Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH:19]1[CH:24]=[C:23]2[C:25]([N:27]([CH2:30][C:31](Cl)=O)[C:28](=[O:29])[C:22]2=[CH:21][CH:20]=1)=[O:26]>ClCCl>[C:25]1(=[O:26])[N:27]([CH2:30][C:31]2[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=3[N:11]=2)[C:28](=[O:29])[C:22]2=[CH:21][CH:20]=[CH:19][CH:24]=[C:23]12
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (1.0 g) and triethylamine (793 mg) in dichloromethane (3 ml) under nitrogen was added portionwise phthalylglycyl chloride (1.61 g) in ice water bath and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. To the resulting crude product was added polyphosphoric acid (5 ml) and stirred at 130° C. for 3 hours. After the mixture was cooled at ambient temperature, ammonia solution (28%) was added to the reaction mixture in ice water bath. The precipitate was collected by vacuum filtration to give 2-phthalimidomethyl-4-nitro-1H-benzimidazole (1.35 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].F[C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:9]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: CC(C)CO
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
After cooling a suspension of sodium hydride (1.64 g, 60% suspension in mineral oil, 37.5 mmol) in N,N-dimethylformamide (50 mL) to 0° C., 2-methyl-1-propanol (3.47 mL, 37.5 mmol) was added stepwise. And the reaction mixture was stirred at 25° C. for 20 minutes. Again, the reaction mixture was cooled to 0° C., 2-fluoro-5-bromobenzonitrile (5.00 g, 25.0 mmol) was added stepwise to the reaction mixture and the mixture was stirred at 25° C. for 15 hours. After the completion of the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with saturated brine (2×50 mL), and dried over sodium sulfate anhydrous. After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure, and the resulting crude compound was purified on silica-gel chromatography (hexane/ethyl acetate=9/1) to obtain the titled compound (6.04 g). Yield: 95%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 60.2 %

Procedure:
Using general procedure A, 4-(trifluoromethoxy)aniline (2.09 g, 11.8 mmol) and 1-Boc-4-piperidone (2.6 g, 13.0 mmol) afforded 4-(4-trifluoromethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.56 g, 60%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[N:21]1C=CC(B(O)O)=CC=1>>[N:21]1[CH:5]=[CH:6][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:2][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccncc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-pyridylboronic acid (153 mg, 1.24 mmol) were coupled to yield 2-pyridin-4-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 45 mg (15%) as a beige solid: m.p. 250° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.13 (m, 2H), 3.41 (m, 2H), 7.29 (app t, J=7.8 Hz, 1H), 7.63 (m, 3H), 7.72 (dd, J =7.2, 0.9 Hz, 1H), 8.14 (br t, 1H), 8.69 (d, J=6.0 Hz, 2H), 11.82 (br s, 1H). MS (FAB, MH+) 364. Anal. (C,6H13N3O) C, H, N.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH:8](OCC)[O:9]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH:8]=[O:9]
Reactant: CCOC(C#CCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=CC#CCCCCCl
Temperature: 62.5 °C
Yield: 95 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 7-chloro-1,1-diethoxy-2-heptyne (218.7 g: 1.0 mol), para-toluenesulfonic acid (8.0 g: 0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 7-chloro-2-heptynal [bp: 66-72° C./0.13 KPa, 137.8 g, 0.95 mol]. [Yield: 95.3%]
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CC=CC=1.C(Cl)(Cl)Cl.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[S:17]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSCCCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 3-methylthio-1-propanol (17) (5.0 g, 47.1 mmol), pyridine (7.43 g, 94.0 mmol) and CHCl3 (47 mL) cooled in an ice bath, tosyl chloride (13.47 g, 70.6 mmol) was added in portions with stirring. The mixture was allowed to warm to room temperature after 1 hour and stirring was continued for an additional 15 hours. The mixture was diluted with CH2Cl2 (200 mL), washed with water (2×100 mL), and the organic phase as dried (Na2SO4). The solvent was evaporated and the resulting yellow oil purified by column chromatography (silica gel, 15 wt % ether/hexanes, 50 wt % ether/hexanes), to give a colorless oil (10.5 g, 86 wt %), namely 3-methylthio-1-propanol tosylate.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, 29.5 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to yield the title compound.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16]([Br:18])[S:17][C:13]=3[CH:12]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.BrC1SC2C=C(CN3C4C=C(OC)C(OC)=CC=4N=C3)C=CC=2N=1>>[N:5]1[C:6]2[C:2]([N:1]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([Br:18])[S:17][C:13]=4[CH:12]=3)[CH:9]=[CH:8][CH:7]=2)=[N:3][CH:4]=1
Reactant: Brc1nc2ccc(Cn3cnc4ncccc43)cc2s1
Agent: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Product: Brc1nc2ccc(Cn3cccc4ncnc3-4)cc2s1

Procedure:
(1R,2R)-2-((6-((1H-Imidazo[4,5-b]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (41 mg, 42%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting the 6-((1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-bromobenzo[d]thiazole (Isomer 2) from Step 1 of this Example for 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.35-8.44 (m, 1H), 8.00 (d, J=7.0 Hz, 2H), 7.69 (s, 1H), 7.12-7.36 (m, 3H), 5.50 (s, 2H), 4.77 (br s, 1H), 3.24-3.40 (m, 2H), 2.02 (d, J=10.2 Hz, 1H), 1.87 (d, J=9.4 Hz, 1H), 1.62 (d, J=4.9 Hz, 2H), 1.22 (d, J=6.0 Hz, 4H). LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.[Pt]=O>[OH:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC1(c2cccc(OC)c2)CCCCC1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CC1(c2cccc(OC)c2)CCCCC1O

Procedure:
200 g of ethyl 1-(m-methoxyphenyl)-2-oxo-cyclohexaneacetate are dissolved in 2000 ml of ethanol, and after treatment with 20 g of platinum oxide, the mixture is reduced with hydrogen at 50° C. and 50 bar. After separation of the catalyst, the solvent is removed by distillation, and there is obtained ethyl 2-hydroxy-1-(m-methoxyphenyl)-cyclohexaneacetate in the form of a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.Cl.[OH:13][NH2:14]>N1C=CC=CC=1.C(O)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5](/[CH:6]=[N:14]/[OH:13])=[C:4]([F:11])[CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(F)c(Br)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: c1ccncc1
Product: O/N=C/c1cc(F)c(Br)cc1F
Yield: 53.5 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzaldehyde (7.0 g, 31.67 mmol), hydroxyl amine hydrochloride (2.42 g, 34.84 mmol) in pyridine (35 mL) and ethanol (35 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, eluting with 5-100% ethyl acetate in hexanes) to provide the title compound as a yellow solid (4.0 g, 53%): ESIMS m/z 238 [(M+2H)+].
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].Br[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1.[Li]C(C)(C)C.CN([CH:29]=[O:30])C>C(OCC)C>[NH:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([CH:29]=[O:30])[CH:20]=2)[CH:16]=[CH:17]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cc[nH]c2c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C

Procedure:
Potassium hexamethyldisilazane (0.5M in toluene) (56 ml) was added dropwise to a ice cold solution of 6-bromoindole (5.0 g) in diethyl ether (50 ml). The reaction mixture was warmed to room temperature for 30 mins and then cooled to −78° C. tBuLi (1.7M) (31.5 ml) was added to the mixture keeping the temperature below −65° C. the mixture was further stirred at −78° C. for 30 mins after which time a solution of DMF (6 ml) in diethyl ether (10 ml) was added, the reaction mixture was warmed to room temperature and quenched with ice cold 2N HCl the product was then extracted into diethyl ether (×3). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with Dichloromethane/Methanol (97/3, v/v) to afford the title compound as a solid (1.49 g).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C=O.N.S(=O)(=O)(O)[OH:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(O)O
Agent: C=O
Agent: N
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
13.2 g of p-cyanobenzylamine, 51 g of a 35% aqueous formalin solution and 24 g of a 28% aqueous ammonia solution were reacted at 90° C. for 2 hours while stirring in a solvent of which pH was adjusted to 3 by sulfuric acid. The reaction solution was cooled to room temperature and then cooled on ice for 2 hours. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.2 g (yield: 40%) of p-cyanobenzaldehyde. The p-cyanobenzaldehyde obtained had a purity of 99.5% or more determined by the analysis of high performance liquid chromatography.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:9][CH:8]=[C:7]([CH:18]2[CH2:20][CH2:19]2)[N:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[CH:18]1([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nc(C2CC2)cnc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid methyl ester (150 mg, 550 μmol) in THF (9 ml) and MeOH (1.8 ml) was cooled at 0° C. and treated with LiOH (1.66 ml, 1N aqueous solution). The ice bath was removed after 10 min and the reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was acidified with HCl (1.66 ml, 1N aqueous solution), diluted with water and extracted with dichloromethane. The combined organic layers were dried and concentrated in vacuo to yield a yellow solid. The aqueous phase was also concentrated in vacuo and the residue was triturated with ethyl acetate and sucked off to yield identical yellow solid (according to analytics). The solid material was combined to yield the product (75 mg, 52%)
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH3:10].C[Si]([C:15]#[N:16])(C)C.O>CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH2:10][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1)[C:15]#[N:16]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(I)cc1
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Solvent: O
Product: N#CC(N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-iodobenzaldehyde (10.4 g) in methanol (36 mL), tetraisopropyl orthotitanate (50.0 mL) and a solution (50 mL) of 8 mol/L ammonia in methanol were added and the mixture was stirred at room temperature for 3.5 hours. Trimethylsilyl cyanide (5.89 mL) was slowly added to the mixture, which was then stirred at the same temperature for 14 hours. Iced water was added to the reaction mixture, which was then filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and the resulting residue was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-25:75) to give amino(4-iodophenyl)acetonitrile as a pale yellow solid (5.05 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH:26]=[CH2:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.[OH2:28].[O-][Mn](=O)(=O)=O.[K+].[OH-:35].[Na+]>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH:26]([OH:35])[CH2:27][OH:28])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: [OH-]
Reactant: O
Reactant: C=Cc1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C(O)CO)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)-3-(3-vinyl-imidazo[1,2-a]pyridin-6-ylmethyl)-imidazo[1,2-b]pyridazine (Example 299, 49 mg, 0.138 mmol) was dissolved in dioxane (0.69 mL) and water (0.69 mL) then KMnO4 (21.8 mg, 0.138 mmol) and 2.5 M NaOH solution (0.165 mL, 0.414 mmol) were added. The RM was stirred at rt for 3 h. It was then filtered through Celite and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated and the residue was triturated with pentane. The precipitate was filtered off and dried to afford the title compound as a white solid (tR 0.3 min (conditions 2), MH+=390).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=1>O1CCCC1>[CH3:13][C:11]1[C:10]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=[C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:12]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC2)nc1-c1ccc(C)cc1
Yield: 92.8 %

Procedure:
Methyl 2-(4-methyl-2-(pyrrolidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from pyrrolidine (0.111 mL; 1.32 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.110 g; 0.264 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-20%) in heptane furnished 90 mg (93%) of the title compound as an oil. ESI/APCI(+): 368 (M+H), 390 (M+Na). ESI/APCI(−): 366 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]12CCCN=C1C[CH2:16][CH2:15][CH2:14][CH2:13]2.BrCCCC#N.C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH2:15][CH2:14][C:13]#[N:12])=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: N#CCCCBr
Solvent: O
Solvent: CC#N
Product: N#CCCCOC(=O)c1cc(O)ccc1O
Yield: 78.4 %

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.6 g; 30 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 g; 33 mmol), 4-bromobutyronitrile (4.9 g; 33 mmol) and acetonitrile (70 ml) was heated under reflux overnight. The reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×150 ml), dried over magnesium sulphate and filtered. The organic solvent was then removed in vacuo. The residue (6.2 g) was recrystallised from ethyl acetate/hexane to yield 5.2 g (78%) of the desired 3-cyanopropyl 2,5-dihydroxybenzoate.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)CCBr
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCCCOc1c(O)c2cccc(OCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-8-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[CH:17][C:16]=2[CH2:20][CH2:21][C:22](O)=[O:23])[CH:12]=[CH:13][CH:14]=1.N=C=N>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[CH:17][C:16]=2[CH2:20][CH2:21][C:22]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:23])[CH:12]=[CH:13][CH:14]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)CCc1cnoc1-c1cccc(Cl)c1
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CCc1cnoc1-c1cccc(Cl)c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 4-hydroxypiperidine (10 mg), 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionic acid (25 mg), PS-carbodiimide (100 mg, manufactured by Argonaut Technologies) and dichloromethane (1 ml) was shaken at room temperature overnight. The reaction mixture was filtrated and the filtrate was concentrated. The obtained residue was purified by preparative HPLC to give 1-{3-[5-(3-chlorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol.
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[C:23]1([CH2:22][C:21]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:9]4[C:4]5[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:32]6[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=6)[C:3]=5[S:11][CH:10]=4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccnc2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 120 °C
Yield: 51.6 %

Procedure:
To a 25 mL pressure tube was charged 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (182 mg, 0.356 mmol), 3-pyridinylboronic acid (43.7 mg, 0.356 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14.53 mg, 0.018 mmol), and sodium carbonate (75 mg, 0.712 mmol) followed by dioxane (5 mL), and water (1 mL). The reaction was heated at 120° C. for 30 min in microwave reactor. Water (20 mL) and ethyl acetate (20 mL) were added and the layers were separated. The organic layer was washed with brine, concentrated, and the residue purified by silica gel chromatography (0%-100% EtOAc in hexanes) to afford the tittle compound 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(3-pyridinyl)thieno[3,2-c]pyridin-4-amine (85 mg) as a gray solid. LC-MS (ES) m/z=463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (d, J=1.8 Hz, 1H) 8.62 (dd, J=4.8, 1.5 Hz, 1H) 8.18 (d, J=8.1 Hz, 1H) 8.10 (dt, J=8.1, 1.9 Hz, 1H) 7.96 (s, 1H) 7.56 (dd, J=8.1, 4.8 Hz, 1H) 7.50 (s, 1H) 7.23-7.40 (m, 7H) 5.63 (br. s., 2H) 4.26 (t, J=8.5 Hz, 2H) 3.90 (s, 2H) 3.24 (t, 2H)