Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[N:1]1([C:6]2([C:9](=[N:19][OH:20])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 82.6 %

Procedure:
24.8 g (0.1 mol) of 4-chlorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone were refluxed for 4 hours with 10.4 g of hydroxylamine hydrochloride, 10.6 g of sodium acetate in 200 ml of ethanol and 100 ml of water, the solvent was removed in vacuo, and the crystal slurry obtained was triturated with water. 21.7 g (83%) of the title compound were obtained as colorless crystals of melting point 186°-218° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13]C)=[O:11].C([O-])([O-])=O.[K+].[K+].CCOCC>CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)c1cc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc2ncccc2[nH]1
Temperature: 55 °C
Yield: 90 %

Procedure:
Add to ethyl 4-azaindole-2-carboxylate 4a (42.3 mmol) in MeOH (50 mL), K2CO3 (1.20 equiv, 50.7 mmol) and stir the suspension with heating to 55° C. for 1 h. Monitor the reaction by tlc (Et2O/hept). When complete, concentrate the reaction in vacuo, dilute with H2O and stir for 15 min. Collect the solid by filtration and dry in a vacuum oven at 65° C. for 3 h to afford about 90% to about 100% of the desired methyl 4-azaindole-2-carboxylate 5a.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[BrH:11]>>[Br-:11].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH+:2]=1
Reactant: Br
Reactant: c1ccc2cnccc2c1
Product: [Br-]
Product: c1ccc2c[nH+]ccc2c1
Yield: 88.5 %

Procedure:
600 g of crude isoquinoline (purity 95% and total sulfur content 0.3%) and 759.6 g of 47% hydrobromic acid were stirred and cooled to undergo reaction. After the reaction, the resultant reactin mixture was distilled to expel water and then washed twice with acetone to afford 864.1 g of isoquinolinium bromide. By recrystallizing this isoquinolinium bromide from 6,881 g of isopropanol, 471.9 g (recovery ratio 85.9%) of refined isoquinolinium bromide having a total sulfur content of 22 ppm was obtained. The refined isoquinolinium bromide was recrystallized again from 6,498 g of isopropanol. The recrystallized isoquinolinium bromide (676.6 g) was dissolved in the same volume of water and decomposed with an aqueous 20% NaOH solution. Then, 495.3 g of the resultant liberated desulfurized isoquinoline was distilled, to afford 374.73 g (recovery ratio 62.5%) of refined isoquinoline (purity 99.7% and total sulfur content less than 1 ppm) was obtained.
Reaction SMILES: [Na].C([C:4](CC)([C:8]([O-:10])=O)C([O-])=O)C.[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=1)=[CH:14][C:15](=[O:17])[CH3:16].[OH-].[K+].[CH2:31]([OH:33])[CH3:32]>O>[C:31]1(=[O:33])[CH2:32][CH:13]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][C:26](=[O:28])[CH2:27][C:8](=[O:10])[CH2:4]3)=[CH:22][CH:23]=2)[CH2:14][C:15](=[O:17])[CH2:16]1
Reactant: CC(=O)C=Cc1ccc(C=CC(C)=O)cc1
Reactant: CCO
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C1CC(=O)CC(c2ccc(C3CC(=O)CC(=O)C3)cc2)C1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of sodium metal (2.9 g) in absolute ethanol (170 ml) was added diethylmalonate (20.1 g) and then with warming and stirring of the solution, 1,4-bis(but-1-ene-3-one-1-yl)benzene (12.2 g) was added. The mixture was stirred and refluxed for 1.5 hours and then a solution of potassium hydroxide (16.7 g) in water (150 ml) was added and refluxing was continued for 4 hours. Most of the ethanol was removed by distillation and the cooled aqueous residue was washed with ether to remove any organic impurities. The aqueous layer was then heated again and acidified slowly with dilute hydrochloric acid. The precipitated solid was removed by filtration to give 1,4-bis(cyclohexane-1,3-dione-5-yl)benzene (18 g, 100%) as a pale yellow solid, mp >260° C. (dec).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium bicarbonate, and 100 mg of 3-fluorobenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 120 mg of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.58 (s, 6H), 3.08 (s, 3H), 7.05 (m, 3H), 7.33 (m, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H). IR (cm−1): 3020, 1697, 1620, 1403, 1318, 1149, 958, 768. MS (FAB): 361 (m+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:20](O)=[O:21])=[C:11]2[C:10]([C:28]([O:30][CH3:31])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:41]1([NH:46][C:20](=[O:21])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=[C:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]=23)[CH2:23][C:24]([F:25])([F:27])[F:26])[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(F)(F)F)C(=O)O)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(F)(F)F)C(=O)NC3CCCC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-4,4,4-trifluorobutanoic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The resulting suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C24H31F3N4O5, 513; found, 513.6.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][O:19][C:18]2[CH:24]=[CH:25][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: N#Cc1ccc(OCC(=O)Cl)cc1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (4.0 g, 17.39 mmol) in dichloromethane (60 mL) was added 2-(4-cyanophenoxy)acetyl chloride (3.74 g, 19.13 mmol, Intermediate 2: step a) to form a thick suspension. An additional 30 mL of dichloromethane was added. The reaction was then cooled to 0° C. and triethylamine (5.32 mL, 38.25 mmol) was added dropwise. The cold bath was removed and the reaction was stirred at room temperature for 2 hours, then filtered to give the title compound as a white solid. The filtrate was washed with water, followed by saturated aqueous NH4Cl solution. The organic layer was dried (MgSO4), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 20% EtOAc-heptane) to afford more of the title compound.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3](OC)=[O:4].[H-].[Na+].[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17](=O)[O:18]C(=O)[N:20]([CH2:21][CH:22]=[CH2:23])[C:15]=2[CH:14]=1.[CH3:28]N(C=O)C>>[F:12][C:13]1[CH:14]=[C:15]2[C:16]([C:17]([OH:18])=[C:2]([C:1]([O:8][CH2:9][CH3:28])=[O:7])[C:3](=[O:4])[N:20]2[CH2:21][CH:22]=[CH2:23])=[CH:26][CH:27]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CN(C)C=O
Reactant: C=CCn1c(=O)oc(=O)c2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2ccc(F)cc21
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of dimethyl malonate (2.84 g, 17.7 mmol) in DMF (50 ml) was added sodium hydride (0.71 g, 17.7 mmol, 60% in paraffin) over 5 min and the solution stirred for 0.5 h until effervescence ceased. 7-Fluoro-1-(2-propen-1-yl)-2H-3,1-benzoxazine-2,4(1H)-dione (3.92 g, 17.7 mmol) was added to the solution in one portion and the solution stirred at ambient temperature for 1 h then heated to 105° C. for 18 h. The solution was cooled and concentrated and the resulting residues separated between ethyl acetate and water. The aqueous was acidified with 2N hydrochloric acid then extracted with ethyl acetate. The organic extracts were dried and concentrated to yield the title compound as a tan solid (4.63 g, 90%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[BrH:1].[Br:14][C:11]1[CH:12]=[C:13]2[C:5]([C:3]3[N:15]=[C:16]([NH2:18])[S:17][CH:2]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: Nc1nc(-c2c[nH]c3ncc(Br)cc23)cs1
Yield: 69.9 %

Procedure:
A solution of 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid (80 mg, 0.251 mmol) and thiourea (21 mg, 0.276 mmol) in EtOH (1 mL) was stirred at 80° C. for 1.5 h. The resulting precipitate was filtered, washed with MeOH, and dried in vacuo to give 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine hydrobromide salt as a beige solid (66 mg, 70% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.11 (s, 1H), 8.00 (d, J=2.5 Hz, 1H), 8.39 (t, J=2.5 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 12.4 (s, 1H). MS: m/z 295 (M+H+).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][C:19]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:21].[Na+].[OH2:23]>C(O)C>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][C:19]([OH:23])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: N#CCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cc(C(F)(F)F)ccc1Sc1ccccc1

Procedure:
15 g of 2-phenylthio-5-trifluoromethyl-phenylacetonitrile, 15.1 g of sodium hydroxide, 90 ml of water and 23 ml of ethanol are heated under reflux for 12 hours and subsequently concentrated. After the addition of 200 ml of water, the residue is extracted with 100 ml of benzene. The aqueous phase is back-extracted with 50 ml of benzene. The combined organic phases are extracted with 0.5-N aqueous sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid and extracted with 150 ml of chloroform. The organic phase is washed with aqueous sodium chloride solution, dried and evaporated. There is obtained 2 -(phenylthio)-5-trifluoromethyl-phenylacetic acid in the form of crystals which melt at 102°-103° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COc1ccc(-n2cnc3c(Cl)nc4ccccc4c32)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cnc3c(OC)nc4ccccc4c32)cc1

Procedure:
A mixture of 3.6 g (0.0116 mole) of 4-chloro-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline (from Example 109), 25.1 g (0.116 mole) of 25% sodium methoxide in methanol and 50 ml of methanol was heated its reflux temperature for one hour. Evaporation provided a residue which was diluted with 75 ml of water. The precipitate was separated by filtration, washed with water and recrystallized from ethanol to provide 4-methoxy-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline, m.p. 180°-182° C. Analysis: Calculated for C18H15N3O2 : %C, 70.8; %H, 5.0; %N, 13.8; Found: %C, 70.6; %H, 5.0; %N, 13.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A stirred mixture of 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (1.88 g, 5 mmol) and aqueous sodium hydroxide (20 mL of 2 M) in ethanol (30 mL) is heated at 90° C. for 3 h. The cooled mixture was then acidified with hydrochloric acid (100 mL of 1.0 M) and the resulting precipitate is filtered off and dried to give 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid as a colourless crystalline solid, m.p. 270-274° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])([CH3:18])[CH3:17].C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:7]1[CH:6]=[N:5][N:4]([CH:30]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:29]([OH:28])=[O:38])[C:3](=[O:15])[CH:2]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: CC(C)(C)c1ccccc1O
Product: CC(C)(C)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-tert-butyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 2-[4-(2-tert-butyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid as a white solid (13.2 g, 81% for the final step); LC-MS 385.2 [M+1]+, tR=5.86 min. Purity on HPLC: 95.7% (214 nm), 88.8% (254 nm), tR=7.87. 1H NMR (300 MHz, CDCl3): δ 10.85 (s, 1H), 7.83 (m, 1H, J=2.4 Hz), 7.44 (d, 1H, J=4.5 Hz), 7.20 (m, 2H), 6.97 (d, 1H, J=7.5 Hz), 6.06 (d, 1H, J=2.4 Hz), 5.36 (dd, 1H, J1=9.6 Hz, J2=4.2 Hz), 2.33˜2.20 (m, 1H), 2.20˜2.05 (m, 1H), 1.66˜1.14 (m, 7H), 1.33 (s, 9H), 1.17˜1.05 (m, 2H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.NC[C:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:20]([N:22](CC)CC)C>CS(C)=O>[F:8][C:7]1[C:2]([NH:22][CH2:20][CH:14]2[CH2:13][CH:12]([C:18]#[N:19])[CH2:17][CH2:16][O:15]2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: N#CC1(CN)CCOCC1
Reactant: CCN(CC)CC
Reactant: Fc1ccc(F)c(F)n1
Solvent: CS(C)=O
Product: N#CC1CCOC(CNc2nc(F)ccc2F)C1
Temperature: 105 °C
Yield: 48.3 %

Procedure:
To 2,3,6-Trifluoropyridine (0.6 g, 4.5 mmol) in DMSO (5 ml) at room temperature was added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 1.01 g, 7.23 mmol) and triethylamine (1.57 ml, 11.24 mmol) sequentially. The light brown mixture was heated at 105° C. in a sealed glass bomb for 18 hours. After cooled to room temperature the reaction mixture was extracted with EtOAc (40 ml), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to give a light brown liquid. This crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%-20% ethyl acetate in hexane to afford 550 mg (48.2% yield) of the desired product. LCMS (m/z): 254.1 [M+H]+; retention time=0.743 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.95 (m, 4H) 3.60-3.82 (m, 4H) 4.00 (ddd, J=12.13, 4.30, 1.96 Hz, 2H) 5.02 (br. S., 1H) 6.12 (td, J=5.58, 2.54 Hz, 1H) 7.19-7.33 (m, 1H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH2:12](Br)[CH:13]=[CH2:14]>>[N+:1]([CH:4]=[C:5]1[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:14][CH:13]=[CH2:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCCCN1
Reactant: C=CCBr
Product: C=CCN1CCCCNC1=C[N+](=O)[O-]

Procedure:
Method B, reacting hexahydro-2-(nitromethylene)-1H-1,3-diazepine with allyl bromide. Melting point: 82°-83°.
Reaction SMILES: [Na].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=O)=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.ClC1C=CC=[C:37]([C:41]([O:43]O)=O)C=1.CC1(C)OCC(COC2C=CN=C(CO)C=2C)C[O:47]1>>[NH:29]1[C:28]2[CH:30]=[C:31]3[O:43][CH2:41][CH2:37][O:47][C:32]3=[CH:33][C:27]=2[N:26]=[C:25]1[SH:23]
Reactant: Cc1c(OCC2COC(C)(C)OC2)ccnc1CO
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Sc1nc2cc3c(cc2[nH]1)OCCO3

Procedure:
The same procedure as in the steps (5f) to (5h) above (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methanol obtained in the step (12b) and 6,7-dihydro-1H-[1.4]dioxino[2′.3′:4.5]benzo[d]imidazole-2-thiol to obtain the title compound (137 mg, total 25.8% yield) as a light yellow solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>ClCCl>[CH:12]([CH2:13][CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])=[O:11]
Reactant: O=C(C(CCO)c1ccccc1)N1CCCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCC(C(=O)N1CCCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
Dimethylsulphoxide (3.97 g, 50.9 mmol) in dichloromethane (25 ml) was added to a solution of oxalyl chloride (3.09 g, 24.4 mmol) at -50° C. in dichloromethane (25 ml). The reaction mixture was kept at this temperature for 5 min, treated with a solution of the product of step (a) (5.54 g, 21.2 mmol) in dichloromethane (30 ml), and, after 1 h, treated with triethylamine (10.72 g, 0.106 mol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature. Water (100 ml) was added and the separated aqueous phase washed with dichloromethane (50 ml). The combined organic phases were washed with brine (50 ml), water (50 ml), dried (Na2SO4) and concentrated in vacuo to afford the title compound as an oil (5.30 g, 96.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:43])[S:10]([C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.CC(OC([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=2)[CH2:53][C@H:52]1[CH3:67])=O)(C)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16](=[O:17])[C:15]3[CH:40]=[CH:41][CH:42]=[C:13]([S:10]([N:9]([CH3:43])[CH2:8][C:4]4[CH:3]=[C:2]([C:62]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:57][N:54]6[CH2:55][CH2:56][NH:51][C@@H:52]([CH3:67])[CH2:53]6)[CH:63]=5)[CH:7]=[CH:6][CH:5]=4)(=[O:12])=[O:11])[CH:14]=3)[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(Br)c2)c1
Reactant: C[C@@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 130 °C
Yield: 30.8 %

Procedure:
To a solution of 3-{[[(3-bromophenyl)methyl](methyl)amino]sulfonyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (120 mg, 0.179 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added {3-[((3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (59.9 mg, 0.179 mmol), Pd(Ph3P)4 (10.35 mg, 8.96 μmol), and K2CO3 (74.3 mg, 0.538 mmol) and the reaction was heated in microwave at 130° C. for 15 min. The organic layer was separated, filtered, concentrated, and purified using a Gilson HPLC (with 0.1% TFA). Before the sample was concentrated with a GeneVac EZ-2, TFA (5 drops) was added to each tube (12 mL). The resultant mixture was concentrated, purified using a Gilson HPLC (with 0.1% TFA), concentrated, and basified with amino cartridge to afford 0.0429 g (30%) of the title compound. LC-MS m/z 779 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.35-1.45 (m, 6 H) 1.48 (t, J=7.28 Hz, 3 H) 1.82-1.96 (m, 2 H) 2.10 (d, J=12.55 Hz, 2 H) 2.66 (s, 3 H) 3.18 (q, J=7.61 Hz, 3 H) 3.33-3.39 (m, 1 H) 3.42-3.53 (m, 1 H) 3.60-3.79 (m, 6 H) 3.98-4.10 (m, J=8.41, 3.14 Hz, 2 H) 4.27 (s, 2 H) 4.31-4.40 (m, 1 H) 4.41-4.54 (m, 4 H) 4.75 (s, 2 H) 7.31-7.37 (m, 1 H) 7.40-7.65 (m, 5 H) 7.68-7.85 (m, 3 H) 8.05 (d, J=7.28 Hz, 1 H) 8.23 (d, J=7.78 Hz, 1 H) 8.28 (s, 1 H) 8.39 (s, 1 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:20](O)=[O:21]>>[CH:20]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])=[O:21]
Reactant: Oc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccccc1O

Procedure:
A mixture of an appropriate phenol and hexamethylene-tetramine are treated with an appropriate acid, such as trifluoroacetic acid, to provide upon aqueous workup the corresponding o-formylphenol. This o-formylphenol is then treated with (bromomethyl)triphenylphosphonium bromide followed by an appropriate base such as potassium tert-butoxide to provide the desired benzofuran.