 1H, ArH), 12.2 (broad s, 2H, 2OH).
Reaction SMILES: [Li+].[OH-].[NH:3]1[C:7]2[CH:8]=[CH:9][C:10](/[C:12](/[C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)\[CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[N:4]1.Cl>C1COCC1.CCO.O>[NH:3]1[C:7]2[CH:8]=[CH:9][C:10](/[C:12](/[C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)\[CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]nnc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]nnc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
An aqueous solution of LiOH (0.22 g, 9.4 mmol) was added to a solution of (E)-ethyl 3-(4-((E)-1-(1H-benzo[d][1,2,3]triazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate (0.2 g, 0.47 mmol) in THF-EtOH (1:1, 24 mL) at room temperature, and the resulting mixture was stirred overnight. The reaction was monitored by LCMS. Upon completion, 1N aqueous HCl was added until the pH was 3. Then, the mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-20% methanol in dichloromethane affording the title compound as an off-white solid (0.12 g). 1H NMR (300 MHz, DMSO-d6): δ 15.65 (br, 1H), 12.29 (br, 1H), 7.92 (d, 1H), 7.78 (s, 1H), 7.48-7.35 (m, 3H), 7.24-7.13 (m, 7H), 6.91 (d, 2H), 6.37 (d, 1H), 2.39 (q, 2H), 0.89 (t, 3H); LCMS: 396 (M+H)+.
Reaction SMILES: S([CH2:11][N:12]=C=O)(C1C=CC(C)=CC=1)(=O)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH:24]=O)=[CH:19][CH:18]=1.CO>COCCOC.O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH2:24][C:11]#[N:12])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: COc1ccc(C(C)(C)C=O)cc1
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(C(C)(C)CC#N)cc1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a mixture of KOBu-t (450 mg, 4.2 mmol) and TosCH2NCO (410 mg, 2.1 mmol) in DME (8 ml) was added a solution of Compound 45 (350 mg, 2.0 mmol) in DME (2 ml) with cooling (-40° C.). The mixture was stirred at same temperature for 10 min. and then at room temperature for 1 h and to this was added MeOH (6 ml) dropwise. The mixture was stirred at same temperature for 1 hr. and then at room temperature for 15 h. The mixture was concentrated to give a solid, which was dissolved in water (10 ml). The aqueous layer was extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give crude product (480 mg) as a yellow oil. The crude product was purified by a column chromatography to give Compound 46 (230 mg, 1.2 mmol,. 60%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]1>C(#N)C>[CH2:10]([O:9][C:7]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]2)[NH:6][N:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: O=C1CCOCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtained as a white solid. M.Pt. 121–123° C.; (M+H) 255.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(O)c1
Reaction time: 2 h

Procedure:
3′-Hydroxyacetophenone (500 mg) was dissolved in tetrahydrofuran (10 ml), and the solution was slowly added dropwise with a 3 M solution of methylmagnesium bromide in diethyl ether (3.7 ml) under ice cooling. The mixture was stirred at the same temperature for 2 hours, and then added with saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (224.3 mg).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCOc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Product: CCOc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(4-ethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:11])[O:10][CH2:18][C:17]=2[C:16]2[CH:21]=[CH:22][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C1OCC(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 45.1 %

Procedure:
In acetonitrile (10 ml), a mixture of 4-chlorophenylacetic acid (1.70 g), 4-chlorophenacyl bromide (2.33 g) and potassium carbonate (5.53 g) was heated at reflux while stirring for 2 hours. Toluene and water were added to the reaction mixture, and the thus-precipitated crystals were filtered and purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5), thereby giving 1.37 g of 3,4-bis(4-chlorophenyl)-2(5H)-furanone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([Cl:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([Cl:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(Cl)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Cl)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
To a solution of 48 mg (0.3 mmol) 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-4-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo to give 141 mg white solid (99%). MS (ISP) 463.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:18])(C(F)(F)F)[CH2:10][C:9]=2[Cl:19])[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[Br:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:18])=[CH:10][C:9]=3[Cl:19])[CH:5]=[C:4]([C:20]([F:21])([F:22])[F:23])[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(C2=C(Cl)CC(Cl)(C(F)(F)F)C=C2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2,4-dichloro-4-trifluoromethylphenyl)-6-trifluoromethyl-pyrimidine (example A.61) (1.50 g, 4.58 mmol) and commercially available 3-bromo-benzene-boronic acid (1.01 g, 5.03 mmol) according to the general procedure IVb. Obtained as a white solid (1.26 g, 61%). MS (EI) 447.9 [(M)+]; mp 124.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[CH3:24]O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: CO
Reactant: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(N)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.4 %

Procedure:
To a solution of 2.5 g (7.8 mmol) of (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of methanol was added 0.125 g (0.66 mmol) of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 2 days and then concentrated to a small volume. The residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to a solid. Recrystallization of this solid from hexane-ethyl acetate gave 2.48 g of methyl (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 91°-93° C.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([C:7]#[N:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br-].[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C1C=CC=CC=1>[Br-:17].[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][P+:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)#[N:8]
Reactant: Cc1ccccc1C#N
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Br-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: N#Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 70 %

Procedure:
Bromination of o-tolunitrile with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine (1.2 equiv.), using the procedure described in example 102, except that the reaction time for the bromination was 2 h, gave the phosphonium salt (547) (70%) as a light brown powder, mp (CH2Cl2/benzene) 237–241° C. 1H NMR (CDCl3) δ 7.90 (dd, J=7.8, 2.3 Hz, 1H), 7.85–7.63 (m, 15H), 7.52 (br t, J=7.7 Hz, 1H), 7.44 (br d, J=7.5 Hz, 1H), 7.38 (tdd, J=7.6, 2.1, 1.0 Hz, 1H), 5.86 (d, J=14.7 Hz, 2H). Found: C, 67.88; H, 4.42; N, 3.09. C26H21BrNP requires C, 68.13; H, 4.62; N, 3.06.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH3:30]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:29][CH3:30])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:14][CH3:15]
Reactant: CCN1CCc2occ(C(=O)O)c2C1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc2c1C(=O)N(CC)CC2
Temperature: 85 °C
Yield: 80.4 %

Procedure:
To a stirred solution of potassium hydroxide (3.79 g, 67.6 mmol) in methyl alcohol (15 mL) under Nitrogen at 0° C. was added dropwise a solution of N-ethyl-2,4-piperidione (9.54 g, 67.6 mmol) in methyl alcohol (20 mL). The mixture was stirred at 0° C. for 1 hour, then a solution of ethyl bromopyruvate (8.9 mL, 71 mmol) in methyl alcohol(50 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 2.5 hours, a 50% aqueous sodium hydroxide solution (10 mL) was added dropwise and stirring continued an additional 17 hours. After cooling in an ice water bath, the solution was acididfied and the methanol removed in vacuo. Ice water was added and the precipitate filtered and dried in vacuo to afford 4-oxo-5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-3-carboxylic acid (3.91 g). More acid (1.15 g) was obtained via extraction of the aqueous filtrate 2X wtih ethyl acetate, drying over magnesium sulfate, filtration, concentrating in vacuo, and purification on Silica gel (5% methyl alcohol/dichloromethane). A stirring mixture of 4-oxo-5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-3-carboxylic acid (4.94 g, 23.6 mmol), potassium carbonate (9.79 g, 70.8 mmol), cesium carbonate (770 mg, 2.4 mmol), and iodoethane (9.4 mL, 118 mmol) in N,N-dimethylformamide was heated at 85° C. for 15.5 hours. The reaction mixture was cooled and concentrated in vacuo. Ethyl acetate was added, the mixture filtered, the filtrate washed with water, and the organic layer dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (4.5 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8]>>[CH3:5][C:3]([OH:9])([CH:2]=[CH2:1])[CH3:4].[CH2:8]([CH2:7][C:6]([O-:10])=[O:9])[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: CCC(=O)O
Product: C=CC(C)(C)O
Product: CC(C)=CCCC(=O)[O-]
Temperature: 35 °C
Reaction time: 6 h

Procedure:
Analogous with Example 1, a solution of 5.6 grams (0.08 moles) of isoprene and 100 milliliters of a 65 volume percent aqueous propionic acid (mole ratios: water to isoprene=24.3, propionic acid to isoprene=10.7) was reacted in the presence of 5 grams of a cation exchanger sold under the trademark Lewatit SPC 118 at 35° C. After stirring at 35° C. for 6 hours, the reaction was 20 percent complete. There was obtained 2-methyl-3-butene-2-ol with a yield of 57 percent and prenylacetate with a yield of 29 percent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.O.O.[OH-].[Li+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
A solution of methyl indole-6-carboxylate (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60° C. for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253°-254°: NMR (80 MHz; CDCl3) 6.51(m, 1H, H3 -indole), 8.04(m, 1H, H7 -indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:20])[C@H:13]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][C@H:12]3[C:11]=2[C:10]=1[Cl:42]>C(Cl)Cl>[ClH:8].[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:20])[C@H:13]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34][C@H:12]3[C:11]=2[C:10]=1[Cl:42]
Reactant: Cc1cccc(NC(=O)CN2c3ccc(Cl)c(Cl)c3[C@@H]3CCN(C(=O)OC(C)(C)C)CC[C@@H]32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CN2c3ccc(Cl)c(Cl)c3[C@@H]3CCNCC[C@@H]32)c1C
Product: Cl

Procedure:
TFA (0.60 mL, 7.7 mmol) was added to a solution of tert-butyl (5aS*,10bS*)-9,10-dichloro-6-{ 2-[(2,3-dimethylphenyl)amino]-2-oxoethyl } -1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.39 mmol) in CH2Cl2 (7 mL). The reaction was quenched with 10% aqueous NaOH (5 mL) after 2.5 h and extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude yellow foam (0.15 g) was purified via column chromatography (Biotage, 40S) with CH2Cl2/MeOH/NH4OH (976:21:3) followed by the preparation of the hydrochloride salt to give 67 mg (38%) of an off white solid: mp 238.5-241.0° C.; 1H NMR (DMSO, 300 MHz) δ 9.60 (s, 1H), 8.92 (br s, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.13 (m, 1H), 7.03 (m, 2H), 6.54 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.16 (d, J=17.1 Hz, 1H), 3.87 (d, J=17.1 Hz, 1H), 3.71 (m, 1H), 3.35 (m, 2H), 3.08 (m, 3H), 2.34 (m, 1H), 2.24 (m, 3H), 2.12 (m, 5H); IR (diffuse reflectance) 2969, 2955, 2938, 2823, 2796, 2772, 2755, 2727, 1676, 1527, 1464, 1285, 1274, 806, 787 cm−1; MS (EI) m/z 417 (M+), 419, 226, 120, 106, 105, 91, 77, 76, 56; HRMS (FAB) calcd for C22H25CL2N3O+H 418.1453, found 418.1439.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[NH3:12]>>[O:10]=[C:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][C:3]([NH2:12])=[O:2]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N
Product: CCCCC(=O)CC(N)=O
Temperature: 90 °C

Procedure:
0.4 mol (63.7 ml) 3-oxo-heptanoic acid methylester and 400 ml 7 N ammonia solution was stirred for three hours at 100° C. in a pressure reactor. After cooling off, the solvents were distilled off on a rotavap, the raw products were taken up in 200 ml water and 40 ml ethanol and set to about pH 3 with 40 ml 32% HCl. The reaction mixture was heated to 90° C. for 4 hours and then again concentrated to dryness in the rotavap, taken up in 600 ml dichloromethane and washed 3 times with 100 ml water. The organic phase was distilled off and the raw product recrystallized from 100 ml toluene. The product was filtrated off and dried in a vacuum drying cabinet at 50° C. 3.5 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:21])[C:19]=1[OH:20])[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[C:19]([OH:20])=[C:18]([Cl:21])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 3,5-dichloro-4-hydroxyaniline as the raw materials, the same operation as the example 16 gave the title compound. 22.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][N+:7]([O-:9])=[O:8])[CH3:2].[Na].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[C:15]=1[CH:22]=O.Cl>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:20][C:16]2[C:15](=[C:14]([O:13][CH3:12])[CH:19]=[CH:18][CH:17]=2)[CH:22]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)CC[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1C=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2c(OC)cccc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-nitro-propionic acid ethyl ester (16.25 g, 110.45 mmol, 4.0 equiv) in EtOH (150 ml) was added at 0° C. under an atmosphere of argon to a freshly prepared solution of sodium (2.54 g, 110.45 mmol, 4.0 equiv) in EtOH (110 ml). After 15 minutes, a solution of 3-methoxy-benzene-1,2-dicarbaldehyde (4.53 g, 27.61 mmol) in EtOH (150 ml) was added at 0° C. The reaction mixture was warmed to room temperature, and after 40 minutes, TLC analysis indicated complete conversion. 2 N aqueous HCl (55 ml, 4 equiv) was carefully added at 0° C., and the mixture was extracted with EtOAc (1.5 liter in total). The combined organic layers were washed with concentrated aqueous NH4Cl solution (200 ml), brine (400 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of toluene/hexane 5:5 to 10:0) to afford the title compound (0.942 g, 12%, inseparable 1:1.15 mixture of regioisomers A:B) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.87 (s, 1H isomer A), 8.69 (s, 1H isomer B), 8.33 (s, 1H isomer B), 8.15 (s, 1H isomer A), 7.64-7.59 (m, 1H isomer A+1H isomer B), 7.53 (d, J=8.1 Hz, 1H isomer B), 7.51 (d, J=8.3 Hz, 1H isomer A), 7.02 (d, J=6.5 Hz, 1H isomer B), 7.00 (d, J=7.8 Hz, 1H isomer A), 4.42 (q, J=7.3 Hz, 2H isomer A), 4.41 (q, J=7.1 Hz, 2H isomer B), 4.04 (s, 3H isomer A), 4.03 (s, 3H isomer B), 1.38 (t, J=6.3 Hz, 3H isomer A+3H isomer B). MS (ES+): 276 (M+H)+.