Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:27][C:28]1[N:37]=[C:36](Cl)[C:35]2[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=2)[N:29]=1>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:36]3[C:35]4[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=4)[N:29]=[C:28]([Cl:27])[N:37]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Cl)nc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (prepared as described in Example 1A) (80 mg, 0.291 mmol) in anhydrous degassed DMF (2 mL) at rt and under an argon atmosphere, was added potassium tert-butoxide (65 mg, 0.581 mmol). The reaction mixture was stirred at rt for a further 2 h. A solution of 2,4-dichloro-6,7-dimethoxyquinazoline (75 mg, 0.291 mmol) in anhydrous DMF (1 mL) was added and the reaction mixture was stirred at rt for a further 15 h. The reaction mixture was partitioned between a mixture of ethyl acetate (20 mL) and brine solution (20 mL), and the organic layer separated. The aqueous layer was extracted further with ethyl acetate (1×20 mL) and the combined organic layers dried over magnesium sulfate. Concentration under reduced pressure gave the crude product which was purified via silica gel flash chromatography (eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (46 mg, 32%) as a solid. 1H NMR (300 MHz, CDCl3) 89.60 (brs, 1H), 9.03 (brs, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.39-7.46 (m, 2H), 7.31 (m,1H), 7.01 (m, 1H), 6.48 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)n1cc(F)c(=O)[nH]c1=O
Yield: 42.7 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in a mixed solution of 35 ml. of dioxane and 10 ml. of pyridine and reacted with 6.7 g (0.048 mole) of benzoylchloride. The reaction mixture was treated in the same manner as in Example 1 and 2.00 g (42.5% yield) of 1-benzoyl-5-fluorouracil was obtained. The product was recrystallized from ethanol to give white needles melting at 170°-172°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[C:21]([CH3:25])[C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[C:21]=3[CH3:25])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C)c(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([O-])(O)=O.[Na+].[C:14](=[O:21])([S:18][CH2:19][CH3:20])[O:15][CH2:16]I>O.ClCCCl>[C:14](=[O:21])([S:18][CH2:19][CH3:20])[O:15][CH2:16][O:7][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCSC(=O)OCOC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furancarboxylic acid (5.6 g, 50 mmol) is added to a stirred solution of NaHCO3 (8.4 g, 100 mmol) and TBA HSO4 (17.0 g, 50 mmol) in H2O (100 mL) at room temperature. After stirring for 10 min 1,2-dichloroethane (100 mL) is added and the stirring continued for 30 min. 5b (12.5 g, 50 mmol) in 1,2-dichloroethane (25 mL) is added over 15 min. The mixture is stirred for 60 min at room temperature. The organic phase is separated, washed with H2O (50 mL), dried (MgSO4), and evaporated. The residue is stirred with Et2O (100 mL), insoluble material filtered off and washed with Et2O. The combined Et2O-phases are evaporated and the residue crystallized from ice-cold pentane to yield 8.5 g (74%) of 6mb, mp 37.2°-38.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (93 mg, 0.27 mmol), 1-methyl-1H-pyrazol-3-ylamine (29 μL, 0.30 mmol) and N,N-diisopropylethylamine (141 μL, 0.81 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (79 mg, 69%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H21ClN4O4S [M+] 424.10, found 425 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.64 (m, 4 H, 2×CH2), 1.86 (m, 4 H, 2×CH2), 3.29 (s, 3 H, SO2CH3), 3.85 (s, 3 H, NCH3), 4.88 (p, J=4.1 Hz, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.3 Hz, 1 H, Ar), 7.66 (d, Jm=1.3 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.16 (s, 1 H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[CH3:15].C(N(CC)CC)C.[CH3:23][C:24]1[C:25](Cl)=[N:26][C:27]([Cl:31])=[N:28][C:29]=1[CH3:30]>CN(C)C=O>[CH3:23][C:24]1[C:25]([N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH:8]2[CH3:15])=[N:26][C:27]([Cl:31])=[N:28][C:29]=1[CH3:30]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: COc1ccc(OC)c2c1CCNC2C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(OC)c2c1CCN(c1nc(Cl)nc(C)c1C)C2C
Yield: 72.9 %

Procedure:
After 5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline(10 g, 4.82 mmol) and triethylamine (0.67 ml, 4.82 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.71 g, 4.02 mmol) in dimethylformamide, 1.02 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 72.8%)
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>[OH-].[Na+].C(OCC)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:1][N:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)On2nnc3ccccc32)cc1
Reaction time: 8 h
Yield: 43.8 %

Procedure:
In 1 N aqueous sodium hydroxide (b 98 ml) is dissolved 1-hydroxy-1,2,3-benzotriazole (13.5 g). To the solution is added powdery p-nitrobenzenesulfonyl chloride (22.2 g) with stirring under ice-cooling, and the mixture is stirred at the same temperature for 15 minutes and further at room temperature for 4.5 hours. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate (150 ml). The extract is washed with water and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off. The resulting powdery residue is washed twice with petroleum ether (30 ml) and recrystallized from benzene (90 ml) to give colorless crystals. The crystals are dissolved in ethyl acetate (100 ml) and the mixture is washed twice with a saturated aqueous sodium hydrogen carbonate (10 ml) and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under a reduced pressure to give colorless crystals of 1-(p-nitrobenzensulfonyloxy)-1,2,3-benzotriazole (14 g), melting point: 119.5°-121.5° C. Ultraviolet spectrum (methanol): λmax 254 nm, E=234.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:25])C>C(O)C>[C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:25])=[O:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: OCCCCOc1cc(-c2ccccc2)nc2ccccc12
Solvent: CCO
Product: O=C(O)CCCOc1cc(-c2ccccc2)nc2ccccc12
Reaction time: 1 h

Procedure:
A solution of 4-[(2-phenyl-4-quinolyl)oxy]butanol (2.20 g) in glacial aceic acid (10 cc) is added slowly to a solution, cooled to 5° C., of chromic anhydride (2.25 g) in 90% strength acetic acid (5 cc). The temperature is allowed to rise to approximately 20° C., and the mixture is then stirred for one hour at this temperature. Ethanol (50 cc) is then added, the solvents are evaporated off under reduced pressure, the residue is taken up with water (100 cc) and the insoluble material is drained and washed several times with water. This insoluble material is taken up with normal sodium hydroxide solution (15 cc) and heated under reflux for two hours. The insoluble material is removed by filtration and the filtrate acidified by adding glacial acetic acid. The precipitate obtained is drained. 4-[(2-Phenyl-4-quinolyl)oxy]butanoic acid (0.740 g), m.p. 264° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[I:26]Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][C:3]=1[I:26]
Reactant: ClI
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (50 mg, 0.15 mmol) [See Ex. 28 above] in glacial acetic acid (5 mL) was added a solution of ICl (24 mg, 0.15 mmol) in glacial acetic acid (1.5 rot,). The resulting mixture was stirred at rt for 1 h, then poured into saturated aqueous Na2S2O5. The pH was adjusted to neutral by the addition of 2.5N NaOH and extracted with EtOAc. The organic extract was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2-10% MeOH/CHCl3. The material that was isolated was recrystallized from Et2O/Hex to afford the title compound: 1H NMR (CDCl3): δ8.42 (d, 2H); 8.18 (d, 1H); 7.68 (dd, 2H); 7.42 (m, 4H); 7.09 (t, 2H); 6.77 (d, 1H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([NH:11][NH2:12])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].F[C:14]1[CH:21]=[C:20](SCCC)[CH:19]=[C:18]([O:26][CH3:27])[C:15]=1[CH:16]=O.CS(C)=O>O>[CH3:27][O:26][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]2[C:15]=1[CH:16]=[N:12][N:11]2[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1
Reactant: CCCSc1nccc(NN)n1
Reactant: CCCSc1cc(F)c(C=O)c(OC)c1
Solvent: O
Solvent: CS(C)=O
Product: CCCSc1nccc(-n2ncc3c(OC)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Propylsulfanyl-pyrimidin-4-yl)-hydrazine (7.036 g), 2-fluoro-6-methoxy-4-propylsulfanyl-benzaldehyde 5.524 g) and DB 16.373 g) were added to DMSO (70 mL) and the mixture was stirred at room temperature for one hour, then stirred at 80° C. for one hour. The mixture was cooled, diluted with water, and filtered. The collected solid was washed with water, and dried under reduced pressure to give 4-methoxy-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](=[O:14])[CH3:13])=[N:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[C:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(=O)c1ccc2c(-c3ccc(F)c(-c4ccccc4C#N)c3)ccnc2n1
Yield: 83 %

Procedure:
This was prepared in 83% yield from 1-(5-chloro-[1,8]naphthyridin-2-yl)ethanone (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in Example 55, step a. δH (400 MHz, CDCl3) 2.97 (3H, s), 7.45 (1H, t, J 9.0), 7.55 (1H, td, J 7.4, 1.2), 7.58-7.62 (4H, m), 7.71 (1H, td, J 7.4, 1.2), 7.84 (1H, dd, J 7.8, 0.8), 8.26 (1H, d, J 8.6), 8.59 (1H, d, J 8.6), 9.26 (1H, d, J 4.3). m/z (ES+) 368 [MH]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C@@H:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21]2>C(OC(C)C)(C)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CC(C)OC(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCC[C@H]1C(=O)O
Yield: 78.3 %

Procedure:
A mixture of 2.3 g (0.01 mole) of 3,5-bistrifluoromethyl aniline and 1.5 g (0.01 mole) of cis-cyclohexane-1,2-dicarboxylic anhydride was stirred in iso-propyl ether at room temperature. The precipitated crystals were filtered off to give 3.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:14][CH:11]1[CH2:13][CH2:12]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: NC1CC1
Product: Clc1cccc(CNC2CC2)c1Cl

Procedure:
Synthesized according to typical procedure J from 2,3-dichlorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [N:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:3]1([NH2:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=NN1CCCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 14.7 mmol) in THF (40 mL) was added dropwise under N2 to a suspension of LAH (0.56 g, 14.7 mmol) in THF (10 mL) cooled with an ice-bath such that the temperature did not rise above 15° C. The mixture was stirred at room temperature for 1 h, quenched with saturated Rochelle's salt solution (15 mL) and extracted with ether (3×20 mL). The organic layer was dried (Na2SO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:4) gave 2,3,4,5-tetrahydro-1H-1-benzazepin-amine (1.63 g, 68%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ 1.50-1.72 (m, 2H), 1.78-1.92 (m, 2H), 2.70-2.82 (m, 2H), 3.180-3.22 (m, 2H), 3.78 (br, 2H), 6.91 (td, J=7.3, 1.5 Hz, 1H), 7.10 (dd, J=1.1, 7.4 Hz, 1H), 7.21 (td, J=8.0, 1.4 Hz, 1H), 7.28 (dd, J=1.4, 8.0 Hz, 1H) ppm.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([CH:17]=[O:18])=[C:12]([Cl:16])[C:13]=1[C:14]#[N:15].C(#N)C>CN(C)C=O>[CH:17]([C:11]1[S:10][CH:9]=[C:13]([C:14]#[N:15])[C:12]=1[Cl:16])=[O:18]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1csc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.6 %

Procedure:
35 g (325 mmol) of tert-butyl nitrite were added dropwise at room temperature to a solution of 53.0 g (250 mmol) of 2-amino-4-chloro-5-formylthiophene-3-carbonitrile (the synthesis of this compound is described in Patent DB 3738910) in 600 ml of a 1:1 mixture of acetonitrile and dimethylformamide, during which process the temperature of the reaction mixture rose from 20° C. to 37° C. and vigorous evolution of gas began. The mixture was cooled to 25° C. and stirred for 7 hours at room temperature, the black solution was concentrated on a rotary evaporator under a high vacuum, the residue was purified by column chromatography (eluant dichloromethane), and 29 g (68%) of the desired compound were obtained as yellow oil. 1H NMR (270 MHz, DMSO-d6): δ=9.1 (s, 1H), 10.0 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][CH:19]=4)=[CH:14][C:13]=3[F:28])[C:8](=[O:11])[NH:9][N:10]=2)[CH2:2]1.[CH3:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O>[F:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:7]1[C:6]([CH2:5][CH:3]2[CH2:4][N:1]([C:33]([C:30]3([CH3:29])[CH2:32][CH2:31]3)=[O:34])[CH2:2]2)=[N:10][NH:9][C:8]1=[O:11]
Reactant: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N2CC(Cc3n[nH]c(=O)n3-c3ccc(-c4ccc5cccnc5c4)cc3F)C2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
In a round bottom flask under nitrogen, a solution of 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (1.07 mmol) in N,N-dimethylformamide (5 mL) was treated with 1-methylcyclopropanecarboxylic acid (1.285 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.14 mmol), N,N-diisopropylethylamine (3.21 mmol) and then 1H-1,2,3-benzotriazol-1-ol (2.14 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile/water with 0.1% NH4OH) and subsequent silica gel chromatography (0-3% methanol/ethyl acetate) followed by trituration in ethanol provided the title compound as a white solid (45 mg, 9.2%). MS(ES)+ m/e 458.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][C:22]2=[O:31])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24]3([CH2:26][CH2:27][N:28]([C:2]4[N:3]=[N:4][C:5]([C:8]5[O:12][N:11]=[C:10]([CH3:13])[N:9]=5)=[CH:6][CH:7]=4)[CH2:29][CH2:30]3)[O:23][C:22]2=[O:31])=[CH:17][CH:16]=1
Reactant: O=C1OC2(CCNCC2)CN1c1ccc(F)cc1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)CN(c3ccc(F)cc3)C(=O)O4)nn2)n1

Procedure:
The object product (24 mg, 58%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (20 mg) obtained in Example 43(2), 3-(4-fluorophenyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (25 mg) obtained in Example 30(3) and potassium carbonate (15 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Br)([Br:18])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=S(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1cccc(Oc2ccccc2)c1
Yield: 81.3 %

Procedure:
A solution of 3-phenoxybenzyl alcohol (36.0 grams, 0.18 mole) in toluene (95 ml) was added dropwise during a thirty minute period to a stirred solution of thionyl bromide (50 grams, 0.24 mole), pyridine (0.5 gram) and toluene (175 ml) while maintaining the temperature below 30° C. After the addition was complete,the reaction mixture was heated at 50°-60° C. for two hours. Upon cooling, the reaction mixture was concentrated under reduced pressure leaving a residue. This residue was dissolved in toluene (200 ml) and washed with water (10×100 ml) until a neutral pH was obtained. The dried (magnesium sulfate) toluene layer was concentrated under reduced pressure leaving a residue. This residue was distilled yielding 38.5 grams of 3-phenoxybenzyl bromide, b.p. 120°-144° C./0.05 mmHg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O.C(Cl)(Cl)Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:12](=[O:13])[CH2:11][CH2:10][Cl:9]
Reactant: O=C(O)CCCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 66.9 %

Procedure:
To a stirred mixture of resorcinol (200 g, 1.82 mol) and 3-chloropropionic acid (200 g, 1.84 mol) was added trifluoromethane sulfonic acid (1 kg) in one portion. The solution was heated slowly over about 45 minutes at about 80° C. then cooled to room temperature over about 15 minutes and poured into chloroform (4.0 L). The organic portion was slowly poured into water (4.0 L) and the layers separated. The aqueous layer was extracted with chloroform (2×2.0 L). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave an orange semi-solid (244.1 g) which was used crude in the next step. 1H-NMR (300 MHz, CDCl3): 12.56 (1H, s), 7.63 (1H, d, J=7.6 Hz), 6.37-6.46 (2H, m), 3.92 (2H, t, J=6.3 Hz), 3.41 (2H, t, J=6.3 Hz).