Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1.Br[CH2:30][CH2:31][O:32][CH3:33]>CN(C)C=O.CO>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:30][CH2:31][O:32][CH3:33])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1
Reactant: COCCBr
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COCCOc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Sodium hydride (17 mg, 60%) was added slowly to an ice-cooled solution of 1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (150 mg) in 2 mL N,N-dimethylformamide (DMF). After stirred for 30 min, 1-Bromo-2-methoxy-ethane (59 mg) in 1 mL DMF was added cautiously by syringe. The mixture was warmed to room temperature and stirred overnight, then diluted with 1 mL methanol and directly sent to prep-HPLC. The product [1-(2,4-difluoro-phenyl)-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (40 mg) was obtained as a yellow solid. LC-MS m/e 411(MH+). 1H NMR (400 MHz, DMSO) 9.12(s, 1H), 7.81(s, 1H), 7.61(m, 1H), 7.43(t, 1H), 7.34(d, 1H), 7.25(t, 1H), 7.10(d, 1H), 6.85(d, 1H), 5.81(s, 1H), 4.23(m, 2H), 3.71(m, 2H), 3.32(s, 3H), 2.20(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[N:24][NH:23][C:22]2=[O:26])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccncc1
Product: C[C@@H](n1ncn(-c2ccncc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 33.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.42 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.92 g of 4-(4-pyridyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R, 2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-pyridyl )-3 (2H, 4H)-1,2,4-triazolone(0.66 g) was obtained as colorless prisms.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1>>[CH3:1][NH:2][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN
Product: CNc1ncccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Methylamine (33% in EtOH) (110 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0° C. using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0° C. and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3×150 mL. Combine organic layer was dried over Na2SO4, filtered and concentrated to give a bright orangish yellow solid (19 g, 98.5%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)(=O)=O.N1C(C)=CC=C[C:16]=1C>CO.CCOCC>[Br:14][C:9]1[CH:8]=[C:7]([CH2:6][O:5][CH3:16])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)OCc1ccc(F)c(Br)c1
Solvent: CCOCC
Solvent: CO
Product: COCc1ccc(F)c(Br)c1

Procedure:
A solution of 3-bromo-4-fluorobenzyl methanesulfonate (Intermediate 14, 330 mg; 1.17 mmol) and 2,6-lutidine (176 μL; 1.52 mmol) in methanol (4 mL) was stirred for 16 hours at RT. Additional aliquots of 2,6-lutidine (176 μL; 1.52 mmol each) were added once a day for a total of three days, during which stirring was continued at RT. The mixture was taken up in Et2O, washed with water, HCl (0.1N in water) and brine. The organic phase was dried over MgSO4, filtered and concentrated with moderate vacuum and without heating affording the title compound as a pale yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH2:20][CH:21]=[CH2:22])[C:16](=[O:19])[NH:17][N:18]=2)=[CH:10][CH:9]=1.Cl[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(#N)C>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:17]1[C:16](=[O:19])[N:15]([CH2:20][CH:21]=[CH2:22])[C:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)=[N:18]1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O

Procedure:
13.87 g (100.35 mmol) of potassium carbonate are added to 21.50 g (91.2 mmol) of 5-(4-chlorophenyl)-4-allyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 210A and 11.88 g (109.5 mmol) of methyl chloroacetate in 350 ml acetonitrile and the mixture is heated under reflux for 5 hrs with stirring. It is then concentrated and the residue taken up in ethyl acetate is washed with 1 N hydrochloric acid and then with saturated sodium chloride solution. The organic phase is dried over sodium sulphate. After filtration, the filtrate is concentrated in vacuo. After purification by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) 24.00 g (85% of theory) of the target compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 95.4 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentylamino)-2-methylbenzoate (0.5 g, 1.86 mmol) in acetonitrile (5 mL) was added cesium carbonate (1.22 g, 3.7 mmol) and methyl iodide (1.32 g, 9.33 mmol). The resulting mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and the filtrate was concentrated and then purified by column chromatography to afford methyl 5-chloro-3-(cyclopentyl(methyl)amino)-2-methylbenzoate (0.5 g, 95%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[NH:7][C:8](=[O:28])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:4].CO.CO.[OH-].[K+].[ClH:39]>C(O)C>[ClH:39].[C:3]([C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[NH:7][C:8](=[O:28])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH2:14][CH2:15]1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(=O)O)CC2)cc1OC

Procedure:
20 Grams of o-methoxycarbonyl- -[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide, 400 ml of methanol and 25 ml of 3.5N-potassium hydroxide methanol solution were mixed together and the mixture was refluxed for 8.5 hours. After completion of the reaction, the reaction mixture was allowed to stand for cooling, then an ethanol solution of hydrochloric acid was added to the mixture to adjust the pH thereof to about 1. The crystals formed were removed by filtration, and the mother liquor was cooled by ice. The crystals were collected by filtration, recrystallized from 80% water-containing methanol to obtain 13.28 g of o-carboxy- -[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride in the form of colorless cotton fiber-like crystals. Melting point: 250.5°-251.5° C. (decomposed).
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]1[O:14][CH:13]1[CH2:15][OH:16]>CO>[CH2:1]([NH:11][CH2:12][CH:13]([OH:14])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCNCC(O)CO
Yield: 100 %

Procedure:
The procedures of Ulsperger et al., J. Prakt. Chemie, Vol. 27, pp. 195-212 (1965), the disclosures of which are hereby incorporated herein by reference in their entirety, were substantially followed. Specifically, 15.8 g decylamine (0.1M) and 7.4 g glycidol (0.1M) were mixed in 250 ml methanol at 60°-80° C. and refluxed for 10 hours. The methanol was rotary evaporatated. The product was a semisolid, 23.2 g (yield 100%). After recrystallization with hexane, pure white solid DDP, m.p. 65°-67° C. (m.p. 70°-70.5° C., lit.), was recovered.
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(=CC=1)NC=C2C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](Cl)[CH:30]=2)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[CH:24]=1)(=[O:22])[NH2:21]>>[CH2:1]([O:8][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[CH:24]=[C:23]2[C:20](=[O:22])[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Product: NC(=O)c1cn(CC(=O)O)c2ccc(OCc3ccccc3)cc12

Procedure:
was prepared from 5-benzyloxy-1H-indole-3-carbaldehyde [6953-22-6] using similar protocols as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 325 [M+H]+, 649 [2M+H]+; tR (HPLC conditions b): 4.04 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:18])[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CCOC(C)=O)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CC(=O)OCCc1ccc(NC(C)=S)cc1
Yield: 142.3 %

Procedure:
4-Acetamidophenethyl acetate (10.0 g, 45.2 mmol) and phosphorus pentasulfide (10.0 g, 22.5 mmol) were suspended in toluene (200 ml). The suspension was refluxed for 40 min. After cooling the supernatant was decanted into a separatory funnel and washed with 50% aqueous Na2CO3 solution (70 ml) and then with water (70 ml). The organic toluene layer was dried over anhydrous sodium sulfate overnight. The dried toluene solution was concentrated to dryness to give a yellowish solid (7.6 g, 71%). This solid was used for next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])[CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[N:29]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])[N:28]=[CH:27][C:26]=1[CH:38]([CH3:40])[CH3:39].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]2[N:29]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:37])[N:28]=[CH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[CH:10][C:9]=1[CH3:15])[CH3:7])[CH3:2]
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CCl
Reactant: CCOC(=O)CC(C)c1ccc(O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of (+/−)-3-(4-Hydroxy-2-methyl-phenyl)-butyric acid ethyl ester (0.366 g, 0.748 mmol) in DMF (4 mL) is added cesium carbonate (1.1 g, 1.5 mmol). After 5 minutes at room temperature, 5-Chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (0.50 g, 0.748 mmol) is added and the reaction is heated to 50° C. overnight. Upon cooling, water is added followed by 1N HCl. The resulting mixture is extracted two times with ethyl acetate and the organic layers are combined and are washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 3-5% ethyl acetate/toluene to give the title compound. 1H NMR (CDCl3) δ 1.113-1.163 (m, 6H), 1.26 (d, 6H), 2.399-2.532 (m, 2H), 2.952 (m, 1H), 3.388 (m, 1H), 4.024 (q, 2H), 4.741 (s, 2H), 6.513 (d, 1H), 6.544 (dd, 1H), 6.970 (d, 1H), 7.264 (t, 1H), 7.372 (d, 2H), 7.661 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])[C:5]#[N:6].Cl.[NH2:13][OH:14].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])/[C:5](=[N:13]/[OH:14])/[NH2:6]
Reactant: NO
Reactant: N#Cc1ccc(CO)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(=N\O)c1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
To a mixture of 3-fluoro-4-(hydroxymethyl)benzonitrile (3.51 g, 23.2 mmol) and hydroxylamine hydrochloride (3.23 g, 46.4 mmol) in methanol (100 mL) under nitrogen was added sodium bicarbonate (7.80 g, 93 mmol). The reaction mixture was stirred at room temperature for 5 min. and then immersed in an oil bath and heated at reflux for 2 h. HPLC analysis indicated that the starting material had been consumed. The heterogeneous mixture was filtered, the solid was washed with methanol, and the filtrate was concentrated under reduced pressure. The white solid residue was diluted with ethyl acetate (400 mL) but remained heterogeneous. The mixture was sonicated for 5 min and filtered under reduced pressure. The filtrated was washed with water (60 mL), and washed with a 10% aqueous solution of lithium chloride (60 mL), and washed with brine (60 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)-3-fluoro-N′-hydroxy-4-(hydroxymethyl)benzimidamide (3.85 g, 20.9 mmol, 90% yield) as a white solid. The compound had an HPLC time=0.263 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=184.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.54 (d, 2H), 5.28 (t, J=5.83 Hz, 1H), 5.86 (s, 2H), 7.40 (dd, J=11.65, 1.39 Hz, 1H), 7.44 (t, J=7.91 Hz, 1H), 7.51 (dd, J=8.05, 1.66 Hz, 1H), and 9.72 (s, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([CH:27]=[N:28][OH:29])[C:11]=1[S:30]([CH3:32])=[O:31].N1C=CN=C1.O>CN(C)C=O>[Si:1]([O:29][N:28]=[CH:27][C:12]1[C:11]([S:30]([CH3:32])=[O:31])=[C:10]([NH2:9])[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:23])[F:24])=[CH:17][C:16]=2[Cl:26])[N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)c1c(C=NO[Si](C)(C)C(C)(C)C)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 50 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (0.8 g) in N,N-dimethylformamide (DMF) was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in (DMF), followed by dropwise addition of a solution of imidazole (0.72 g) in DMF during 7-minutes. The mixture was heated at 50° C. for 3.5-hours and then held at 20° C. for 18 hours. The mixture was diluted (water), extracted (methyl tert-butyl ether) and the organic phase washed in turn with NaHCO3 solution, 5% HCl solution and with NaHCO3 solution, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(tert-butyldimethylsilyl)oxime (0.76 g)as a light yellow solid m.p. 150-154° C. compound 21.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:13]O.Cl.CC(OC(C)=O)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-bromo-1H-indole-3-carbaldehyde (1.2 g, 5.36 mmol) in pyridine (10 mL) was added NH2OH.HCl (0.424 g, 6.11 mmol) portionwise and the resulting mixture was stirred at rt for 1.5 h. 25 mL of Ac2O was added and the mixture was heated at reflux overnight. After this time the reaction mixture was cooled to rt and poured into ice. The resulting solid was filtered and the product was purified by flash column chromatography to give 6-bromo-1H-indole-3-carbonitrile slightly impure but was used for the next step. Mass Spectrum (ESI) m/e=222 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:13].[CH3:14][N:15](C)C=O>ClCCl.O.[C-]#N.[Zn+2].[C-]#N.[Pd]>[NH2:13][C:5]1[C:4]2[C:9](=[C:10]([C:14]#[N:15])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: Nc1ncnc2c(I)cc(Cl)cc12
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(Cl)cc2c(N)ncnc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To an 8 mL screw-cap vial was added 6-chloro-8-iodo-quinazolin-4-amine (450 mg, 1.47 mmol), dimethylformamide (2 mL), zinc cyanide (0.65 equiv., 1.0 mmol, 115 mg), and palladium tetra is(triphenylphosphine), (0.1 equiv., 0.15 mmol), 179 mg). The reaction was capped and shaken at 110° C. overnight. The reaction was cooled to room temperature, diluted with 3 mL of dichloromethane, and 2 mL of water was added. The precipitate that followed was collected by filtration, and washed with water, then dichloromethane yielding 240 mg of 4-amino-6-chloro-quinazoline-8-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO) δ 8.72-8.67 (d, J=2.2 Hz, 1H), 8.54-8.50 (s, 1H), 8.50-8.46 (d, J=2.1 Hz, 1H), 8.29-8.22 (bs, 2H). LCMS M/Z (M+H)=205.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:32]=[CH:31]3)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:32]=[CH:31]4)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(CSc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CSc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Reaction time: 4.5 h
Yield: 64.8 %

Procedure:
To a solution of [3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (22 mg, 0.066 mmol), ethyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (19 mg, 0.066 mmol) and triphenylphosphine (35 mg, 0.13 mmol) in dichloromethane (1 mL) was added di-tert-butyl azodicarboxylate (30 mg, 0.13 mmol). The solution was stirred at ambient temperature approximately 4.5 hours and then was adsorbed onto silica gel. Purification was done by chromatography (silica gel, 0-75% ethyl acetate in hexanes gradient elution) to afford ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (26 mg, 65%). 1H-NMR (400 MHz, CDCl3) δ 8.36-8.31 (m, 2H), 8.20 (d, J=9 Hz, 1H), 8.03-8.00 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.32-7.13 (m, 3H), 7.08 (d, J=9 Hz, 2H), 5.08 (s, 2H), 4.56 (q, J=7 Hz, 2H), 4.16 (s, 2H), 3.20 (septet, J=7 Hz, 1H), 1.49 (t, J=7 Hz, 3H), 1.31 (d, J=7 Hz, 6H). LRMS (APCI) m/z 607 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1F)=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([O:13][C:7]2[CH:8]=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])[C:17]=1[C:15](=[O:16])[CH3:14]
Reactant: Oc1cnc2c(F)c(F)ccc2c1
Reactant: CC(=O)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1Oc1cnc2c(F)c(F)ccc2c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
0.5 g of 7,8-difluoro-3-hydroxyquinoline was dissolved in 10 mL of dimethylformamide. 0.52 g of 2,6-difluoroacetophenone and 0.46 g of potassium carbonate were added to the solution, and the mixture was stirred for 2.5 hours at 100° C. The thus obtained reaction solution was poured into ice water and then neutralized with dilute hydrochloric acid, the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 0.38 g of 1-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)-phenyl]-ethanone (Compound Number 391).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>[Ni].C(O)(=O)C>[C:18]([NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[CH2:7][CH2:8]2)(=[O:20])[CH3:19]
Reactant: O=C(O)CCC1CCc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2CCC(=O)O
Reaction time: 30 h

Procedure:
A mixture of 2-carboxyethyl-5-nitroindane (34 g, 0.15 mol), Raney nickel (5 g), acetic anhydride (25 mL) and acetic acid (225 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 30 h. After removing the catalyst, the filtrate was evaporated to give a dark syrup. The residue was purified by column chromatography (3:2 hexane:EtOAc).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[C:17]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Oc1cccnc1Cl
Reactant: N#Cc1cc(F)ccc1F
Product: N#Cc1cc(F)ccc1Oc1cccnc1Cl

Procedure:
2,5-Difluoro-benzonitrile was reacted with 2-chloropyridin-3-ol according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 249 (M)+, 251(M+2)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[C:13]([O:17][C:18](=[O:28])[NH:19][C:20]1[S:21][C:22]([CH2:25][CH2:26][NH2:27])=[CH:23][N:24]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[C:13]([O:17][C:18](=[O:28])[NH:19][C:20]1[S:21][C:22]([CH2:25][CH2:26][NH:27][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[CH:10]=[CH:11][S:12][C:3]=23)=[CH:23][N:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCN)s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ncc(CCNc2c(C#N)cnc3ccsc23)s1
Yield: 40.9 %

Procedure:
A stirred mixture of 7-chloro-thieno[3,2-b]pyridine-6-carbonitrile (47.8 mg, 0.25 mmol), [5-(2-amino-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (J Med Chem, 1992, 35, 3239-3246) (54.6 mg, 0.22 mmol), and triethylamine (0.04 ml, 0.28 mmol) in 3 ml of ethanol was heated to reflux for 17 hr. Ethanol was evaporated, and the residue was partitioned between dichloromethane and aqueous NaHCO3. The organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (MeOH/CH2Cl2/NH3=1/20/0.1) to give 36.1 mg (40%) of yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.82 (d, J=5.4 Hz, 1H), 7.52 (d, J=5.4 Hz, 1H), 7.18 (s, 1H), 5.32 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 1.55 (s, 9H); LC-MS (ESI) m/z 402.1 (M+1).