Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7](=[CH:10][CH:11]=1)[O:8][CH3:9]>ClCCl>[Cl:3][C:4]1[C:11]([Br:1])=[CH:10][C:7]([O:8][CH3:9])=[C:6]([NH2:12])[CH:5]=1
Reactant: BrBr
Reactant: COc1ccc(Cl)cc1N
Solvent: ClCCl
Product: COc1cc(Br)c(Cl)cc1N
Reaction time: 10 h
Yield: 33.4 %

Procedure:
Bromine (26.4 g) was added to a solution of 4-chloro-o-anisidine (23.55 g) in dichloromethane (400 mL) at room temperature. The resulting mixture was stirred for 10 hours and quenched with NaOH. The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography over silica gel (elution with 10% ethyl acetate in hexanes) gave 11.8 g (33%) of the desired 4-chloro-5-bromo-2-aminoanisole. 1H NMR (300 MHz, CDC13) d 6.94 (s, 1 H), 6.78 (s, 1 H), 3.83 (s, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)C(OCC)=O)C.[OH-].[K+]>C(O)C.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:5]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:4]([OH:37])=[O:3])=[CH:13][CH:14]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(CC(Cc2ccc(C(=O)C(C)(C)C)cc2)C(=O)O)cc1

Procedure:
To a solution of 10g (0.03 mole) of bis-(p-pivaloylbenzyl) malonic acid diethyl ester in 45 ml of ethanol and 45 ml of water, there is added 8.4 g (0.15 mole) potassium hydroxide which is refluxed for 5 hours. The solvents are removed in vacuo and the residue partitioned between ether and water. The aqueous layer is made acidic at 0°C with concentrated hydrochloric acid, extracted with ether, dried and evaporated. The resulting oil is treated with 200 ml of concentrated hydrochloric acid and the mixture is refluxed for 20 hours. The cooled mixture is extracted with ether, the ether extracted with 2N sodium hydroxide and the basic solution is made acidic at 0°C with concentrated hydrochloric acid, extracted with ether, and the ether is then dried and evaporated. The resulting residue is crystallized from ether/petroleum ether to give bis-(p-pivaloylbenzyl) acetic acid, m.p. 107°-109°C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:23](N(CC)CC)C.[BH4-].[Na+].C[Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:23][O:5][C:4](=[O:6])[CH:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][NH:1][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Reactant: CCN(CC)CC
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(CNCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
3-Amino-2-tert-butoxycarbonylamino-propionic acid (5.0 g, 24.5 mmol) was suspended in methanol (100 mL) and benzaldehyde (5.2 g, 49 mmol) was added, followed by triethylamine (TEA, 10.2 mL, 73.5 mmol). The reaction mixture was stirred at ambient temperature for 90 minutes and cooled to 0° C. Solid sodium borohydride (2.78 g, 73.5 mmol) was added in small portions and the reaction was stirred for additional 60 minutes after addition was complete. All volatiles were removed in vacuo and the crude was dissolved in NaOHaq (0.1 M, 100 mL). The solution was washed with diethyl ether and acidified with HCl aq. The mixture was extracted with chloroform. The organic extracts were washed with brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded crude semi-solid (9.0 g). The crude material was dissolved in methanol (40 mL) and toluene (20 mL) and the solution was cooled to 0° C. Trimethysilyl diazomethane solution (2M, in hexanes) was added until the yellow color persisted (˜25 mL). The reaction mixture was stirred for additional 60 minutes at room temperature. The volatiles were removed in vacuo and the crude product was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the pure product 3-Benzylamino-2-tert-butoxycarbonylamino-propionic acid methyl ester (4.09 g): LCMS-ESI+: calc'd for C16H24N2O4: 308.3 (M+). Found: 309.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:32])[C:20](=[O:31])[N:21]2[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O1CCCC1.ClCCl>[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([OH:32])([C:7]1[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=1)[C:20](=[O:31])[N:21]2[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (12.8 g, 92.9 mmol) in tetrahydrofuran (200 mL) was added isopropylmagnesium chloride solution (50.7 mL, 101 mmol, 2.0 M in ether) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, upon which time the colorless precipitate was formed. After the solvent was removed under reduced pressure, the residue was dissolved in methylene chloride (100 mL) and added to a solution of 4-bromo-1-pentyl-1H-indole-2,3-dione (25.0 g, 84.5 mmol) in dichloromethane (100 mL) via a canula over 10 min at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with saturated ammonium chloride solution (100 mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate-hexane to give the title compound (34.9 g, 97%) as a brown gummy material: 1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.29-7.21 (m, 2H), 6.88-6.81 (m, 1H), 6.55, (s, 1H), 6.14 (s, 1H), 5.86 (dd, 2H), 4.24 (s, 1H), 3.70-3.52 (m, 2H), 1.69-1.55 (m, 2H), 1.31-1.24 (m, 4H), 0.83 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 152.6, 149.1, 144.8, 141.2, 131.7, 127.7, 127.6, 121.0, 113.8, 108.3, 106.7, 101.7, 101.4, 80.5 40.5, 28.8, 26.7 22.2, 13.9.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1.C(OCC)(=O)C.C(O)(=O)C.[H][H]>[Pd].CCCCCC>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 16.6 %

Procedure:
A solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran in a mixed solvent of 50 ml of ethyl acetate and 2 ml of acetic acid was vigorously stirred with 1.0 g of 10%palladium on carbon for 20 hours in a hydrogen atmosphere. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 20%ethyl acetate) to give 0.11 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran as a white crystal (yield 17%).
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCC=CCCCC(CCC/C=C\CCCCC)C(CCCC=CCCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (0.4 g, 0.9 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.2 g, 1.3 mmol), EDCI hydrochloride (0.25 g, 1.3 mmol), diisopropylethylamine (0.4 mL, 2.6 mmol) in anhydrous dichloromethane (10 mL) was added dimethylaminopyridine (5 mg). The solution was refluxed for 2 hours then stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to dryness and purified by column chromatography (100% ethyl acetate) to afford 6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 4-(dimethylamino)butanoate 9 as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 6H), 4.93 (m, 1H), 2.30 (m, 4H), 2.22 (s, 6H), 2.03 (m, 12H), 1.88 (m, 2H), 1.66-1.18 (m, 31H), 0.90 (m, 9H). Rf 0.3 (10% MeOH—CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[CH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24]([CH3:27])(=[O:26])=[O:25].C(N(CC)CC)C.CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[C:17][C:19]3[S:20][CH:21]=[CH:22][C:23]=3[S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C#CC1CCN(Cc2cccnc2OC)CC1
Reactant: CS(=O)(=O)c1ccsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(C#Cc2sccc2S(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
500 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-(1-ethynyl)piperidine, 530 mg of 2-bromo-3-(methylsulfonyl)thiophene, 21 mg of anhydrous cupric iodide and 127 mg of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent of 2.2 ml of triethylamine and 2.2 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 2 hours under nitrogen flow. Ethyl acetate was added to the reaction solution, and the resulting precipitates were filtered off. Then, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and then the crude product was purified by silica gel column chromatography (ethyl acetate), to give 450 mg of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N#Cc1c(N)cccc1Oc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(Oc3ccccc3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-phenoxybenzonitrile and ethyl 3-oxobutanoate as a yellow oil (72%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 2.59 (s, 3H), 4.33 (q, J=8.0 Hz, 2H), 6.61 (dd, J=8.0 Hz, 1H), 7.16 (d, J=4.0 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.39-7.52 (m, 4H), 7.93 (brs, 2H). MS 323 (MH+).
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].[Br:9]Br.N1C=NC=N1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CC(C)=O>[F:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH2:5][Br:9]
Reactant: CC(=O)C(C)(C)CF
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1nc[nH]n1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(CF)C(=O)CBr
Yield: 99.9 %

Procedure:
4.18 kg (35.4 mol) of 1-fluoro-2,2-dimethyl-butan-3-one were dissolved in 30 liters of methylene chloride, and 5.67 kg of bromine were added dropwise at 20° C. in the course of 2 hours such that continuous decolorisation occurred. The solvent was distilled off under a waterpump vacuum, a further 15 liters of methylene chloride were added to the residue and the solvent was again distilled off under a waterpump vacuum. The crude 1-fluoro-4-bromo-2,2-dimethyl-butan-3-one (6.97 kg, quantitative yield) was added dropwise to 2.45 kg of 1,2,4-triazole and 4.89 kg of potassium carbonate in 21.4 liters of acetone at 30° to 35° C. in the course of 2 hours, whilst cooling. The mixture was subsequently stirred at room temperature for 15 hours, the insoluble material was filtered off and the solvent was distilled off from the filtrate under a waterpump vacuum. 6.12 kg (93% of theory) of 1-fluoro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one, which could be further reacted directly, were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:8].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[CH:6][C:7]=1[O:8][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=1[Cl:17]
Reactant: O=c1c(Cl)c(O)cnn1-c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2Cl)cnn1-c1ccc(Cl)cc1
Reaction time: 7 h
Yield: 70 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 1.5 g (5.9 m mol) of 4-chloro-2-(4-chlorophenyl)-5-hydroxy-3(2H)-pyridazinone and 1.3 g (6.6 m mol) of 2,4-dichlorobenzyl chloride, and thereto was added 0.7 g of triethylamine. The reaction mixture was heated under stirring on an oil bath at 100° to 120° C. for 7 hours. After allowing to cool, the reaction mixture was poured into 200 ml of water and the precipitated solid was taken out by filtration, washed with water, dried and then recrystallized from benzene to give 1.7 g of the intended compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:21]1[CH2:22][CH2:23][N:24]([S:27]([CH2:30][C:31]2([CH3:38])[C:35](=[O:36])[NH:34][C:33](=[O:37])[NH:32]2)(=[O:29])=[O:28])[CH2:25][CH:26]=1)(=O)=O>CN(C=O)C.[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>[CH3:38][C@:31]1([CH2:30][S:27]([N:24]2[CH2:23][CH:22]=[C:21]([C:10]#[C:9][C:6]3[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=3)[CH2:26][CH2:25]2)(=[O:29])=[O:28])[NH:32][C:33](=[O:37])[NH:34][C:35]1=[O:36]
Reactant: CSc1ncc(C#C[Si](C)(C)C)cn1
Reactant: CC1(CS(=O)(=O)N2CC=C(OS(=O)(=O)C(F)(F)F)CC2)NC(=O)NC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CSc1ncc(C#CC2=CCN(S(=O)(=O)C[C@@]3(C)NC(=O)NC3=O)CC2)cn1
Temperature: 85 °C

Procedure:
The title compound was prepared by the general method described by Nishihara et al., J. Org. Chem., 2000, 65, 1780-1787. To a solution of 2-(methylthio)-5-[(trimethylsilyl)ethynyl]pyrimidine (0.55 g, 2.47 mmol) and 1-{[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]sulfonyl}-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (0.94 g, 2.22 mmol) in DMF (5 mL) was added CuI (10 mol %) and PdCl2(PPh3)2 (5 mol %) and the mixture was heated at 85° C. for 6 hours. The mixture was partitioned between EtOAc (20 mL) and water (10 mL), and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, water and concentrated to a brown oil (1.6 g). The title compound was obtained as a solid (10 mg) following purification by preparative HPLC (using a Xterra-Prep-MS-C18 (50×19) column with a 12 minutes gradient 5-35% of acetonitrile in water with 0.06% NH3).
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>CO>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:3]2[C:4](=[O:10])[C:5](=[O:9])[C:6]=2[O:7][CH3:8])=[CH:14][CH:13]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1ccc(Cl)cc1
Solvent: CO
Product: COc1c(Nc2ccc(Cl)cc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.5 %

Procedure:
To a stirred mixture of 3,4-dimethoxycyclobut-3-ene-1,2-dione (O1, 1.00 g, 7.04 mmol) in methanol (7 mL) at 0° C. under nitrogen was added a solution of 4-chloroaniline (0.898 g, 7.04 mmol) in methanol (8 mL) dropwise over 0.5 h. After addition, the reaction mixture was slowly warmed to room temperature and stirred at room temperature for another 2 days. The reaction mixture was filtered. The filter cake was washed with cold methanol (5 mL) and dried under reduced pressure to afford compound O2 as a yellow solid (1.48 g, 89%): 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.44-7.35 (m, 4H), 4.38 (s, 3H). MS (M+H) 238.
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[OH:27][N:26]=[C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(=O)O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C(C)=NO)c(O)cc1OCCCCCC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 7.1 g of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanoic acid, 0.149 g of hydroxylamine hydrochloride, 0.176 g of sodium acetate, and 50 ml of methanol were heated at reflux for 48 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The solid was crystallized from methylene chloride/hexane to provide 0.32 g of the desired titled product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:11]=1[C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26].P(=O)(O)(O)O.C[O:33][C:34]1C=CC(C=O)=C[CH:39]=1>ClCCl>[C:1]([O:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[C:11]1[C:12]([O:18][CH3:19])=[CH:13][C:14]([O:16][CH3:17])=[C:15]([C:34](=[O:33])[CH3:39])[C:10]=1[O:9][CH3:8])(=[O:3])[CH3:2]
Reactant: COc1cc(OC)c([C@@H]2CCCC[C@H]2O)c(OC)c1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C=O)cc1
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: COc1cc(OC)c([C@@H]2CCCC[C@H]2OC(C)=O)c(OC)c1C(C)=O
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Acetic anhydride (660 ml; 6.975 mol) was added to the solution of the trans-(+/-)-2-(2,4,6-trimethoxyphenyl)cyclohexanol (II; 60 g; 0.225 mol) in dichloromethane (300 ml) at room temperature, while stirring. It was followed by the dropwise addition of orthophosphoric acid (85%; 40 ml; 0.347 mol) over 45 min. Reaction progress was monitored by TLC (tlc system 30% ethyl acetate-pet ether; spray reagent--anisaldehyde; product Rf--value=0.5). TLC of the reaction mixture after 15 min. revealed complete consumption of the starting material. The reaction mixture was then diluted with 250 ml of cold water, neutralized with solid sodium bicarbonate and extracted with dichloromethane (3×500 ml). The combined organic layer was washed with bicarbonate solution, water, brine and dried over sodium sulphate. It was then concentrated in-vacuo and the residue chromatographed over silica gel (column diam. 9.0 cm; silica gel--1 kg; eluent--5% and 10% ethyl acetate-pet ether) to get the title compound (64 gm; yield 81%; m.p. 82-85° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN1CCCC1=O.C(N(CC)CC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:20](=[O:21])[CH2:19][N:18]([CH3:23])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-nitrophenyl)piperazine and N,N-dimethylglycine hydrochloride were allowed to undergo the reaction using WSC hydrochloride and HOBt in 1-methyl-2-pyrrolidone in the presence of triethylamine. The resulting compound was subjected to-catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-[4-(4-aminophenyl)piperazin-1-yl]-2-dimethylaminoethanone. NMR2: 2.30 (6H, s), 3.74-3.76 (4H, m), 6.64-6.68 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([N:1]([S:33]([CH3:32])(=[O:35])=[O:34])[C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N(S(C)(=O)=O)S(C)(=O)=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 98.7 %

Procedure:
To a solution of ethyl 3-amino-6-chloro-2-(3-chlorobenzoyl)-]-1H-indole-1-carboxylate (step 1 of Example 4, 507 mg, 1.25 mmol) in dichloromethane (15 ml) was added pyridine (0.32 ml, 4.04 mmol) and methanesulfonyl chloride (0.16 ml, 2.02 mmol). After stirring for 19 h, additional pyridine (1.3 ml, 16.2 mmol) and methanesulfonyl chloride (0.32 ml, 4.04 mmol) were added and the mixture heated at reflux for 17 h and then cooled to room temperature. The mixture was concentrated, and partitioned between ethyl acetate (200 ml) and 2 M aqueous HCl (100 ml). The organic layer was separated and washed with 2 M aqueous HCl (100 ml×2), saturated aqueous sodium bicarbonate (100 ml×3), and dried (Na2SO4). After removal of solvent the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford the title compound (532 mg, 74%) as an oil.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]2[C:16](=[O:17])OC(C)(C)OC2=O)=C1.[CH3:27][NH2:28].[N:29]1C=CC=C[CH:30]=1>>[NH:28]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([CH:10]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:11][C:16]([NH:29][CH3:30])=[O:17])=[CH:27]1
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ccccc23)C(=O)O1
Reactant: c1ccncc1
Reactant: CN
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 85 %

Procedure:
5-[(1H-Indol-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.500 g) was dissolved in dry pyridine (5 ml) in a sealable test tube. To this solution was added methyl amine (2.0 ml, 2M in THF) and the tube was sealed and immersed in an oil bath which had been preheated to 120° C. The tube was heated at this temperature for 2 hours, after which time it was cooled and diluted with ice water. The product was extracted into ethyl acetate, washed with dilute HCl, dried (MgSO4) and evaporated to dryness to afford 0.338 g of 3-(1H-indol-3-yl)-N-methyl-3-phenyl-propionamide, (85%, MS (M+H)=279), which was used in the following step without further purification.