Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC1=CCCC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC=C(C#N)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Hydroxycyclohex-1-ene-1-carbonitrile (500 mg, 4.06 mmol) was dissolved in anhydrous DMF (5.1 mL) and then cooled to 0° C. Imidazole (276 mg, 4.06 mmol) and TBS-Cl (612 mg, 4.06 mmol) were added and the reaction mixture was allowed to stir at 0° C. for 2 hours. The reaction mixture was partitioned between water and DCM. The organic layer was collected and the aqueous layer was again extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:34]=C(CCN)[CH:36]=[CH:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: COc1cccc(CCN)c1
Product: COc1cccc(CCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-methoxyphenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (1H, br. s.) 10.34 (1H, s) 8.19 (1H, t, J=5.61 Hz) 8.03 (1H, d, J=5.66 Hz) 7.79 (1H, d, J=5.37 Hz) 7.45 (1H, d, J=5.37 Hz) 7.34 (1H, d, J=3.32 Hz) 7.16 (1H, t, J=8.10 Hz) 6.72-6.82 (4H, m) 6.48 (1H, d, J=3.32 Hz) 3.71 (3H, s) 3.46 (2H, dt, J=8.00, 6.25 Hz) 2.79 (2H, t, J=7.27 Hz)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH:1]=[N:2][CH:3]=[CH:4]4)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: OB(O)c1ccc2cnccc2c1
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2cnccc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using isoquinolin-6-ylboronic acid and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 2.34 (s, 3 H), 7.67 (d, J=8.30 Hz, 1 H), 7.76 (d, J=8.79 Hz, 1 H), 7.90 (d, J=5.86 Hz, 1 H), 7.94 (s, 1 H), 8.28 (t, J=8.30 Hz, 2 H), 8.50 (d, J=5.86 Hz, 1H), 9.35 (s, 1 H); ESI-MS m/z [M+H]+ 330.4.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([CH:45]([OH:47])[CH3:46])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[OH:47][CH:45]([C:37]1[CH:36]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH:20]2[NH:2][N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[C:18](=[O:17])[NH:19]2)[CH:40]=[C:39]([O:41][CH3:42])[C:38]=1[O:43][CH3:44])[CH3:46]
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(C(C)O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C2NC(=O)N(c3ncccn3)N2)cc(C(C)O)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
After adding 22 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 112 mg of {2-[3-(1-hydroxyethyl)-4,5-dimethoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{[3-(1-hydroxyethyl)-4,5-dimethoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-one (93 mg) as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.[CH2:13]=[O:14]>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:13][OH:14]
Reactant: C=O
Reactant: Cc1cn(C)cn1
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydromidazo[1,5-a]pyridine (used for Example 224) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125-126° (ethyl acetate-petroleum ether).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[H-].[Na+].[CH3:15][CH:16]([OH:18])[CH3:17].O>O1CCCC1>[CH:16]([O:18][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10])([CH3:17])[CH3:15]
Reactant: CC(C)O
Reactant: FC(F)(F)c1cnccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccncc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-chloro-3-trifluoromethylpyridine hydrochloride salt (2.0 g) in tetrahydrofuran (5 mL) were added sodium hydride (60%, 2.8 g) and propan-2-ol (2.8 g), and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 4-isopropoxy-3-trifluoromethylpyridine (1.5 g). To a solution of the obtained compound (1.5 g) in ethyl acetate (20 mL) was added 4-bromomethylbenzoic acid methyl ester (2.0 g) at room temperature, and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was removed to give 4-isopropoxy-1-(4-methoxycarbonylbenzyl)-3-trifluoromethyl-pyridinium bromide (2.1 g). To a solution of the obtained compound (2.1 g) in dimethoxyethane (10 mL) were added acrylonitrile (1.3 g), manganese dioxide (2.1 g) and triethylamine (1.5 g), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was filtered through a Celite pad, and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.04 g).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=[O:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[I-:42].[Na+].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:17][C:13]1[C:12](/[C:18](/[I:42])=[CH:19]/[C:20](=[O:21])[C:22]2[NH:23][CH:24]=[CH:25][CH:26]=2)=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[CH2:10]2
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: [I-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (5.90 g, 10.4 mmol) and sodium iodide (Aldrich, 4.67 g, 31.4 mmol) was added TFA (Aldrich, 35 mL) slowly at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then poured into a mixture of a saturated aqueous sodium bicarbonate solution (400 mL) and ethyl acetate (500 mL). After separation, the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate, filtered, and dried to give (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one as a brown solid which was used in the next step without further purification. (Yield 3.86 g, 93.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:12]1[N:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(NCc3ccccc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (300 mg, 0.918 mmol) and benzylamine were reacted as starting materials at 120° C. for 19 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (365 mg, quantitative). Melting point: 125.4-126.3° C. (ethyl acetate-hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:30])([CH3:29])[C:23]#[C:24][C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][C:17]=2[O:31][CH3:32])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O)(C)(C)C.[ClH:39].CO>CCOC(C)=O>[ClH:39].[ClH:39].[CH3:30][C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:31][CH3:32])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:29])[C:23]#[C:24][C:25]([F:28])([F:26])[F:27]
Reactant: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of Compound 59 (34 mg, 0.064 mmol) in AcOEt (8 ml) was added an excess amount of HCl-MeOH. The mixture was stirred for 18 h and then evaporated in vacuo, the residual solid was recrystallized from MeOH-Et2O to give Compound 60 (24 mg, 75%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([NH:16][C:17]1[C:22]([CH:23]=O)=[CH:21][N:20]=[C:19]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1)[CH3:15]>CN(C)C=O>[CH2:14]([NH:16][C:17]1[C:22]([CH:23]=[CH:5][C:3]#[N:4])=[CH:21][N:20]=[C:19]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1)[CH3:15]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1nc(Nc2ccccc2)ncc1C=CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
To a room temperature suspension of sodium hydride (38 mg of a 60% suspension of NaH in oil) in 5 mL of dimethylformamide was added diethyl cyanomethylphosphonate (150 μL, 0.93 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldeyde (200 mg, 0.83 mmol) in 2 mL of dimethylformamide was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was partitioned between brine and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo The residue was purified by flash chromatography eluting with 1:1 ethyl acetate:hexane. The fractions containing product were concentrated, and hexane was added to the residue. The resultant solid was collected by filtration to give 91 mg (43%) of 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)acrylonitrile, mp 244-246° C. Concentration of the filtrate provided an additional 68 mg (32%) of product.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28](O)=[O:29].O>ClCCl.CN(C)C1C=CN=CC=1>[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])=[O:29]
Reactant: O=C(O)C1CCCO1
Reactant: OCCCCCCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(OCCCCCCCCCl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.7 g) in dichloromethane (100 ml) was slowly added to a solution of 8-chloro-1-octanol (4.1 g), tetrahydro-2-furancarboxylic acid (3.5 g) and 4-dimethylaminopyridine (1.5 g) in dichloromethane (50 ml) at 0° C. The mixture was stirred overnight at room temperature. The resulting solution was then added to water (500 ml) and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with water (2×200 ml), dried over magnesium sulphate and filtered. The solvent removed in vacuum. The residue (7 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (90:10) as eluent to give 8-chlorooctyl tetrahydro-2-furancarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([Cu])#[N:10]>CN(C=O)C>[OH:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=1)[C:9]#[N:10]
Reactant: Oc1cncc(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cncc(O)c1
Temperature: 135 °C
Yield: 38.5 %

Procedure:
A mixture of 5-bromo-pyridin-3-ol (9.94 mL, 54.0 mmol) and CuCN (7.4 g, 82.62 mmol) in DMF (20 mL) was heated at 135° C. for 5 hour. DMF was removed under reduced pressure, the residue was diluted with NH4OH (10 mL) at 0° C. The mixture was bubbled with ammonia gas for 1 hour, cooled to 0° C. and acidified with conc. HCl (35 mL) until pH reached to ˜4. The resulting mixture was extracted with EtOAc (5×100 mL). The organic layer was washed with water (2×100 mL) and brine (2×100 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow solid. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (2.5 g, 39%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1 H), 8.46 (d, J=2.0 Hz, 1 H), 8.41 (d, J=2.7 Hz, 1 H), 7.61-7.57 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([CH:17]([OH:19])[CH3:18])=[CH:4][N:3]=1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][N:3]=1
Reactant: CC(O)c1cnc(Cl)c2cc(-c3ccccc3)sc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC(=O)c1cnc(Cl)c2cc(-c3ccccc3)sc12

Procedure:
To a suspension of 1-(4-chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanol 96 (92 mg, 0.32 mmol) and 168 mg of powdered 4 Å molecular sieves in dichloromethane (35 mL) was added TPAP (11 mg, 0.03 mmol). The resultant mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium thiosulfate (1×) and saturated aqueous copper sulfate (1×). The organic layer was dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 17:3) to give 97. 1H NMR (400 MHz, CDCl3) δ: 2.79 (s, 3H), 7.40–7.53 (m, 3H), 7.75 (s, 1H), 7.78–7.83 (m, 2H), 8.83 (s, 1H). MS (EI) m/z (M+H+) 288.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10]OCC)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[BH4-].[Li+].C[CH2:17][O:18]CC>C1COCC1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:17][OH:18])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOCC
Reactant: CCOCCP(=O)(OCC)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCCO)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of (2-ethoxy-ethyl)-phosphonic acid diethyl ester (0.500 g, 2.1 mmol) in ether (8.5 mL) and THF (1.5 mL) was treated with lithium borohydride. The reaction mixture stirred at room temperature for 1 hour and was then concentrated in vacuo. The crude mixture was partitioned between dichloromethane and water. The organic phase was washed with saturated NaHCO3 and brine, dried (MgSO4), then concentrated in vacuo. The residue was purified by silica gel chromatography (5/95—methanol/dichloromethane) to afford (3-hydroxy-propyl)-phosphonic acid diethyl ester 178 (0.100 g, 24%) as an oil: 1H NMR (CDCl3) δ 4.1 (m, 4H), 3.7 (m, 2H), 2.95 (bs, 1H), 1.85 (m, 4H), 1.30 (t, 3H); 31P NMR (CDCl3) δ 33.26; MS: 197 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:12]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: BrCCCCc1ccccc1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)N1CCN(CCCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2.47 g of 1-bromo-4-phenylbutane in 5 ml of 2-butanone was added to a mixture of 1.93 g of 1-ethoxycarbonylpiperazine, 1.76 g of potassium carbonate and 15 ml of 2-butanone at room temperature. After stirring at 80° C. for 12 hours, the mixture was cooled and, after addition of water, extracted with ethyl acetate. The extract was washed with water and saturated aqueous solution of sodium chloride in that order and dried over anhydrous sodium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give 1-ethoxycarbonyl-4-(4-phenylbutyl)piperazine. The compound obtained was dissolved in 20 ml of ethanol and 20 ml of 10% aqueous solution of sodium hydroxide, and the solution was stirred at 100° C. for 12 hours. After cooling, the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent:chloroform-methanol-25% aqueous ammonia=100:10:1) to give 1.5 g cf 1-(4-phenylbutyl)piperazine as an oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc(-c2cc(Br)c(OCc3ccc(OC)cc3)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
Sodium hydride (100 mg of a 60% suspension in oil, 2.5 mmol) was added to a stirred solution of ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (980 mg, 2.5 mmol) in dry dimethylformamide (5 mL) under nitrogen and the mixture was stirred at room temperature for 15 minutes. 4-Methoxybenzyl chloride (470 mg, 3.0 mmol) was added and the resulting solution was stirred at 50° C. for 20 h. The cooled mixture was treated with water (10 mL) to give a colourless solid that was filtered, washed with water and dried. Crystallization from di-isopropyl ether gave the title compound (840 mg, 65%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 1.41 (3 H, t), 3.52 (3 H, s), 4.49 (2 H, t), 5.06 (2 H, s), 7.01 (2 H, d), 7.53 (2H, d), 8.30 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][CH3:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:33][N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CNCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)CC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1.5 mL) were added 2,2,2-trifluoro-N-methylethanamine hydrochloride (60 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1.Cl[CH2:34][C:35](=[O:37])[CH3:36]>CC(N(C)C)=O>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:34][C:35](=[O:37])[CH3:36])=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Potassium carbonate (1.214 g, 8.79 mmol) was added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 46, preparation of starting materials) (1.07 g, 2.93 mmol) and 1-chloropropan-2-one (0.466 mL, 5.86 mmol) in DMA (10 mL). The resulting mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and diluted with water (25 mL) then extracted with DCM (2×25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)propan-2-one (1.190 g, 96%) as a gum.