Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (58.90 g) in tetrahydrofuran (500 ml) was added aluminum lithium hydride (6.64 g) at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the precipitate was filtered off. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)methanol (45.30 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 79–80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>CS(C)=O>[CH3:16][S:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)[O-]
Reactant: Oc1cnc(-c2ccc(Br)cc2)nc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ncc(O)cn2)cc1
Yield: 24.5 %

Procedure:
2-[4-(Methylsulfonyl)phenyl]-5-pyrimidinol (0.19 g, 40%) was prepared as a light brown solid from 2-(4-bromophenyl)-pyrimidin-5-ol (0.50 g, 1.89 mmol), methanesulfinic acid sodium salt (0.73 g, 80%, 5.68 mmol) and Cul (1.08 g, 5.68 mmol) in DMSO (15 mL) in a manner similar to Example 83, Step 2. The crude product was purified by chromatography on a silica gel column eluted with 2:4:0.1 EtOAc/CH2Cl2/MeOH to give 0.116 g 2-[4-(methylsulfonyl)phenyl]-5-pyrimidinol as a light brown solid. Impure fractions were combined and further purified by chromatography on a silica gel column eluted with 2:6:0.1 EtOAc/CH2Cl2/MeOH to give additional 0.075 g of 2-[4-(methylsulfonyl)phenyl]-5-pyrimidinol as a light brown solid (40% yield overall). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.60-8.40 (m, 4H), 8.00 (d, 2H, J=8.5 Hz), 3.23 (s, 3H); LRMS (ESI), m/z 251 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11]2)[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)C(=O)NC1CCC(Oc2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCC(NC(=O)C(C)C)CC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide (Example 40b) and ethyl 3-oxobutanoate as a yellow solid (57%). MS 414 (MH+).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([OH:17])[C:11]([OH:18])=[N:10]2>S(=O)(=O)(O)O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N+:1]([O-:4])=[O:2])[N:13]=[C:12]([OH:17])[C:11]([OH:18])=[N:10]2
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc(Cl)cc2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2cc1Cl
Reaction time: 1 h
Yield: 87.8 %

Procedure:
Finely powdered potassium nitrate (1.01 g, 10 mmol) is added during 5 min. to a stirred solution of 6-chloro-2,3-dihydroxyquinoxaline (1.97 g, 10 mmol) in 50 ml of concentrated sulfuric acid at 0° C. After 1 h, the ice bath was removed and stirring continued for 2.5 h at room temperature. The mixture is poured into 200 ml of ice/water and the precipitate is isolated, washed with water, ethanol, and ether. The product is dissolved in 70 ml of hot 2N sodium hydroxide, filtered while hot, and reprecipitated with concentrated hypochloric acid to give 2.12 g (88%) of pure title compound. 3H-NMR (DMSO-d6): δ 7.23 (s, 1H, H-5); δ 7.82 (s, 1H, h-8); δ 12.1 (broad s, 2H, 2NH).
Reaction SMILES: [Br-].C([N+:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.[BH4-].[Na+]>CC(C)=O>[O:20]1[CH2:19][CH2:18][CH:17]([CH2:16][O:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH2:22][CH2:21]1
Reactant: c1ccc(C[n+]2ccc(OCC3CCOCC3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: C1CC(OCC2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
1-Benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g) was mixed with MeOH (35 ml), and NaBH4 (850 mg) was added thereto, followed by stirring at room temperature for 1 hour. Acetone (6 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and then activated carbon (1 g) was added thereto, followed by stirring at room temperature for 30 minutes and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with MeOH (35 ml), and ammonium formate (3 g) and 10% palladium carbon (400 mg) were added thereto, followed by stirring at 50° C. for 4 hours and filtering using Celite, and the filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 4-(tetrahydro-2H-pyran-4-ylmethoxy)piperidine (1.01 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[C:31]1([S:37](F)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:31]1([S:37]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Reactant: O=S(=O)(F)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.1 h
Yield: 45.3 %

Procedure:
To as stirred solution of 6-bromo-1-triisopropylsilanyl-1H-indole (0.687 g, 1.95 mmol) in THF (12 mL) at −78° C. under nitrogen was added, dropwise over 0.3 h, a solution of tert-butyllithium in pentane (1.7 M, 2.52 mL, 4.29 mmol) (internal temperature was kept below −70° C.). The mixture was stirred at −78° C. for 0.1 h then phenylsulfonyl fluoride (0.26 mL, 0.343 g, 2.15 mmol) was added dropwise. The mixture was stirred at −78° C. then warmed to 20° C. and stirred thus for 1 h. Excess tert-butyllithium was quenched by addition of ice and the resulting mixture was partitioned between water (100 mL) and EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give semi-solid. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (0.365 g, 45%). 1H NMR (CDCl3): 8.21 (1H, s), 8.00-7.89 (2H, m), 7.70 (1H, d), 7.63 (1H, dd), 7.57-7.41 (4H, m), 6.69 (1H, d), 1.82-1.65 (3H, m), 1.16 (18H, d).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[CH:4][CH:3]=1.[N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]=[S:26]>CS(C)=O>[C:18]([O:17][C:16]([NH:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[Cl:23])[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[S:26])=[N:7][CH:6]=1)=[O:22])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccc1Cl
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(Cl)c(NC(=O)OC(C)(C)C)c2)cn1
Yield: 96.8 %

Procedure:
In the same manner as in Reference Example 30 and using tert-butyl {5-[(6-aminopyridin-3-yl)oxy]-2-chlorophenyl}carbamate (10.8 g, 32.3 mmol), ethyl isothiocyanatoformate (4.60 mL, 38.9 mmol) and DMSO (60 mL) as starting materials, the title compound (14.6 g, 97%) was obtained as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O.COCCOC>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:28])=[O:5]
Reactant: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)O)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)Cl)c1C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, the compound (400 mg) prepared in Example 9 was dissolved to 1,2-dimethoxyethane (6.0 mL). Anhydrous N,N-dimethylformamide (one drop) and oxalyl chloride (0.22 mL) were added to the reaction mixture, which was stirred for 30 minutes at 40° C. The title compound was obtained by concentrating the reaction mixture.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1.[CH3:25]C(O)C>>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH:20]([CH3:25])[CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1
Reactant: CC(C)O
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Temperature: 25 °C

Procedure:
100 ml of 2-propanol are treated with 100 mg of sodium hydride. 5 g of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are added thereto and the mixture is heated to boiling under reflux for 1 hour. Subsequently, the mixture is left to cool to room temperature, the separated crystals are filtered off and washed with 2-propanol and water, there being obtained isopropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 243°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 85.5 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C[O-].[Na+].[C:4]([N:6]=[C:7]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:9][CH3:10])#[N:5]>CO>[NH2:5][C:4]1[N:6]=[C:7]([CH2:8][CH2:9][CH3:10])[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCC(=NC#N)NCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(N)c(C(=O)OC)[nH]1
Temperature: 13 °C
Yield: 37.6 %

Procedure:
To stirred methanol at -2° C. was added sodium methoxide (108 g, 2.0 mol) in portions over a period of 40 minutes. To this clear solution at -3° C. was added a solution of methyl N-(N'-cyanobutyrimidoyl)glycinate (Example 3, 344 g, 1.9 mol) in methanol (600 mL) over a period of 30 minutes. The resulting orange solution was allowed to warm to 13° C. over a period of 1 hour, then refluxed for 1 hour. The dark solution was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (4×1 L) and the combined organic layers washed with a saturated aqueous solution of sodium chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate at -10° C. to afford 131 g (38% yield) of methyl 4-amino-2-propylimidazol-5-carboxylate, mp 133°-136° C. MS (DEI) 184 (M+1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][C:8](=[O:9])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Nc1ccccn1
Reactant: C=CC(=O)OCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCC(=O)Nc1ccccn1
Reaction time: 18 h

Procedure:
3-Chloro-3-oxopropyl acrylate, 1, (1 eq.), 2-aminopyridine (1 eq.) and triethylamine (3 eq.) are dissolved in toluene at 0° C. A few crystals of hydroquinone is added to inhibit any polymerization side reactions. The solution is allowed to stir approximately 18 hours at a temperature from about 0° C. to room temperature. The solvent is removed under reduced pressure and the crude material purified over silica. For a more detailed account of this procedure See M. A. Diab, A. Z. El-Sonbati, A. A. El-S anabori, F. I. Taha, Polymer Degrad. Stab. 1989, 24, 51, included herein by reference.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]2)[CH2:11][CH:10]=1>[C].[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: CCC[C@H]1CC[C@H](C2CC=C(c3cc(F)ccc3F)CC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](C2CCC(c3cc(F)ccc3F)CC2)CC1

Procedure:
A mixture of 2,5-difluoro(4-(trans-4-propylcyclohexyl)cyclohexenyl)benzene (0.84 mmol), ethyl acetate (30 ml), and 5% palladium carbon (0.013 g) is stirred under an atmosphere of hydrogen. After ceasing the absorption of hydrogen, 5% palladium carbon is filtered off from the reaction mixture. The filtrate is concentrated under reduced pressure and purified by silica-gel chromatography, and further recrystallized to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:3]=1.[Cl:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1.N1C=CC=CC=1>>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=3)[N:3]=2)(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C#N)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Yield: 85 %

Procedure:
To 3-{[3-amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 2) (7.89 g, 28.3 mmol) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (Aldrich) (6.15 g, 28.3 mmol) in pyridine (9.17 mL, 113 mmol) under nitrogen at room temperature. Reaction was exothermic and went deep red. After 40 minutes the reaction mixture was separated between ethyl acetate (500 mL) and 2N hydrochloric acid (500 mL). The aqueous phase was washed with ethyl acetate (400 mL). The combined organic solutions were dried over magnesium sulphate and evaporated in vacuo. The deep red residue was dissolved in DCM and applied to a 340 g silica cartridge. The cartridge was eluted with a gradient of 0-10% ethyl acetate in dichloromethane over 8 CV. Evaporation of the appropriate fractions gave the title compound (11.1 g, 85%) as an off-white solid. LCMS (System A) RT=1.15 min, ES+ve m/z 459/461 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:29]=[CH:28][C:27]([O:30][Si](C(C)(C)C)(C)C)=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:38])=[N:25]2>O1CCCC1.ClCCl>[Br:19][C:20]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:38])=[N:25]2
Reactant: Cc1ccc2c(Br)ccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(Br)ccc(O)c2n1
Reaction time: 0.17 h

Procedure:
Tetrabutylammonium fluoride (54 ml, 1M in tetrahydrofuran) was added dropwise to a stirred solution of 5-bromo-8-t-butyldimethylsilyloxyquinaldine (16.3 g) in tetrahydrofuran (500 ml). After stirring for 10 minutes the reaction was diluted with dichloromethane (500 ml) and extracted with water (3×200 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. Purification by recrystallisation from aqueous methanol afforded the title compound as an off white solid (7.7 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[C:17]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])(=[O:20])[CH2:18][CH3:19]
Reactant: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N(CCCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene and propionylchloride
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 1-(4-bromophenyl)piperazine hydrochloride (5.09 g, 18.3 mmol) and triethylamine (7.67 ml) in dichloromethane (100 ml) was added methanesulfonyl chloride (2.83 ml, 36.3 mmol) dropwise. The mixture was stirred for 1 hour at room temperature then dichloromethane (100 ml) was added. The organics were washed with water (2×), brine and dried (Na2SO4) and evaporated in vacuo to a yellow solid which crystallised from Ethanol and washed with diethyl ether to give 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (4.74 g, 81% yield) as a white fluffy powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:23]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>CN(C=O)C.CCOC(C)=O>[C:14]([CH:10]1[S:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:23]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCSC(C(N)=O)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (2.47 g, 10 mmol) and HOBt (1.62 g, 12 mmol) were dissolved in DMF (20 mL), and EDCl (2.11 g, 11 mmol) was added. The reaction mixture was stirred for 1 hour, and 25% aqueous ammonia (5 mL) was added, and the reaction was stirred for another 2 hours. The reaction was then diluted with EtOAc (200 mL) and partitioned with water (100 mL). The organic layer was washed with saturated aq. NaHCO3 (2×100 mL), and then dried with Na2SO4. The solvent was removed in vacuo to afford title compound as white solid 2.46 g. MS (m/z): 147 (M+H-Boc)+
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:11].[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15](SC)[NH:14]1>C(#N)C>[IH:11].[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:14]1
Reactant: NCCOc1ccccc1
Reactant: CSC1=Nc2ccccc2C(C)N1
Agent: I
Solvent: CC#N
Product: CC1NC(NCCOc2ccccc2)=Nc2ccccc21
Temperature: 80 °C
Yield: 79.4 %

Procedure:
2-Phenoxyethylamine (26 mg, 0.19 mmol) was added to a solution of 4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.16 mmol) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The solvent was then evaporated and the mixture was suspended in diethyl ether. The title compound (52 mg, 62%) was obtained from this mixture by filtration.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:25][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccccc3)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccccc3)c2c1

Procedure:
A mixed solution of 6.8 g of the above-mentioned 2-tert-butyl-9-phenylanthracene, 4.3 g of N-bromosuccinimide and 60 ml of dimethylformamide was stirred under nitrogen gas stream at room temperature for 2 hours. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-phenylanthracene.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([O:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=4[N+:31]([O-])=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[NH2:31][C:23]1[CH:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:22]=1[O:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][C:11]([CH3:35])([CH3:36])[CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:34]
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1Oc1ccc(N)cc1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 101.2 %

Procedure:
3-(4-Isopropylphenyl)-5-(2,4-dinitrophenyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (800 mg, 1.63 mmol) and 10% palladium-carbon (hydrate) (80 mg) were dispersed in ethanol (40 mL), and the mixture was stirred in a hydrogen atmosphere at 60° C. for 4 hours. The reaction mixture, from which was removed the catalyst through filtration, was concentrated under reduced pressure to obtain 5-(2,4-diaminophenoxy)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (710 mg). Acetyl chloride (0.26 mL, 3.63 mmol) was added to a solution of the thus-obtained compound (710 mg, 1.65 mmol) and triethylamine (290 mg, 1.70 mmol) in chloroform (30 mL) at 0° C., and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water (30 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/5) to obtain the title compound (640 mg, yield 76%). This was amorphous.