Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]2)[CH:9]=1.[Br:49]N1C(=O)CCC1=O>C(#N)C>[CH3:44][Si:43]([CH3:46])([CH3:45])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:47])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:49]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a 25 mL roundbottom flask was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (198 mg, 287 μmol) and acetonitrile (10 mL). To this solution was added N-bromosuccinimide (56 mg, 316 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting oil was then purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (205 mg, 266 μmol, 93% yield) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]#[C:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1.CC(C)([O-])C.[K+].ClCCl.C(OCC)(=O)C>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:24][C:18]2=[N:19][CH:20]=[C:21]([F:23])[CH:22]=[C:17]2[CH:16]=1
Reactant: COc1cc2c(C#Cc3cc(F)cnc3N)cn(C)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(C)c2cc1OC
Yield: 24.2 %

Procedure:
But using 0.19 g of 3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)-5-fluoropyridin-2-ylamine and 0.263 g of potassium tert-butoxide in 15 ml of 1-methylpyrrolidin-2-one. After flash chromatography on a silica column [eluent: dichloromethane/ethyl acetate (90/10 by volume)], 0.046 g of 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Triethylamine (2.65 g, 26.2 mmol) was slowly added to a mixture of 2-mercapto-benzoic acid methyl ester (4.0 g, 23.8 mmol) and trityl chloride (6.63 g, 23.8 mmol) in CH2Cl2 at rt. The reaction mixture was stirred at rt for 3 h and washed with water (100 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide 2-tritylsulfanyl-benzoic acid methyl ester (9.6 g), which was used directly to the next reaction without further purification. MS ESI(+) m/e: 411.15 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][C@H:20]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][O:22]2)(=O)=O>>[CH2:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:20]1[CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)[O:22][CH2:21]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: OB(O)c1ccnc(F)c1
Product: Fc1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)ccn1
Yield: 68 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 68% yield, starting from 2-fluoro-4-pyridinylboronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate. The reaction was irradiated in a microwave at 150° C. for 3 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (d, 1 H), 7.33-7.37 (m, 1 H), 7.24-7.33 (m, 8 H), 7.15-7.22 (m, 4 H), 6.79-6.87 (m, 2 H), 4.32-4.38 (m, 1 H), 4.04-4.10 (m, 1 H), 3.61-3.74 (m, 4 H), 2.93-3.10 (m, 2 H), 2.42-2.48 (m, 1 H); MS (ESI) m/z 425[M+H+].
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[C:8]([F:10])[CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: N#CCc1cc(F)cc(CC#N)c1
Agent: Cl
Product: N#CCc1cc(F)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 28.1 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-fluorobenzene (1.6 g, 9.2 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (1.98 g, 9.2 mmol) and the resultant product was crystallized from isopropyl ether to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-fluorophenylacetonitrile (868 mg, 28%) as a colorless powder.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[NH:4][C:5]([CH:24]([F:26])[F:25])=[C:6]([C:22]#[N:23])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][C:19]=2[F:20])[NH:16][N:15]=[C:14]3[CH3:21])[C:8]=1[C:9]#[N:10].C(=O)([O-])O.[OH:32][CH2:33][CH2:34][N+:35]([CH3:38])([CH3:37])[CH3:36]>C(O)C>[C:9]([C:8]1[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][C:19]=2[F:20])[NH:16][N:15]=[C:14]3[CH3:21])[C:6]([C:22]#[N:23])=[C:5]([CH:24]([F:25])[F:26])[N-:4][C:3]=1[CH:2]([F:1])[F:27])#[N:10].[OH:32][CH2:33][CH2:34][N+:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(C(F)F)[N-]C(C(F)F)=C3C#N)cc12

Procedure:
To a suspension of 100 mg (0.26 mmol) 2,6-bis(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 14) in ethanol (1.52 ml) under argon atmosphere was added 47 μl (0.26 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 1 h.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:9]([NH:10]C(OC)=O)=[CH:8][C:7]([O:15][CH3:16])=[CH:6][C:5]=1[CH2:17][CH3:18].CO.[OH-].[Li+]>O.C1COCC1>[NH2:10][C:9]1[CH:8]=[C:7]([O:15][CH3:16])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:3]([OH:19])=[O:2]
Reactant: CCc1cc(OC)cc(NC(=O)OC)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cc(OC)cc(N)c1C(=O)O
Yield: 98.1 %

Procedure:
Compound O (21.9 g, 82.0 mmol) in H2O, THF, and MeOH (3:1:1, 255 mL) was treated with lithium hydroxide (9.80 g, 410 mmol) at 100° C. for 2 hours under N2. The reaction mixture was partially concentrated and the remaining aqueous phase was washed with dichloromethane (50 mL). The aqueous phase was acidified to pH 4-5 with 3 N HCl and then extracted with ethyl acetate (3×400 mL). The combined organic solutions were washed with saturated NaCl solution and dried over anhydrous Na2SO4. Filtration and concentration by rotary evaporation provided compound R (15.71 g, 98%) as an off-white powder. 1H NMR (CDCl3, 400 MHz) δ: 6.18 (d, 1H, J=2.0 Hz), 6.01 (d, 1H, J=2.0 Hz), 3.79 (s, 3H), 2.93 (q, 2H, J=7.0 Hz), 1.23 (t, 3H, J=7.5 Hz). ESMS m/z: 196.0 [M+H]+, 178.0 [M−OH]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[NH:5][C:4](=[O:17])[CH:3]=1.[CH3:18][N:19]([CH3:22])[CH:20]=O.CN(C(OC)OC)C.C(O)(C)C>O>[F:15][C:9]1[CH:10]=[C:11]([I:14])[CH:12]=[CH:13][C:8]=1[N:7]1[C:2]([N:1]=[CH:18][N:19]([CH3:22])[CH3:20])=[CH:3][C:4](=[O:17])[NH:5][C:6]1=[O:16]
Reactant: CN(C)C=O
Reactant: Nc1cc(=O)[nH]c(=O)n1-c1ccc(I)cc1F
Agent: COC(OC)N(C)C
Solvent: CC(C)O
Solvent: O
Product: CN(C)C=Nc1cc(=O)[nH]c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 67.7 %

Procedure:
To a mixture (21.8 g) of 6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 80 and 78 was added N,N-dimethylformamide (42.0 ml) and N,N-dimethylformamidedimethylacetal (21.0 ml) and the mixture was stirred at room temperature for 4.5 hrs. With stirring at room temperature, isopropyl alcohol (20.0 ml) was added, and water (100 ml) was added dropwise. The mixture was stirred at room temperature for 45 min, and the precipitated crystals were collected by filtration, washed with water and dried to give N′-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine 81 (21.7 g, yield 67.7% from 78) as colorless crystals.
Reaction SMILES: [ClH:1].[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].Cl.C(OCC)(=O)C>C(O)C>[ClH:1].[C:2]12([CH2:12][CH2:13][NH:14][CH2:24][CH2:23][C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: C=CC(=O)OC(C)(C)C
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNCCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
2-(1-Adamantyl)ethylamine hydrochloride (1.0 g, 4.6 mmol) was dissolved in ethanol (10 ml), and triethylamine (0.65 ml, 4.6 mmol) and t-butyl acrylate (0.75 ml, 5.1 mmol) were added to the solution under ice-cooling. Then, the temperature was raised to room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, a 1 N aqueous sodium hydroxide solution (30 ml) and ethyl acetate (50 ml) were added to the residue, and layers were separated. The ethyl acetate layer was washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml) successively and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography. The resulting oily matter (0.50 g, 1.6 mmol) was dissolved in diethyl ether (20 ml), and a 4 N solution of hydrogen chloride in ethyl acetate (1.0 ml, 4.0 mmol) was added thereto to precipitate a solid. This solid was filtered off with diethyl ether to give 0.33 g (23%) of the titled compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=49:49:3) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9]CC)[CH2:4][CH2:3]1.C(O)CO>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH:8]2[O:9][CH2:14][CH2:13][O:12]2)[CH2:6][CH2:7]1
Reactant: CCOC(OCC)N1CCN(C)CC1
Solvent: CCO
Solvent: OCCO
Product: CN1CCN(C2OCCO2)CC1
Reaction time: 18 h

Procedure:
The amide acetal produced in Example 1 (3.03 g, 0.015 mole) was combined while stirring with ethylene glycol (0.93 g, 0.015 mole) in a glass flask at ambient temperature under nitrogen. The reaction was continued with stirring for 18 hours. The by-product ethanol formed during the reaction was removed by vacuum and the reaction continued for an additional 18 hours with stirring under vacuum. The resulting product was found to have a boiling point of about 220° C., and identified as the desired product by NMR spectroscopy.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1([F:17])[O:11][C:10]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:9]=2[O:8]1.[I:18]I>O1CCCC1>[F:17][C:7]1([F:6])[O:11][C:10]2[CH:12]=[CH:13][C:14]([F:16])=[C:15]([I:18])[C:9]=2[O:8]1
Reactant: Fc1ccc2c(c1)OC(F)(F)O2
Reactant: II
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Fc1ccc2c(c1I)OC(F)(F)O2
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
Sec-Butyllithium (1.4 M in cyclohexane; 6.1 mL, 8.5 mmol) was added to dry tetrahydrofuran (15 mL) which had been pre-cooled to −40° C. The solution was cooled to −75° C., treated with 2,2,5-trifluorobenzo[d][1,3]dioxole (1.5 g, 8.5 mmol) and stirred at this temperature for 90 min. This solution was rapidly transferred via cannula into a stirred solution of iodine (2.8 g, 11 mmol) in tetrahydrofuran (25 mL), and the mixture was cooled to −75° C. The mixture was stirred for 1 h during which time the temperature rose to −20° C. The reaction was quenched by addition of saturated NH4Cl (10 mL) and then combined with 10% NaHSO3 (15 mL) and ethyl acetate (30 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated. The material was purified by flash chromatography with hexane to give the title compound as a clear liquid (1.5 g, 58%): 1H NMR (400 MHz, CDCl3) δ 6.97 (dd, J=8.8, 4.0 Hz, 1H), 6.81 (dd, J=11.7, 5.4 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −49.06, −103.15; EIMS m/z 302.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.CC([O-])(C)C.[K+].CCOC(C)=O>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Brc1nccs1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2nccs2)cc1F
Temperature: 150 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of 427A (0.814 g, 6.41 mmol), 2-bromothiazole (1.0 g, 6.10 mmol) and t-BuOK (0.821 g, 7.32 mmol) in DMA (25 ml) was stirred at 150° C. under argon for 1 h, then cooled to rt. Treated with EtOAc (150 ml), the mixture was washed with H2O (50 ml), 3N NaOH (2×50 ml), H2O (50 ml), dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10%-25% EtOAc-hexanes) gave 427B (1.02 g, 80%) as a colorless oil. It has a retention time of 4.02 min (standard LC1 method, 8 min run). MS Found: (M+H)+=211.1
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][NH2:13]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH3:12])=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1F

Procedure:
A solution of 2,4-difluoro-benzoylchloride D in a solution of methylamine and tetrahydrofuran (THF) is allowed to react to produce 2,4-difluoro-N-methylbenzamide M (quantitative yield). The 2,4-difluoro-N-methylbenzamide M is mixed with in a solution of acetonitrile and 4-methoxy-benzenemethanamine and heated in a microwave for 20 minutes at 190° C. to produce 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S (yield of 40%). The 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S is reacted in a solution of dichloromethane and trifluoroacetic acid to produce 2-fluoro-4-amino-N-methylbenzamide T (yield greater than 95%). The 2-fluoro-4-amino-N-methylbenzamide T is reacted with a solution of sodium cyanide and cyclobutanone to produce 4-(1-cyanocyclobutylamino)-2-fluoro-N-methylbenzamide B.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:19])([F:20])[F:18])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 80 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using 4-aminotetrahydropyran instead of methylamine (2 M in THF), to the title compound (94 mg, 80%) which was obtained as a white solid. MS: m/e=466.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CNCCNC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCNCC3)cc21
Temperature: 140 °C
Yield: 40.2 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Med Chem.. 23. 1358 (1980)] (2.7 g, 10 mmol) and homopiperazine, (5.0 g, 50 mmol) was heated at 140° C. for 51/2 hours. The excess homopiperazine was removed by distillation at 85°-95° C./10 mm Hg. The residue was triturated with water and filtered. The solid collected was dissolved in glacial acetic acid (1.5 mL), water (10 mL) was added, and the pH was adjusted to 8.0 with solid sodium bicarbonate. The resulting precipitate was collected by filtration, washed with water (3×5 mL) and air dried to give the product as a white crystalline solid (1.34 g, 40% yield): mp 196°-198° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1.C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18]>CC(C)=O>[NH2:1][C:2]1[N:3]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: N#Cc1nc(N)[nH]c1C#N
Reactant: CCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCOC(=O)n1c(N)nc(C#N)c1C#N

Procedure:
2 g of 2-amino-4,5-dicyanoimidazole was dissolved in 20 ml of suspension of acetone containing 1.3 g of sodium bicarbonate and then 2.1 g of n-butyl chloroformate was added dropwise to said solution at a room temperature. The resulting solution was refluxed during 30 minutes, and white crystal was separated out when the rection mixture was poured into ice-water. After recrystallizing the crude product from methanol, 2.7 g of the purified compound having a melting point of 170° to 172°C was obtained as needles (Yield rate: 77%).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C(O)(=O)C>CO.O>[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CCCCCCCCC(=O)/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCC(O)/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
483 mg of sodium borohydride is added to a solution of 6.5 g of the above-produced ketone in 270 ml of methanol under argon at 0° C. and stirred for one hour at this temperature. Then, it is mixed with 1.5 ml of glacial acetic acid, diluted with 150 ml of water and extracted three times with 200 ml of ethyl acetate each. The organic phase is washed neutral with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-20% ethyl acetate, 5.65 g of 1-[3-(tert-butyldimethylsilyloxymethyl)-phenyl]-(1E)-undecen-3-ol is obtained as colorless oil.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][P:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:28])[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OP(=O)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Kurumada T. et. al., loc. cit., and diphenylphosphinic chloride in a procedure otherwise similar to that for preparing the compound 101 gives an 84% yield of the compound 116 which is obtained in the form of colourless crystals; melting point: 169–173° C. (dichloromethane/hexane).