Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([CH3:34])[CH3:33])[CH:25]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1>C(O)C.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:21][C:19]1[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([CH3:34])[CH3:33])[CH:25]=2)=[CH:17][C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Iron (68 mg, 1.22 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-N-methyl-6-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (112 mg, 0.203 mmol) in ethanol (2.3 mL) and AcOH (2.3 mL) at rt. It was placed in a reaction block set to 100° C. and allowed to stir for 1 hr. The mixture was allowed to cool and was diluted with EtOAc and washed with 1M HCl, followed by 1N NaOH and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with Et2O to give the titled compound (52 mg, 47%). 1H NMR (500 MHz, CD3OD) δ ppm 6.58-6.65 (3 H, m), 6.52 (1 H, d, J=7.63 Hz), 6.37 (1 H, d, J=7.93 Hz), 6.30 (1 H, t, J=7.63 Hz), 6.18 (2 H, d, J=7.32 Hz), 6.08 (1 H, s), 6.03 (2 H, t, J=7.78 Hz), 5.88-5.97 (3 H, m), 5.73 (1 H, s), 1.65 (3 H, s), 0.50 (6 H, s). LC-MS retention time 1.54 min; m/z (MH−): 520. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.11 min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=11.11 min, purity=94%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:10][C:11]=1[CH2:12][CH3:13])[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:12]([C:11]1[S:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[N:8][C:7]=1[CH:5]([CH3:6])[CH2:4][OH:3])[CH3:13]
Reactant: CCOC(=O)C(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)CO
Temperature: 0 °C
Yield: 96.4 %

Procedure:
2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid ethyl ester (1.05 g, 3.06 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (10 mL) and then cooled to 0° C. with stirring. Lithium aluminum hydride (3.10 mL, 1M in THF, 3.10 mmol) is slowly added by syringe and the reaction is monitored by TLC. Upon complete conversion, the reaction is carefully quenched using water, base, and water. Celite is added to the reaction, followed by diethyl ether and the mixture is then filtered through a celite plug. The two phases are then separated and the organic layer is washed using water and brine. The organic layer is the dried over anhydrous sodium sulfate and concentrated. The pure 2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (0.930 g, 2.95 mmol) is obtained in 95% yield after flash column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([N+:23]([O-])=O)=[CH:17][CH:16]=3)=[O:11])=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>[Ni].O>[NH2:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11])=[C:21]2[OH:22]
Reactant: [H][H]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc([N+](=O)[O-])cc2c1O
Agent: [Ni]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Yield: 84.5 %

Procedure:
N-[(4-chlorophenyl)methyl]-4-hydroxy-6-nitro-3-quinolinecarboxamide (500 mg) is suspended in 50 mL of freshly degassed dimethylformamide and treated with 0.5 mL of 50% Raney nickel in water (Aldrich). The mixture is agitated under 45 psi hydrogen pressure for 24 h, and then it is filtered through celite. The solvent is removed by evaporation at reduced pressure and the residue is suspended in 5 mL of absolute ethanol and it is collected by filtration. After drying at 0.1 torr/100 ° C./1.5 h, the product is obtained as 387 mg of a pale yellow powder.
Reaction SMILES: C(OC([N:6]1[C:14]([NH2:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[C:16]([F:19])([F:18])[F:17])=[N:7]1)=O)C>C(OC(OC(OCC)=O)=O)C>[NH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:16]([F:18])([F:17])[F:19])[NH:7][N:6]=1
Reactant: CCOC(=O)n1nc2cccc(C(F)(F)F)c2c1N
Agent: CCOC(=O)OC(=O)OCC
Product: Nc1n[nH]c2cccc(C(F)(F)F)c12

Procedure:
Analogously to Example 1, 0.06 mol of 3-amino-4-trifluoromethylindazole in 50 ml of pyrocarbonic acid diethyl ester gives 3-amino-4-trifluoromethylindazole-2-carboxylic acid ethyl ester (melting point: 100°-101° C; 85% of theory) in 10 minutes at 20° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]=2[Cl:21])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)on1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A mixture of ethyl 5-(4-tert-butylphenyl)isoxazole-3-carboxylate (2.0 g, 7.32 mmol) and N-chlorosuccinimide (2.44 g, 18.3 mmol) in acetic acid (50 mL) was heated to reflux for 3 days. The reaction mixture was then allowed to cool to room temperature, poured over ice and the resulting white solid was collected, dissolved in ethyl acetate and the organics washed with water, brine and dried with sodium sulphate before being filtered, and evaporated in vacuo. The resultant residue was re-dissolved in dichloromethane, this was then extracted with sodium carbonate solution, and dried using a hydrophobic frit. The organics were removed in vacuo to obtain ethyl 5-(4-tert-butylphenyl)-4-chloroisoxazole-3-carboxylate (0.81 g, 2.63 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:3].[CH2:13]([O:15][C:16](Cl)=[O:17])[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16]([N:5]([C:6](=[O:11])[CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:4][C:2]([CH3:1])([CH3:12])[NH2:3])=[O:17])[CH3:14]
Reactant: CC(C)CC(=O)NCC(C)(C)N
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N(CC(C)(C)N)C(=O)CC(C)C

Procedure:
A mixture of 5.1 parts of 2,2,7,7-tetramethyl-1,4-diazaheptan-5-one, 30 parts of ethylchloroformate and 150 parts of anhydrous toluene were heated at reflux for 16 hours. Removal of the solvent under reduced pressure was followed by addition of 10 parts of water to the residue basification with sodium carbonate solution and chloroform extraction. The yellow oil produced was distilled under reduced pressure to yield 4-ethoxycarbonyl-2,2,7,7-tetramethyl-1,4-diazaheptan-5-one of boiling point 98° - 100°C at 0.2mm pressure. The hydrochloric acid salt of this material gave the following elemental analysis by weight:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:41])=[CH:28]\[CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[C:21]=1[CH3:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:30][CH2:29]/[CH:28]=[C:27](\[C:22]1[C:21]([CH3:42])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:25]([CH3:26])=[CH:24][CH:23]=1)/[CH3:41]
Reactant: C/C(=C/CN1C(=O)c2ccccc2C1=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Agent: NN
Solvent: CCO
Solvent: O
Product: C/C(=C/CN)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Yield: 90.8 %

Procedure:
To a suspension of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-1-methyl-3-phthalimido-1-propenyl)benzene (94 mg) in ethanol (1 ml) was added hydrazine monohydrate (16.4 mg), and the mixture was refluxed for 1 hour. After cooling, the insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added dichloromethane, and the insoluble material was filtered off. The filtrate was concentrated in vacuo to give 3-((Z)-3-amino-1-methyl-1-propenyl)-1-tert-butyldiphenylsilyloxymethyl-2,6-dimethylbenzene (66 mg) as pale yellow amorphous.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC1C=CC(S(O[CH2:21][CH2:22][CH2:23][NH:24][C:25]2[C:26](=[O:42])[N:27]([C:38]([CH3:41])([CH3:40])[CH3:39])[S:28](=[O:37])(=[O:36])[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=O)=O)=CC=1>>[C:38]([N:27]1[C:26](=[O:42])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:28]1(=[O:36])=[O:37])([CH3:39])([CH3:40])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: OCc1ccc(O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(CO)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 34 %

Procedure:
The title compound was prepared as described for Example 12 from 4-(hydroxymethyl)phenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate. Purified by silica gel column chromatography (Horizons Biotage) using 0-10% EtOAc in DCM as eluent to give the title compound (0.037 mg, 34%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.29 (d, 2H), 6.85 (d, 2H), 5.74 (t, 1H), 4.64 (s, 2H), 3.90 (t, 2H), 3.11-3.00 (m, 2H), 1.87-1.82 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158.2, 135.3, 133.8, 131.8, 129.8, 128.9, 128.8, 125.3, 114.7, 107.2, 66.1, 65.2, 61.7, 42.5, 28.9, 27.8, Mass Spectrum M+H+ 445.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O>[CH2:3]([C:2](=[CH:1][CH2:2][CH2:3][CH3:4])[CH:1]=[O:5])[CH3:4]
Reactant: CCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC=C(C=O)CC

Procedure:
n-Butyraldehyde was added to an approx. 3% aqueous sodium hydroxide solution with a ratio of 9 parts by weight sodium hydroxide solution to 1 part by weight aldehyde, and intensively mixed at a temperature of 100° to 130° C. 2-Ethylhexenal, which was formed by cleavage of water, was then hydrogenated with a fixed bed nickel catalyst in the gas phase at approx. 110° C. The hydrogenation product had the following composition:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=2)[C:6]2[NH:10][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:27]=1.[CH3:38][C:39]([CH3:41])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[CH:39]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:5]2[C:6]3[NH:10][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:13][CH2:12]4)=[N:8][C:7]=3[CH:27]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=2)=[CH:29][CH:30]=1)([CH3:41])[CH3:38]
Reactant: NCc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)NCc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-benzimidazol-7-yl)benzylamine (172 mg, 0.33 mmol, Example 75) and acetone (1 mL) in chloroform (5 mL) were added NaBH(OAc)3 (211 mg, 1 mmol) and one drop of acetic acid. The mixture was stirred at room temperature for 2 h, diluted with dichloromethane (30 mL), washed with satd aq. NaHCO3 solution (25 mL), dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 5% MeOH in dichloromethane to give the title compound as white amorphous solid. MS (ESI, pos. ion) m/z: 563 (M+1), (ESI, neg. ion)
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:17][C:18]1[S:19][C:20](Cl)=[N:21][N:22]=1>C(O)C>[NH2:17][C:18]1[S:19][C:20]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:21][N:22]=1
Reactant: Nc1nnc(Cl)s1
Reactant: CCCCNCCCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCN(CCCC)c1nnc(N)s1

Procedure:
28 parts of dibutylamine and 25 parts of triethylamine are added to 27 parts of 2-amino-5-chloro-1,3,4-thiadiazole in 200 parts of ethanol. The reaction mixture is heated under reflux for 2 hours and then concentrated to dryness. The residue is suspended in 250 ml of water and filtered. The 2-amino-5-dibutylamino-1,3,4-thiadiazole obtained in this manner can be recrystallised from ethanol/water.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([OH:15])=[O:14].O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a stirred mixture of 2-bromo-4-fluorotrifluoromethylbenzene (33.7 g, 0.1387 mol) in sulfuric acid (98%, 34 mL) at 5° C. under nitrogen is added dropwise a mixture of sulfuric acid (98%, 10.1 mL) with fuming nitric acid (6.7 mL). The mixture is warmed up to room temperature for 2 hours and cooled down to 5° C. before adding water (60 mL). The resulting mixture is extracted twice with ethyl acetate (10 mL). The combined organic phases are washed with a saturated solution of sodium hydrogencarbonate (60 mL), water (60 mL) and dried over sodium sulfate. Concentration affords the title compound as a yellow solid (37.1 g, 92.9%)
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)[CH2:3][CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:9]([O:8][CH2:7][CH2:6][CH:5]([CH3:12])[CH2:4][CH:3]=[CH:2][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)([CH3:11])[CH3:10]
Reactant: CC(CCOC(C)C)CCC(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(CC=Cc1ccc2c(c1)OCO2)CCOC(C)C
Temperature: 25 °C

Procedure:
6.50 g (0.022 mol) of 1-(1-hydroxy-6-isopropoxy-4-methyl-hexyl)-3,4-methylenedioxybenzene are boiled at reflux together with 0.30 g (0.0016 mol) of p-toluenesulphonic acid monohydrate in 500 cc of benzene over the course of 2 hours and using a Dean-Stark trap. After cooling to room temperature, the benzene solution is washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried with sodium sulphate and evaporated in a vacuum. After chromatography of the residue on silica gel wth hexane/ethyl acetate (98:2), pure 1-(6-isopropoxy-4-methyl-1-hexenyl)-3,4-methylenedioxybenzene is obtained as a colourless oil. nD20 = 1.5258.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].[I-].[K+]>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:20][CH2:19][CH2:18][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCl)c1
Temperature: 25 °C

Procedure:
60 g of 3-nitrophenol, 88 g of potassium carbonate and 178 ml of 1-bromo-2-chloroethane are boiled under reflux for 36 h in 800 ml of acetone together with 1.5 g of tetrabutylammonium bromide and 2.0 g of potassium iodide. The mixture is then cooled to RT and concentrated in an RE. The mixture is treated with water, extracted 3 times with ethyl acetate and concentrated. The residue is chromatographed using methylene chloride and the product-containing fractions are concentrated. 1-(2-chloroethoxy)-3-nitrobenzene are obtained as an oil which may crystallize (m.p. 58°-60° C).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH2:20][CH2:21][OH:22])[C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCI
Reactant: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2n1CCO
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (200 mg, 0.82 mmol), 2-iodoethanol (77 μL, 0.98 mmol), cesium carbonate (534 mg, 1.64 mmol) and DMF (1.3 mL) was heated to 90° C. overnight. Then more 2-iodoethanol (77 μL, 0.98 mmol) was added and the reaction was stirred at 90° C. for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and then the combined ethyl acetate layers were washed with water (×3) and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% CH2Cl2-Hexanes) to yield the product as a yellow solid (180 mg, -25% purity by NMR, product co-elutes with the indole starting material). ESI-MS m/z calc. 287.1, found 288.5 (M+1)+. Retention time 1.59 minutes. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.14 (d, J=9.1 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 6.60 (s, 1H), 5.10 (t, J=5.5 Hz, 1H), 4.55 (t, J=6.3 Hz, 2H), 3.78-3.73 (m, 2H) and 1.49 (s, 9H) ppm.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1)=[O:43]>ClCCl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]1)=[O:43])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: COc1cc(CO)c(CC(=O)N2CCN(C)CC2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCc1cc(OC)c(OC)cc1CC(=O)N1CCN(C)CC1
Reaction time: 15 h

Procedure:
Triethylamine (0.41 ml) and octadecyl isocyanate (0.91 ml) were added to a solution of 2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]-1-(4-methylpiperazinyl)-1-ethanone (0.82 g) in dichloromethane (8.5 ml) at room temperature. After being stirred for 15 hours, resulting insoluble materials were filtrated out under a vacuum and washed with chloroform. A mixture of the filtrate and chloroform used for washing was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-30:1), thereby yielding 0.83 g of the aimed compound as light brown solid.
Reaction SMILES: CN(N[C:5]([S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)C.[OH-].[Na+].BrC[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CO>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][CH2:5][S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: CN(C)NC(=O)Sc1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCCSc1cccnc1
Yield: 4.5 %

Procedure:
To a solution of 3.64 g (20 mmol) of 3-dimethylaminocarbamoylthiopyridine in 100 ml of methanol was added 1.6 g (40 mmol) of sodium hydroxide. The mixture was heated and refluxed for 3 hours under nitrogen atmosphere. After cooling, 5.64 g (20 mmol) of N-(4-bromobutyl)phthalimide was added. The mixture was heated and refluxed for 2.5 hours. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:1) to obtain 280 mg of the desired compound (4.5%, colorless oil).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:23][CH2:22][CH2:21][C:20]=2[C:24](OCC)=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:25])[C:20]3[CH2:21][CH2:22][CH2:23][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(F)cc2F)CCC1
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1F

Procedure:
using isopropyl 2,4-difluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-difluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 231°-234° C.,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:17]C(=O)C)([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:17])([CH3:15])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(C)c1ccc(-c2ccc(Br)cc2)nc1
Agent: Cl
Solvent: O
Product: CC(C)(N)c1ccc(-c2ccc(Br)cc2)nc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a solution of compound 33-e (5 g, 15 mmol) in H2O (25 ml) was added concentrated HCl (12.3 ml, 150 mmol). The reaction mixture was then refluxed for 60 hours. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate. The water phase was adjusted to a pH of about 8-10 by aqueous NaOH (2N), then extracted with ethyl acetate and washed with brine, dried and concentrated to give 2-(6-(4-bromophenyl)pyridin-3-yl)propan-2-amine (2.6 g, 59%).