Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[CH2:17]([Mg]Br)[CH3:18]>O1CCCC1.CCOCC.CCOC(C)=O.CSC.[Cu+].[Br-]>[CH2:17]([C@@H:5]1[C@@H:1]([OH:6])[CH2:2][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1)[CH3:18]
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: CC[Mg]Br
Agent: [Cu+]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: -30 °C
Yield: 379.2 %

Procedure:
A mixture of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (4 g, 18.25 mmol) and bromo(dimethylsulfide) copper(I) (3.75 g, 18.25 mmol) in tetrahydrofuran (40 ml) was cooled to −30° C. A 3M solution of ethylmagnesium bromide (15.20 ml, 45.6 mmol) in Et2O was added dropwise to the reaction mixture over 35 minutes, maintaining an internal temperature of at or below −30° C. After the addition was complete, the resulting reaction mixture was allowed to warm to −15° C. over 45 minutes. At this time, the reaction was checked by HPLC. The reaction mixture was allowed to gradually warm up to rt and HPLC indicated that the reaction was complete. The reaction mixture was diluted with EtOAc (50 mL). The reaction mixture was then cooled in an ice bath and was quenched by slow addition of sat′d aq. ammonium chloride (˜10 mL). The organic layer was separated and was washed with H2O (20 ml). The organic layer was concentrated and the crude was purified by silica gel chromatography to give (3S,4R)-benzyl 3-ethyl-4-hydroxypyrrolidine-1-carboxylate (17.25 g, 69.2 mmol, 69.0% yield). LCMS: (M+23)=242, t=1.87 min.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[N:22]=[C:12]3[C:11]=2[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[N:22]=[C:12]3[C:11]=2[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reaction time: 0.33 h

Procedure:
To 10 mL of trifluoroacetic acid was added 9-(t-Butoxycarbonylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (100 mg). After the solid dissolved, the solution was stirred for 20 minutes and the TFA removed in vacuo. To the residue was added 10 mL of water followed by sufficient saturated aqueous sodium bicarbonate to neutralize the mixture. The mixture was subsequently cooled and the solid collected to yield 9-Amino-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 29), m.p.>325° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 4 h
Yield: 19.7 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring. The solution was chilled in an ice-water bath and 4-morpholinecarbonyl chloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for an additional 4 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (25 mL). The phases were separated and the organic layer was washed with water (3×25 ml), brine (25 mL), dried (Na2SO4), filtered and concentrated to yield a yellow foam. The product was recrystallized from dichloromethane and ethyl acetate. The crystals were triturated with ether (2×5 mL) to remove residual solvent. The final product was dried in a vacuum oven to provide 200 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a tan crystalline solid, m.p. 164–166° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20]([CH3:24])=[N:21][C:22]#[N:23])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(O)(=[O:27])C.[Mn]([O-])(=O)(=O)=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+]>O.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20]([CH3:24])(=[N:21][C:22]#[N:23])=[O:27])[CH2:5][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]1=[O:15]
Reactant: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F

Procedure:
2-(3-Fluoro-4-(N-cyano-S-methylsulfinimidoyl)-benzyl)-isoindole-1,3-dione (preparation 15b, 1.60 g, 4.22 mmol) and acetic acid (0.25 g, 4.22 mmol) are added to a solution of potassium permanganate (670 mg, 4.22 mmol) in a mixture of water (8 mL) and acetonitrile (9.6 ml). The mixture is stirred over night, and saturated aqueous Na2S2O3 solution is added. The mixture is extracted with ethyl acetate and the organic layer is dried over Na2SO4. The residue is directly used in the next step without further purification. Yield: 1.34 g (80% of theory); ESI mass spectrum: [M+H]+=358; r.t. HPLC: 0.73 min (5-95AB).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][CH2:65][CH2:66][N:67](C)[C:68](=O)OC(C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:63][CH2:64][CH2:65][CH2:66][NH:67][CH3:68])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCCNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. tert-Butyl 3-aminopropyl(methyl)carbamate (0.164 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The product was recrystallised from EtOAc to yield colourless solid. The solid was dissolved in DCM (2.0 mL), treated with trifluoroacetic acid (0.50 mL) and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH. Evaporation of appropriate fractions gave the product as a colourless solid (0.042 g, 50%).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:12][N:13]1[CH:17]=[C:16]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:15]=[N:14]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1ncsc1Br
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: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ncsc1-c1cnn(C)c1

Procedure:
To a suspension of ethyl 5-bromothiazole-4-carboxylate, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and Pd(PPh3)4 in dioxane was added a 2 M aqueous Na2CO3 solution, followed by heating under reflux for 4 hours. To the reaction mixture was added water and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:EtOAc) to obtain ethyl 5-(1-methyl-1H-pyrazol-4-yl)-1,3-thiazole-4-carboxylate as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH:13]=1)[C:5](N(OC)C)=[O:6].Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=2)=[O:6])[CH:11]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[CH:13]=1
Reactant: COc1ccc(Br)cc1C
Reactant: CON(C)C(=O)c1cc(Br)cc(OCC2CC2)c1
Product: COc1ccc(C(=O)c2cc(Br)cc(OCC3CC3)c2)cc1C
Yield: 76 %

Procedure:
In analogy to the procedure described for the preparation of the Building Block AU, the reaction of the 3-bromo-5-cyclopropylmethoxy-N-methoxy-N-methyl-benzamide and 4-bromo-1-methoxy-2-methyl-benzene, beforehand transformed to the Grignard reagent, yielded the title compound as a colourless oil (yield: 76% of theory). Mass (calculated) C19H19BrO3 [374]; (found) [M+H]+=375, 377.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:9]1COCC1.[H-].[Na+].CI>O>[CH3:9][O:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1cccnc1
Reaction time: 0.25 h

Procedure:
To a mixture of 10.0 g of 3-hydroxymethylpyridine and 200 ml of THF, 3.7 g of 60% sodium hydride (in oil) was added in small portions at room temperature and then stirred for 15 minutes. To the reaction mixture, 13.0 g of methyl iodide was added dropwise, and the reaction mixture was stirred at room temperature for three hours. To the reaction mixture, 25 ml of water was added. Then, the reaction mixture was concentrated under reduced pressure. To the residue, 25 ml of water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8.17 g of 3-methoxymethylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.[Li]CCCC.C([Cu])#N.[Li+].[Cl-].[C:24](Cl)(=[O:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:24](=[O:26])[CH3:25])=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1cn(-c2ccccc2F)nn1
Reactant: CC(=O)Cl
Agent: N#C[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(=O)c1c(C)nnn1-c1ccccc1F
Temperature: -35 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a suspension of 1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazole (2.43 g, 13.7 mmol) in DME (40 mL) was added n-BuLi (1.6 M in hexane, 10.3 mL, 16.5 mmol) dropwise at −75° C. The mixture was allowed to warm up to −35° C. and was stirred at −35° C. for 1 h. The reaction mixture was cooled again to −78° C. and a light green suspension of CuCN (1.23 g, 13.7 mmol) and LiCl (1.16 g, 27.4 mmol) in THF (20 mL) was added rapidly while stirring at −78° C. After 1 h the mixture was allowed to warm up to −35° C. and acetyl chloride (4.88 mL, 68.6 mmol) was added dropwise at this temperature. Then the reaction mixture was stirred at room temperature for 2 h and then poured carefully into aqueous saturated sodium carbonate solution (100 mL) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (1.69 g, 56%) as a light yellow oil. MS: m/e=220.2 [M+H]+.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[C:11](N)[C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]>CN(C)C=O>[CH3:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1N
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 83.4 %

Procedure:
To a solution of t-butyl nitrite (t-BuONO) (7.32 g) in dimethyl formamide (DMF) (50 mL, from Mallinckrodt) at 65° C. was added dropwise a solution of 3,6-dimethyl-2.4-dinitro-phenylamine (10 g, from above) in DMF (50 mL) during 5-10 min. The mixture was heated at 65° C. for 15 min and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and half-saturated sodium chloride solution. The dichloromethane solution was washed with additional half-saturated sodium chloride solution (300 mL) and dried over magnesium sulfate. After evaporation of the solvent, the residue was taken up in dichloromethane (250 mL) and passed through a short column (silica gel). Eluting with dichloromethane gave 2,5-dimethyl-1,3-dinitro-benzene (7.75 g).
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>N1C=CC=CC=1>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:4]2[N:3]=1)=[O:33])[CH3:30]
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A mixture of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (304 mg, 0.805 mmol), ethyl isocyanate (314 μL, 3.98 mmol) and pyridine (10 mL) was stirred at 50° C. for 18 hr. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→O/100) and recrystallized from ethyl acetate-hexane to give the title compound (151 mg, 42%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13]Br)(=[O:4])=[O:3].[CH3:15][CH:16]([CH3:18])[O-:17].[Na+]>C(O)(C)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13][O:17][CH:16]([CH3:18])[CH3:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Br)c(Cl)c1CBr
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OCc1c(S(C)(=O)=O)ccc(Br)c1Cl
Reaction time: 8 h
Yield: 315.7 %

Procedure:
To a suspension comprising 20.0 g of 4-bromo-2-bromomethyl-3-chlorophenyl methyl sulfone and 200 ml of isopropanol, 100 ml of an isopropanol solution of sodium isopropoxide (prepared from 1.4 g of metal sodium) was added at room temperature, and the mixture was stirred overnight. The post treatment was conducted in the same manner as in Example 1-3-(2) to obtain 18.4 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][O:29][C:28]1[CH:23]=[CH:24][C:25]([CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:26][C:27]=1[NH:11][C:7]1[N:8]=[CH:9][C:10]2=[C:2]([CH3:1])[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:5]2[N:6]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: COc1ccc(CCNC(C)=O)cc1Br
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CCNC(C)=O)cc1Nc1ncc2c(C)nc(-c3cccc(C(F)(F)F)c3)n2n1
Yield: 69.2 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)-phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.050 g, 0.17 mmol), N-[2-(3-bromo-4-methoxyphenyl)ethyl]acetamide (0.046 g, 0.17 mmol), Pd2(dba)3 (0.016 g, 0.02 mmol), 2-(Di-t-butylphosphino)biphenyl (0.015 g, 0.05 mmol), and NaOtBu (0.033 g, 0.34 mmol) in 1,4-dioxane (2 mL) gave N-{2-[4-methoxy-3-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]-ethyl}acetamide (0.057 g) as a yellow solid. 1H NMR (CDCl3): δ8.85 (s, 1H), 8.80 (d, J=7.7 Hz, 1H), 8.62 (s, 1H), 8.23 (s, 1H), 7.73-7.63 (m, 3H), 6.88 (s, 2H), 5.83 (s, 1H), 5.39 (bs, 1H), 3.93 (s, 3H), 3.50 (q, J=6.6 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 2.24 (s, 3H), 1.86 (s, 3H). MS m/z 485 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[CH:40][NH:41]2)=[CH:37][CH:36]=1.C([O-])(O)=O.[Na+].CN(C=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[CH:40][NH:41]3)=[CH:37][CH:36]=2)[CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3cc[nH]c3c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90 mg, 0.2 mmol), 6-Bromo-1H-indole (1 eq., 49 mg), Pd[P(Ph)3]4 (5 mol %, 10 mg), in methanol (4 mL), NaHCO3 (sat. aq., 600 uL) and DMF (800 uL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 5.7 mg. MS: 440.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 11.1 (s, 1H), 10.1 (s, 1H), 8.0 (m, 1H), 7.6-7.2 (m, 12H), 7.0 (m, 2H), 6.4 (m, 1H), 5.0 (m, 2H), 4.4 (m, 1H), 3.5 (m, 1H), 2.2 (m, 1H), 1.9 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:6].C(O)(=O)C(O)=O.[CH3:30][C:31]([O:34][C:35]([N:37]1[CH2:40][C:39]2([CH2:43][NH:42][CH2:41]2)[CH2:38]1)=[O:36])([CH3:33])[CH3:32]>>[C:31]([O:34][C:35]([N:37]1[CH2:40][C:39]2([CH2:41][N:42]([CH:9]3[CH2:10][CH2:11][CH2:12][CH:8]3[NH:7][C:5](=[O:6])[C:4]3[C:14]([S:22][CH3:23])=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:3]=3[O:2][CH3:1])[CH2:43]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:30])[CH3:32]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1=O
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Agent: O=C(O)C(=O)O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CC2(CN(C(=O)OC(C)(C)C)C2)C1

Procedure:
The title compound, brown gum, MS: m/e=530.3 [(M+H, was prepared in accordance with the general method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclopentyl)-4-trifluoromethyl-benzamide (intermediate M) and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid 1,1-dimethylethyl ester ethanedioate (CAS 1041026-71-4). The cis- and trans-isomer could be separated by column chromatography.
Reaction SMILES: [Na].Cl.[CH2:3]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[NH:18])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:24][C:25](=O)[CH:26]([CH2:32][CH2:33][C@@H:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:27](OCC)=[O:28])C.Cl>CO>[OH:24][C:25]1[C:26]([CH2:32][CH2:33][C@@H:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:27]([OH:28])[N:19]=[C:17]([C:16]2[CH:15]=[CH:14][C:13]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:21][CH:20]=2)[N:18]=1
Reactant: CCCCCC[C@H](F)CCC(C(=O)OCC)C(=O)OCC
Reactant: CCCCCCCCCCc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCc1ccc(-c2nc(O)c(CC[C@@H](F)CCCCCC)c(O)n2)cc1
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
Under nitrogen atmosphere, 3 ml of dry methanol was placed in a two-necked round-bottomed flask. To the methanol, 113 mg (4.92 mM) of metal sodium was added and dissolved therein. To the solution, 584 mg (1.97 mM) of 4-decylbenzamidine hydrochloride was added and stirred for 20 minutes. To the mixture, a solution of 500 mg (1.64 mM) of (S)-2-(3-fluorononyl)malonic diethyl ester in 1 ml of dry methanol was added, followed by stirring for 16 hours at room temperature and distilling-off of methanol under reduced pressure. To the resultant reaction mixture, 4 ml of 6M-HCl was added to precipitate a crystal. The crystal was recovered by filtration and washed with ethanol and Et2O and further dried. The resultant crystal was recrystallized from 2.5 ml of N,N-dimethylformamide (DMF) to obtain 428 mg (0.91 mM) of (S)-4,6-dihydroxy-5-(3-fluorononyl)-2-(4-decylphenyl)pyrimidine (Yield: 55.3%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([CH3:14])[CH2:12][OH:13].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(Cl)Cl>[C:18]([O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH:10]([O:16][CH3:17])[O:9][CH3:8])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: COC(OC)C(C)(C)CO
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(C)(C)C(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml four-neck round bottom flask equipped with a mechanical stirrer, condenser thermometer and addition funnel were added 21.24 g triethylamine, 29.8 g 3,3-dimethoxy-2,2 dimethylpropanol, and 180 ml methylene chloride. The temperature was reduced to about 0° C. to -5° C. A total of 24.6 g methacryloyl chloride was added dropwise through an addition funnel. While maintaining the temperature at about 0° to -5° C., the mixture was then allowed to warm to room temperature and stirred for 30 min, and added to an equal volume (180 ml) of ice-water. The methylene chloride layer was separated from the aqueous layer, a small amount of anhydrous magnesium sulfate (3 g) was added, the solution was filtered, and methylene chloride was stripped off to isolate the product. Purification was done by as above at 65.2° C. under 0.5 mm Hg pressure.