Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][CH:14]([F:21])[C:15](N(OC)C)=[O:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[F:13][CH:14]([F:21])[C:15]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:16]
Reactant: CON(C)C(=O)C(F)F
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1cccnc1)C(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
To toluene (7.0 mL) were added dropwise at −78° C. n-butyllithium (2.76 mol/L solution in n-hexane, 2.60 mL, 7.19 mmol) and a solution of 3-bromopyridine (1.00 mL, 10.4 mmol) in toluene (2.5 mL), and the mixture was stirred at the same temperature for 30 minutes. THF (4.0 mL) was added to the resulting suspension and the mixture was stirred at −78° C. for 15 minutes. To the mixture was added 2,2-difluoro-N-methoxy-N-methylacetamide (1.00 g, 7.19 mmol) and the mixture was stirred for 3 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 2,2-difluoro-1-(pyridin-3-yl)ethanone (868 mg, 91% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]=[CH:10][N:11](C)C)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.N[OH:16]>CO>[Br:1][C:2]1[C:3]([NH:9][CH:10]=[N:11][OH:16])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: CN(C)C=Nc1nc(Br)cnc1Br
Agent: Cl
Solvent: CO
Product: ON=CNc1nc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of N′-(3,6-dibromo-pyrazin-2-yl)-N,N-dimethylformamidine (18.6 g, 60.80 mmol) in methanol (200 mL) is added hydroxylamine hydrochloride (5.91 g, 85.12 mmol) in one portion. The reaction is stirred at room temperature for 16 hours. The solvent is evaporated and the solid residue is treated with cold (ice cooling) water and collected by filtration. The precipitate is washed twice with water and petroleum ether and dried in vacuo yielding the title compound (17.45 g) as a white solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 7.82 (1H, br s), 8.21 (1H, s), 8.34 (1H, m), 11.17 (1H, br s). LCMS: Rt 3.17 min (98.7%), m/z (APCI) 295 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].C(N(C(C)C)CC)(C)C.Cl[C:36](OCC)=[O:37]>O1CCCC1>[Br:1][C:2]1[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]2[NH:21][C:36](=[O:37])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 150 °C

Procedure:
A stirred solution of 5-bromo-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-(trifluoromethyl)-1,2-benzenediamine (D55) (0.34 mmol) in tetrahydrofuran (8 ml) at room temperature under argon was treated with diisopropylethylamine (0.12 ml, 0.68 mmol) followed by ethyl chloroformate (40 mg, 0.38 mmol) and then heated under reflux for 2 hrs. The mixture was concentrated under vacuum and the residue dissolved in dimethylformamide, treated with more diisopropylethylamine (0.12 ml) and heated at 150° C. for 0.75 hr. The solution was then concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum. The residue was triturated with diethyl ether to afford 6-bromo-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one as a beige solid. This was converted to its HCl salt as a beige solid (55 mg, 33%). MH+=448, 450.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[NH2:8][C@@H:9]([CH2:20][CH2:21][C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:26]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>O1CCCC1.C(OCC)(=O)C>[C:27]1([C:25]2[N:26]=[C:22]([CH2:21][CH2:20][C@H:9]([NH:8][CH2:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[NH:23][CH:24]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ccsc1
Reactant: N[C@@H](CCc1nc(-c2ccccc2)c[nH]1)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1ccsc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-1H-imidazol-2-yl)butanoate in the form of a free base (3.6 g; 1 eq.) in tetrahydrofuran (hereafter THF, 40 ml). The mixture is stirred for 15 hours at approximately 20° C. and diluted by adding 50 ml of tetrahydrofuran. NaBH(OAc)3 (4.73 g; 2 eq.) is then added. After 1 hour of stirring at approximately 20° C., the reaction is stopped by adding water (40 ml) and ethyl acetate is then added (100 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Flash chromatography purification on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound in the form of a yellow oil (3.08 g; 66% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]2[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CSc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CSc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
4-Bromophenylacetic acid (10.8 g, 0.050 mol) was disolved in thionyl chloride (50 mL) and stirred for 30 min at 90° C. The mixture was concentrated and the residual oil was disolved in carbon disulfide (100 mL) and thioanisole (12.5 g, 0.10 mol) was added and the mixture was cooled to 0° C. and AlCl3 (14.7 g, 0.11 mol) was added portionwise. The mixture was stirred at room temperature for 16 h. The resultant dark green suspension was poured into ice water (150 mL) and extracted with CH2Cl2 (150 mL×2), washed with aqueous saturated NaHCO3 (50 mL), dried over MgSO4, and concentarted in vacuo gave the solid. The solid was suspended in ether and collected by filtration to give the title compound (8.4 g, 46%).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:11]=[C:12]([NH2:13])[C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH:11]=[C:12]([NH:13][C:25](=[O:27])[CH3:26])[C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1nnc2c(N)cc(-c3ccc(OC(F)(F)F)cc3)cn12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)cn2c(C(C)C)nnc12

Procedure:
In a heavy-wall pressure tube was added 3-isopropyl-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-8-amine prepared in 9A in toluene. To this suspension was added the acetic anhydride (0.1 mL) followed my triethylamine (0.1 mL). The mixture was heated in a 110 C oil bath for 12 hours. The reaction mixture was evaporated in vacuo and purified by preparative HPLC to afford N-(3-isopropyl-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetamide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=1>>[CH3:30][C:26]1[N:25]=[C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]([C:18]3[CH:19]=[N:14][CH:15]=[N:16][CH:17]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1nccc(N)n1
Product: Cc1ccc2c(-c3cncnc3)cnc(Nc3ccnc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=330.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 4-amino-2-methylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][N:13]=[C:14]=[O:15]>O1CCCC1.C(N(CC)CC)C>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: CN=C=O
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc([N+](=O)[O-])c(C)c1

Procedure:
3-Methyl-4-nitrophenol (46.0g., 0.30 mole) was dissolved in tetrahydrofuran (200 ml.) and triethylamine (2 ml.). To this solution was added dropwise methylisocyanate (18.8g., 0.33 mole, 25 ml.) which resulted in an exotherm to about 40° C. Refluxing for one hour, followed by quenching in excess water, yieldig a light tan precipitate. After filtration and drying the material (51g.) melted at .99°-101° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1(=O)Cc2ccccc2C12CCNCC2
Yield: 95 %

Procedure:
170 mg (0.5 mmole) of 1'-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4'-piperidine]-2,2-dioxide [prepared as described in step (a) above] were dissolved in 3 ml of methylene chloride, and 1 ml of a 4 N solution of hydrogen chloride in dioxane was added, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling, for 1 hour, after which the crystals which deposited were collected by filtration, to give 131 mg (yield 95%) of the title compound as white crystals.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>C(OCC)C>[C:1]1([C:7]#[C:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
25 g of 3-phenyl-2-propyn-1-ol and 40 g of toluene-4-sulfonic acid chloride are dissolved in 500 ml of diethyl ether and cooled to −20° C. 26.6 g of finely powdered potassium hydroxide are added in portions to that solution, over a period of 20 minutes, in such a manner that the internal temperature of the reaction mixture does not exceed −5° C. When the addition is complete, the reaction mixture is stirred for 2 hours at from 0 to 5° C. and then introduced into one litre of ice-water. Extraction is carried out twice using one litre of diethyl ether each time. The organic phases are washed once with 500 ml of saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated, yielding toluene-4-sulfonic acid (3-phenyl-2-propyn-1-yl) ester in the form of a colourless resin.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)OC(=O)CBr
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)cc(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (see example 16) (1.0 g, 2.78 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (1.36 g, 3.34 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 1 h, then isopropyl 2-bromoacetate (624 mg, 3.34 mmol, 1.2 eq) was added and the reaction mixture was stirred for h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue obtained was purified by column chromatography, (EtOAc:petroleum ether 0:1 to 1:20) to give the title compound as a colourless oil (0.8 g, 62%).
Reaction SMILES: [C:1]([N:11]1[CH2:13][C:12]1([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:16][C:17]1([CH3:25])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH:18]1[OH:24].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][C:12]([CH3:14])([CH3:15])[CH2:13][O:24][CH:18]1[C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21][C:17]1([CH3:25])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: CC1(C)CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(COC1C(C)(C)CCC1(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2,2-dimethyl aziridine and 2,2,5,5-tetramethyl-1-cyclopentanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>C(O)C>[CH3:9][C:10]1[CH:11]=[C:12]([CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1cccc(CN)c1
Solvent: CCO
Product: Cc1cccc(CNC(=O)CC#N)c1
Yield: 51.5 %

Procedure:
5.6 g of ethyl cyanoacetate and 6.06 g of 3-methylbenzylamine are refluxed for 9 h in 40 ml of ethanol to give a solution. After cooling, this solution gives a precipitate which is filtered off and washed with ethanol and ether to give 4.8 g of N-(3-methylphenyl)methylcyanoacetamide in the form of a white solid melting at 115° C. Yield 51%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si]([O:14][CH2:15][C@H:16]([CH3:36])[O:17][C:18]1[CH:19]=[C:20]([CH:32]=[C:33]([OH:35])[CH:34]=1)[C:21]([NH:23][C:24]1[CH:28]=[CH:27][N:26]([CH:29]([CH3:31])[CH3:30])[N:25]=1)=[O:22])(C(C)(C)C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]([CH:47]=[CH:48][C:49]=1F)[C:41]([N:43]1[CH2:46][CH2:45][CH2:44]1)=[O:42]>C(#N)C>[N:43]1([C:41]([C:40]2[CH:47]=[CH:48][C:49]([O:35][C:33]3[CH:32]=[C:20]([CH:19]=[C:18]([O:17][C@@H:16]([CH3:36])[CH2:15][OH:14])[CH:34]=3)[C:21]([NH:23][C:24]3[CH:28]=[CH:27][N:26]([CH:29]([CH3:30])[CH3:31])[N:25]=3)=[O:22])=[C:38]([Cl:37])[CH:39]=2)=[O:42])[CH2:46][CH2:45][CH2:44]1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Reactant: CC(C)n1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO)c2)n1
Temperature: 160 °C
Yield: 79.7 %

Procedure:
Potassium carbonate (182 mg, 1.32 mmol) was added to a mixture of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-hydroxy-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide (350 mg, 0.81 mmol) and 1-(3-Chloro-4-fluorobenzoyl)azetidine (181 mg, 0.85 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 15 hours. The mixture was allowed to reach ambient temperature and pressure and reduced in vacuo. The residual oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (331 mg)
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:11]([C:26]([F:29])([F:28])[F:27])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:39])[CH2:33][CH2:32]2)=[C:11]([C:26]([F:28])([F:27])[F:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.14 mmol, 0.075 g) and aqueous formaldehyde (37%, 0.68 mmol, 0.070 mL) in dry DCM (1.2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.82 mmol, 0.35 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 493 [M+1]; 1H NMR (400 MHz, CD3OD) δ 7.10-7.19 (2 H, m), 7.00-7.09 (2 H, d), 5.54-5.82 (1 H, m), 4.38-4.43 (1 H, m), 3.66 (1 h, d), 3.54 (1 H, d), 3.10-3.35 (2 H, m), 2.89-2.98 (3 H, m), 2.64-2.73 (2 H, m), 2.58 (1 H, d), 2.46 (1 H, d), 2.27 (1 H, t), 1.96-2.13 (3 H, m), 1.78-1.83 (2 H, m), 1.14-1.66 (10 H, m), 0.77 (3 H, t).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1>C1(C)C=CC=CC=1>[N:7]([C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16]([F:19])([F:17])[F:18])[N:9]=1)=[C:2]=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(F)(F)F)nc(N)n1
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)nc(N=C=O)n1
Reaction time: 4 h
Yield: 57.9 %

Procedure:
38.3 g of oxalyl chloride (0.3 mol) were added dropwise to a suspension of 2-amino-4-methoxy-6-trifluoromethylpyrimidine (78 mmol) in 100 ml of toluene. The refluxing mixture was stirred for 4 hours, after which the homogeneous solution obtained was subjected to fractional distillation. The title compound (9.9 g; 58% of theory) was obtained as an oil of boiling point 44°-50° C. (0.5 mbar).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(Nc3ccccc3)c2)CC1
Temperature: 100 °C
Reaction time: 21 h
Yield: 112 %

Procedure:
In a dry Schlenk tube under argon atmosphere tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (800 mg, 2.745 mmol) was dissolved in dry toluene (14 mL). Argon was bubbled through the mixture for a few minutes before adding bromobenzene (0.32 mL, 3.02 mmol, 1.1 eq), Cs2CO2 (1.34 g, 4.118 mmol, 1.5 eq), Pd(OAc)2 (16 mg, 0.069 mmol, 2.5 mol %) and Rac-BINAP (88 mg, 0.137 mmol, 5 mol %). The mixture was then stirred at 100° C. for 21 hours. The mixture was allowed to cool to room temperature and diluted with dichloromethane. Salts were filtered over a Celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography over silica gel (DCM/EtOH/NH3 7% in methanol 95:5:0.5) to give 1.13 g of title compound (quant. yield) as off-white solid
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C1C=CC=CC=1>[CH2:21]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[C:2]([F:12])([F:1])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCO
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1CNCc1ccccc1

Procedure:
A mixture of 3.9 g. (0.0138 mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzylamine, 1.77 g. (0.014 mole) of benzyl chloride, 2.5 g. of anhydrous potassium carbonate, and 25 ml. of benzene is stirred and heated to refluxing for about 40 hours. After filtration, the solvent is evaporated under reduced pressure, leaving the product as the residual oil. Purification is effected by column chromatography on 250 g. of silica, the product being eluted with 1% methanol in chloroform. The fractions that show one spot of rf 0.7 on a fluorescent silica thin layer plate developed with 5% methanol in chloroform are combined. Evaporation of the solvent under reduced pressure leaves the product as the residual oil. The base is converted to the hydrochloride salt by treating an ethanolic solution with a slight excess of 8N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the hydrochloride as white crystals, m.p. 188°-189.5° C. Recrystallization from acetone yields a purified sample, m.p. 188.5-190° C. Anal. Calc'd. for C22H19F4N .HCl: C, 64.48; H, 4.92; Cl, 8.65. Found: C, 64.75; H, 4.89; Cl, 8.64.