Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[C:4]([C:10]([CH3:12])=[O:11])[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:11])[CH3:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Product: CC(=O)Oc1c(C)cc(C(C)O)cc1C

Procedure:
In the process for the production of 3,5-dimethyl-4-acetoxystyrene monomer, one may begin with commercially available 2,6-dimethyl phenol and esterify it with acetic anhydride to produce 2,6-dimethyl phenyl acetate. Then, via a Friedel-Crafts catalysis or Fries rearrangement this is converted to 3,5-dimethyl-4-hydroxy acetophenone. The 3,5-dimethyl-4-hydroxy acetophenone is then esterified with acetic anhydride. The latter is then hydrogenated to form 1-(3,5-dimethyl-4-acetoxyphenyl)ethanol. This is then dehydrated with an acid to form 3,5-dimethyl-4-acetoxystyrene monomer, copolymerized with unsubstituted 4-acetoxystyrene, and hydrolyzed to produce poly (3,5,-dimethyl-4-hydroxystyrene-co-4-hydroxystyrene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:15].CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Next, to a dioxane solution containing 6-bromo-3H-quinazolin-4-one (B, 15.0 g, 66.7 mmol, 1.0 equiv) is added POCl3 (20.0 mL, d=1.67, 33.4 g, 219 mmol, 3.3 equiv). Et3N (30.0 mL, d=0.726, 21.8 g, 215 mmol) is then added dropwise to the solution. The reaction mixture is heated at reflux for 12 h. The solution is cooled to room temperature and poured into an ice-water mixture. Then, the resultant precipitate is collected by filtration, washed with H2O (100 mL), and dried under vacuum to provide the desired 6-bromo-4-chloro-quinazoline (C, 15.4 g, 63.2 mmol) in 95% yield: ESI-MS m/z 243.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].N1CCCCC1>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(OCc2cccnc2)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.1 %

Procedure:
A mixture in acetone (40 mL) and water (10 mL) of 2,4-dihydroxybenzoic acid methyl ester (1.19 g, 7.08 mmol), prepared as in Example 240A, 3-chloromethylpyridine hydrochloride (2.32 g, 14.2 mmol) and potassium carbonate (2.44 g, 21.2 mmol) was stirred at reflux for 24 hours, then acetone (10 mL) and piperidine (1 g) were added and reflux was continued for 12 hours. The reaction mixture was cooled to ambient temperature, poured into water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with aqueous sodium hydroxide and water, dried, filtered and concentrated in vacuo. The residue was recrystallized from aqueous ethanol to give 4-(3-pyridylmethyloxy)-2-hydroxybenzoic acid methyl ester (0.57 g, 31%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:11]
Reactant: COc1cccnc1Br
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccnc1Oc1cccc(C#N)c1
Temperature: 140 °C
Yield: 72.2 %

Procedure:
2-Bromo-3-methoxypyridine (15 g, 68 mmol) and 3-cyanophenol (8.9 g, 75 mmol) are dissolved in DMF (150 ml), and thereto are added potassium carbonate (28 g, 0.2 mol) and cuprous bromide (10.7 g, 75 mmol), and the mixture is heated under reflux at 140° C. for 1.5 hours. After being allowed to cool, to the reaction solution is added ethyl acetate (1000 ml), and the mixture is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from isopropyl ether/ hexane to give the title compound (11.1 g) as pale brown crystals, m.p. 88-89° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([C:26](OCC)=[O:27])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:26][OH:27])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)n1cc(CO)cc1-c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A solution (30 mL) of ethyl 5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate (1.33 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (8.0 mL) of diisobutylaluminum hydride in toluene was added dropwise, and the mixture was further stirred at −78° C. for 3 hr. 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate. Insoluble material was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2) to give the title compound as an oil (yield 0.71 g, 59%).
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.C(C1[O:67][C:68]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[C:69]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[N:70]=1)=C.S([O-])([O-])=O.[Na+].[Na+].[C:89]([OH:93])([CH3:92])([CH3:91])C>O>[OH:93][C@H:89]([C:92]1[O:67][C:68]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[C:69]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[N:70]=1)[CH2:91][OH:22]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 1 h

Procedure:
A solution of AD-mix-β (trade name, Aldrich) (114 g) in a mixture of t-butyl alcohol (400 ml) and water (400 ml) was stirred for 1 hour, and then methanesulfonamide (7.6 g) and 2-vinyl-4,5-diphenyloxazole (20 g) was added to the solution at 0° C. After being stirred for 8 hours at the same temperature, sodium sulfite (50 g) was added, and the mixture was stirred for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by trituration with hexane-ether to afford 2-((1S)-1,2-dihydroxyethyl)-4,5-diphenyloxazole (21 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1B1OBOBO1.N1C=CC=CC=1.Cl>[Cu].C(OCC)(=O)C.CN(C)C=O>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[C:15]([CH3:17])[CH:16]=1
Reactant: FC(F)(F)c1nc[nH]n1
Reactant: Cc1ccc(B2OBOBO2)c(C)c1
Agent: [Cu]
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
In a 50-ml eggplant flask provided with a magnetic stirrer were placed 1.37 g (10 mmol) of 3-trifluoromethyl-1H-1,2,4-triazole, 1.32 g (3.33 mmol) of 2,4-dimethylphenylboroxine, 64 mg (1 mmol) of a copper powder, 0.8 g (10 mmol) of pyridine and then 5 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 4 hours. Thereto were added 30 ml of ethyl acetate and 3% hydrochloric acid to give rise to phase separation. The aqueous phase was extracted with 30 mol of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution. The ethyl acetate phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to distill off ethyl acetate to obtain a title compound as 2.3 g of a crystal. Yield: 95%
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:15][C:14](=O)[CH2:13][NH:12][C:11]2=O)[CH:6]=[CH:5][CH:4]=1.CSC.B.C1COCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CC2NC(=O)CNC2=O)n1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cccc(CC2CNCCN2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 50-mL round-bottomed flask was added 3-((6-methoxy-2-pyridinyl)methyl)-2,5-piperazinedione (423 mg, 1.80 mmol), borane methyl sulfide, complex (0.68 mL, 7.19 mmol, Aldrich, St. Louis, Mo.), and THF (6 mL). The reaction mixture was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction mixture was diluted with MeOH (1 mL), followed by 1N NaOH (12 mL), and extracted with DCM (2×50 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude 2-((6-methoxy-2-pyridinyl)methyl)piperazine as light-yellow viscous oil, which was used without purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:20][C:19]([CH:30]=O)=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:20][C:19]([CH2:30][NH:13][CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH3:12])=[CH:18][CH:17]=1
Reactant: CC(N)c1ccnc2ccccc12
Reactant: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The 1-quinolin-4-yl-ethylamine (510 mg, 3 mmol) and 6,4′-dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) were stirred with acetic acid (300 mg, J. T. Baker) in methyl alcohol (15 mL0 at room temperature for 4 h. To the reaction solution was added sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich) at 0° C. The mixture was stirred under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with saturated aqueous sodium bicarbonate (30 mL). The methyl alcohol was removed from the mixture via vacuo. The residue was extracted by ethyl acetate (30 mL×4). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated via vacuo. The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 72% yield (287 mg, 0.72 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH:3]=[O:4].C(O)(C)C.[BH4-].[Na+].Cl>C(OCC)C>[CH3:1][C:2]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH2:3][OH:4]
Reactant: Cc1cccc(CC(C)(C)C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cccc(CC(C)(C)CO)c1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
44 g of 2,2-dimethyl-3-(3-methylphenyl)-propionaldehyde (according to Example 3) were added in small portions under argon and at 20° C. to a pre-mix of 150 ml of isopropanol and 3.8 g of sodium borohydride. The entire mixture was stirred for 24 hours at 20° C. Excess sodium borohydride was then decomposed by the dropwise addition of 2N HCl. The reaction mixture was then taken up in 150 ml of diethyl ether and extracted with water, 2N NaOH and, again, with water.
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=C(C)C=1N.C([Li])CCC.CC1C=C2C(=CC=1)[NH:22][C:21](=O)C2.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:21][N:22]1[C:2]2[C:28](=[CH:29][CH:6]=[C:7]([CH3:9])[CH:8]=2)[CH2:27][C:31]1=[O:30]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: C1CCOC1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: [Li]CCCC
Product: Cc1ccc2c(c1)N(C)C(=O)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of 2,4,6-trimethylaniline (6.86 g, 5 mmol) in dry THF (100 mL) under an atmosphere of N2 was cooled to -78° C. and n-butyllithium (21 mL, 2.5M solution in hexanes) was added dropwise. The mixture was allowed to warm to 0° C., and dry CO2 gas was bubbled in for 2-3 minutes. The excess CO2 was removed under vacuum, and after the addition of further THF to replace that lost by evaporation, the solution was recooled to -78° C. n-Butyllithium (22 mL, 2.5M solution in hexanes) was again added dropwise, and the temperature was then allowed to rise slowly to -10° C. where a deep red colored solution was obtained. After a further 30 minutes at that temperature, the mixture was again recooled to -78° C. and CO2 gas was bubbled in until the red color disappeared. The reaction mixture was allowed to warm to 20° C., and after removal of the solvent, 0.1M HCL (50 mL) was added to initiate both deprotection of the nitrogen and ring-closure. The resulting mixture was extracted with EtOAc, and this was then washed successively with 0.1M HCl, water, and dilute aqueous Na2CO3. After drying (Na2SO4), the solvent was removed under vacuum, to leave an oil which was purified by chromatography on Al2O3 to give 1,6-dimethyl-2-indolinone (3.37 g, 42% yield) [VII: R1 =6-Me; R3 =Me]; mp (hexane) 94.5°-96° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C(#N)C.CC1(C)C(C)(C)OB([C:43]2[CH:51]=[CH:50][CH:49]=[C:48]3[C:44]=2[CH:45]=[N:46][NH:47]3)O1>C([O-])([O-])=O.[Na+].[Na+].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>[NH:47]1[C:48]2[C:44](=[C:43]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([C:27]5[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=5)=[C:8]([CH3:12])[C:6]=4[N:7]=3)[CH:51]=[CH:50][CH:49]=2)[CH:45]=[N:46]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2cccc(S(C)(=O)=O)c2)sc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc12
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine from Example 12 (0.6 g, 1.5 mmol), 3-(methylsulfonyl)phenylboronic acid (0.3 g, 1.5 mmol), and bis(triphenylphosphine)palladium(II) dichloride (53 mg, 80 mop in 1 M aqueous Na2CO3 (3 mL) and acetonitrile (3 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organics were concentrated in vacuo. A portion of the residue (0.38 mmol) was dissolved in 1 M Na2CO3 (1.5 mL) and CH3CN (1.5 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 (0.2 g, 0.8 mmol) and bis(triphenylphosphine)palladium(II) dichloride (13 mg, 20 μmol) were added into the same pot. The reaction mixture was heated to 150° C. in a sealed microwave reactor for 30 min. The mixture was extracted with EtOAc and CH2Cl2. The combined organics were concentrated to yield 360 after reverse phase HPLC purification (90 mg). MS (Q1) 506 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#N.[OH-:11].[Na+].[OH2:13].S(=O)(=O)(O)O>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH2:1])[C:3]=1[C:4]([OH:13])=[O:11]
Reactant: O
Reactant: N#Cc1c(N)cccc1F
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(F)c1C(=O)O
Yield: 90.9 %

Procedure:
56 parts of 2-amino-6-fluoro-benzonitrile, 33 parts of sodium hydroxide, 250 parts of water and 20 parts by volume of ethanol are refluxed for 8 hours. The pH is then brought to 3-4 with 20 percent strength by weight aqueous sulfuric acid and the precipitate formed is filtered off, washed with water and dried. The aqueous phase is extracted with methylene chloride, the solvent is stripped off under reduced pressure and the residue is dried, also under reduced pressure. In this way, a total of 58 parts of 6-fluoroanthranilic acid (90.9% of theory), of solidification point 165°-167° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:26]([Mg]Br)[CH3:27].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:26][CH3:27]
Reactant: CC[Mg]Br
Reactant: COc1ccc(C=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml), and a 1 M tetrahydrofuran solution of ethylmagnesium bromide (0.5 ml) was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH2:3]1.[Cl:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][CH:18]1[O:20][CH2:19]1>C(O)C>[ClH:13].[OH:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][CH:2]([NH:1][CH2:19][CH:18]([OH:20])[CH2:17][O:16][C:15]3[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=3[Cl:13])[CH2:3]2)=[CH:8][CH:7]=1
Reactant: NC1CCc2ccc(O)cc2C1
Reactant: Clc1ccccc1OCC1CO1
Solvent: CCO
Product: Cl
Product: Oc1ccc2c(c1)CC(NCC(O)COc1ccccc1Cl)CC2
Yield: 100.6 %

Procedure:
A mixture of 2-amino-7-hydroxytetralin (1.9 g) and 1-(2-chlorophenoxy)-2,3-epoxypropane (2.15 g) in absolute ethanol (60 ml) is refluxed for 5 hours and then ethanol is evaporated off under reduced pressure. The thus obtained residue is chromatographed on a silica gel column eluting first with ethyl acetate up to the complete elution of the first spot and then with a mixture ethyl acetate/methanol 9/1 v/v. The obtained fractions are pooled and concentrated to dryness. The residue is dissolved in isopropanol (20 ml) and the obtained solution is acidified by the addition of HC1/isopropanol. The precipitate is recovered by filtration yielding 2.25 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine hydrochloride; m.p. 201°-203° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH2:14][CH3:15])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:24](=[O:27])[CH2:25][Br:26]>C(Cl)Cl>[Br-:26].[CH3:18][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[N:8][N+:9]2[CH:13]=[CH:12][N:11]([CH2:25][C:24]([C:23]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:27])[C:10]=2[CH2:14][CH3:15])=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: CCc1nccn1N=Cc1ccc(N(C)C)cc1
Solvent: ClCCl
Product: CCc1n(CC(=O)c2cc(OC)c(OC)c(OC)c2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Product: [Br-]
Reaction time: 46 h

Procedure:
1.44 g (6 mmol) of 1-[[p-(dimethylamino)benzylidene]-amino]-2-ethylimidazole are dissolved in 20 ml of methylene chloride. The solution is treated with 1.72 g (6 mmol) of 3,4,5-trimethoxyphenacyl bromide and left to stand at room temperature for 46 hours. The product is crystallized out by the addition of ether and recrystallized from ethanol. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethyl-3-(3,4,5-trimethoxyphenacyl)-imidazolium bromide of melting point 232° (decomposition).
Reaction SMILES: C(N([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[CH2:17][CH2:18][CH2:19][CH:10]([C:11]=23)[CH2:9]1)CCC)CC.C[Mg]Br.[NH4+:23].[Cl-].C([O:27][CH2:28][CH3:29])C>C1C=CC=CC=1>[C:28]([C:13]1[CH:14]=[CH:15][C:16]2[NH:8][CH2:9][C@@H:10]3[CH2:19][C@H:18]([N:23]([CH2:13][CH2:12][CH3:17])[CH2:9][CH2:10][CH3:11])[CH2:17][C:12]=1[C:11]=23)(=[O:27])[CH3:29]
Reactant: [NH4+]
Reactant: CCOCC
Reactant: CCCN(CCC)N1CC2CCCc3cccc1c32
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(C(C)=O)ccc3c2[C@H](CN3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.5 g (1.8 mmol) of 6-cyano-4-(di-n-propylamino-1,2,2a,3,4,5-hexahydrobenz[cd]indole prepared as in Part B hereof in 75 mL of benzene was treated with 5 mL of 2.0 M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 2 days. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of saturated aqueous NH4Cl solution. The benzene layer was separated as washed once with saturated aqueous NaCl solution. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL of 5 N HCl and the solution was stirred at room temperature for 30 minutes. The acidic solution was made alkaline with the addition of excess concentrated aqueous NH4OH solution. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed once with saturated aqueous NaCl solution and dried over MgSO4. The CH2Cl2 solution was evaporated to yield 0.5 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 0.4 g (75%) of product as an oil, which upon standing solidified, m.p. 76°-77° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[N:8]=[C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:6][C:5]=2[N:19]=1.P(Cl)(Cl)([Cl:22])=O.CN(C)C1C=CC=CC=1>CO.ClCCl>[Cl:22][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2[nH]c(SCc3ccccc3)nc(=O)c2s1
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reaction time: 2 h

Procedure:
The product from step (b) (0.89 g), phosphorus oxychloride (12 ml) and N,N-dimethylaniline (1.2 ml) were heated at reflux for 2 hours. The cooled reaction mixture was poured onto ice water and stirred for 2 hours. Chromatography (SiO2, methanol/dichloromethane as eluant) gave the sub-title compound.