Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[C:25]#[N:26]>>[C:25]([C:24]1[CH:27]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:21]=[CH:22][C:23]=1[F:28])#[N:26]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cc(N)ccc1F
Agent: [Na+]
Product: N#Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 22.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 163 mg of 5-amino-2-fluorobenzonitrile in place of the 3-(tert-butyl)aniline. The reaction mixture is concentrated to dryness under reduced pressure and the residue is then purified by silica column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 90/10 in dichloromethane of 0% to 100%. 81 mg of N-(3-cyano-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an amber solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C>[OH:1][C:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:26])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
To a solution of 0.6 g of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 31/2 hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanol-butanone to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, M.P. 195°-197° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][N:16]([CH3:18])[CH3:17])[CH:6]=[CH:7][CH:8]=1>Br>[CH3:18][N:16]([CH2:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH3:17]
Reactant: COc1cccc(C2CCCCC2CN(C)C)c1
Agent: Br
Product: CN(C)CC1CCCCC1c1cccc(O)c1

Procedure:
125 g (440 mmole) of the precursor 1-(2-(3-methoxyphenyl)cyclohexyl)-N,N-dimethylmethaneamine and 500 ml of hydrobromic acid (47%, in water) were introduced together into a single necked flask and stirred under reflux for 2 hours using a magnetic stirrer. After conclusion of the reaction, the hydrogen bromide was distilled off by applying a vacuum (water-jet pump). The distillation residue was added to 250 ml water, and the suspension was covered with a layer of 1000 ml ethyl acetate. The pH of the reaction mixture was adjusted to pH 8 with aqueous sodium-hydroxide solution (c=32% w/w), accompanied by cooling of the reaction mixture with ice. Organic and aqueous phases were separated, the aqueous phase was extracted three times with 350 ml portions of ethyl acetate. In the process, the pH value was monitored and maintained at a value of at least pH 8 using aqueous sodium-hydroxide solution (c=32% w/w). The mixture was extracted two more times with 150 ml portions of ethyl acetate, and the organic phase was dried with MgSO4. The solvent was removed in a rotary evaporator (bath temperature 44° C., vacuum <20 mbar). The yield of crude product 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol amounted to 101 g. The crude product 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol was added to 100 ml acetone and stirred until the light-brown material solidified. Subsequently the material was filtered out by suction and washed with a little diethyl ether. The yield amounted to 48%, relative to the quantity of crude product employed.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:14][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1
Reactant: Cc1nc2ccc(CO)cc2o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(CBr)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (2-methyl-1,3-benzoxazol-6-yl)methanol (66.5 mg, 0.408 mmol) in toluene (1 mL) were added carbon tetrabromide (135 mg, 0.408 mmol) and triphenylphosphine (106 mg, 0.408 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was directly applied to silica gel, and concentrated to dryness to give 6-(bromomethyl)-2-methyl-1,3-benzoxazole as an oil. To the obtained oil (92.0 mg, 0.408 mmol) were added DMF (4 mL), N-[1-(5-hydroxy-1-benzofuran-2-yl)ethyl]acetamide (30.0 mg, 0.136 mmol) obtained in Reference Example 38 and potassium carbonate (37.8 mg, 0.274 mmol), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was directly purified by basic silica gel column chromatography (hexane:ethyl acetate-4:1 to 3:7), and the solvent was evaporated. The residue was triturated with a small amount of ethyl acetate and diethyl ether to give the title compound (17.8 mg, yield 36%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].Cl[CH2:17][CH2:18][CH2:19][Si:20]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:22]>C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][CH2:18][CH2:19][Si:20]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:22])=[CH:3][CH:4]=1)=[O:7]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CO[Si](CCCOc1ccc(C=O)cc1)(OC)OC
Yield: 85 %

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 62.2 g (0.55 mole) p-hydroxybenzaldehyde, 112 cc dimethylsulfoxide, 120 cc toluene and 43.2 g of a 50% aqueous sodium hydroxide solution containing 0.54 mole NaOH. All of the water present was removed by azeotropic distillation at a temperature of about 110° to 115° C. The reaction mixture was heated to the boiling point during the gradual addition of 109 g (0.55 mole) of 3-chloropropyl trimethoxysilane. The product, 3(p-formylphenoxy)propyl trimethoxysilane, was isolated by filtration and removal of the solvents from the recovered liquid phase under reduced pressure, followed by fractional distillation of the residue. The fraction boiling at 208° C. at a pressure of 3 mm of mercury was collected (85% yield, based on silane). The infrared and nuclear magnetic resonance spectra of the distillate confirm the proposed structure ##STR17## The vapor phase chromatogram of the product indicated a purity of greater than 98%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][CH2:13][OH:14].CO.C1C(=O)N(Br)C(=O)C1>ClCCl>[CH3:10][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:14][CH2:13][CH2:12][CH2:11][O:9]1
Reactant: OCCCO
Reactant: CC(=O)c1ccc(C)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C2(C)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 25 %

Procedure:
To a stirred mixture of 4-methylacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-1,3-dioxane (22) as a colourless oil (480 mg, 24%). 1H nmr (200 MHz, CDCl3) 1.50 (s, 3H, CH3), 1.96-2.25 (m, 2H, OCH2CH2CH2O), 2.37 (s, 3H, ArCH3), 3.70-4.00 (m, 4H, OCH2CH2CH2O), 7.23 (d, J=8.3 Hz, 2H, 2×ArH), 7.33 (d, J=8.3 Hz, 2H, 2×ArH).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: NCc1ccncc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccncc3)n2)cc1
Yield: 57 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-pyrimidine (0.10 g, 0.26 mmol) in MeCN (4 ml) was added 4-(aminomethyl)-pyridine (0.14 ml, 5 eq) and the resultant solution heated under reflux for 18 h. The cooled reaction mixture was concentrated in vacuo and purified by SPE chromatography using chloroform, diethyl ether, ethyl acetate, acetone and methanol as the eluotropic series of solvents. Concentration in vacuo of the combined fractions containing pure product gave the title compound as a colourless solid (0.061 g, 57%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[NH:5][C:4](=[O:19])[CH:3]1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].[H-].[Na+].Br[CH2:33][C:34]([N:36]([CH:43]([CH3:45])[CH3:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>CN(C)C=O>[O:19]=[C:4]1[N:5]([CH2:33][C:34]([N:36]([CH:43]([CH3:45])[CH3:44])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2](=[O:1])[CH:3]1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: O=C(Nc1ccccc1)NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Yield: 45.4 %

Procedure:
To a solution of 1-(2, 4-dioxo-1-phenyl-2,3,4,5-tetrahydro-1H-benzo [b][1, 4]-diazepin-3-yl)-3-phenyl urea (0.100 g.) in N,N-dimethylformamide (2 ml) cooled to 3° C., was added sodium hydride (0.0104 g; 60% suspension in mineral oil) with stirring. The mixture was stirred 20 minutes, then 2-bromo-N-isopropyl-N-phenyl acetamide (0.0656 g) was added in one portion. The resultant mixture was stirred at ambient temperature overnight. The crude reaction mixture was purified by preparative RP-HPLC with a gradient elution of 60-72% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to provide the title compound (0.0653 g) as a white powder. 1H NMR (300 MHz, DMSO-d6): d 0.95 (d, J=7.3 Hz, 3H), 0.98 (d, J=7.3 Hz, 3H), 4.19 (d, J=16.6 Hz, 1H), 4.48 (d, J=16.9 Hz, 1H), 4.79 (m, 1H), 5.04 (d, J=7.8 Hz, 1H), 6.87-6.92(m, 1H), 6.95(d, J=7.6 Hz, 1H), 7.18-7.57 (m, 17H), 9.14 (s, 1H); MS (FAB): m/z=562 (MH+); TLC (CH2Cl2 /CH3OH, 19:1): Rf =0.19; RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 60-72% CH3CN in H2O with 0.1% TFA buffer;, 30 minutes; 1 ml/min): tf =17.5 min (t0 =2.5 min); m.p.: 230°-235° C.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].F>>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([C:14](=[O:16])[CH3:15])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: F
Product: CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 24 °C
Yield: 99.25 %

Procedure:
To a frozen solution of 1.70 g. (0.010 mole) diphenyl ether in 1.30 g. (0.012 mole; a 20 mole % excess) acetic anhydride, was added 3.0 ml anhydrous hydrogen fluoride (50% by weight of reactants). A magnetic stirrer was added and the reaction mixture was stirred magnetically and degassed several times while warming to 24° C. in air, and stirred for 18 hours at 24° C. The resultant red solution was poured into a plastic beaker and allowed to evaporate in an air stream/24° C., leaving a crystalline residue. This was crushed in ca 30 ml ice water, collected by filtration, partly air dried and further dried at 40° C. under a vacuum for about 2 hours, yielding 2.0 g. (94.2%) of nearly colorless crystals with a yellow tinge. Analysis showed only 0.73% unreacted diphenyl ether or 99.25% yield of p-phenoxyacetophenone by gas-liquid chromatography GLC. Thin layer chromatography (TLC) showed a very weak fast moving impurity spot corresponding to diphenyl ether while no trace of a slower moving spot which would correspond to a diacylation product was observed. The product had a melting point of 47°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(Cl)cc2)cc1

Procedure:
Reaction of p-chlorobenzoyl chloride with 2-p-methoxyphenylbenzofuran gave 3-p-chlorobenzoyl-2-p-methoxyphenylbenzofuran.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24].[OH-].[Na+]>O1CCOCC1.[Na].O>[C:7]1([CH:2]([NH:1][S:23]([C:16]2[C:17]([Cl:22])=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])(=[O:25])=[O:24])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium. hydroxide and 1.95 g of 2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are gradually added, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 100 ml of water, extracted twice with EtOAc and acidified to pH=2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40° C. 2.09 g of the expected product are obtained, m.p.=218-219° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (80 mg, 90%), MS (ISP) m/z=356.3 [(M+H)+], mp 330.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (S)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of toluene was cooled to −20° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 91% (2R,3S)/(2S,3S)=92/8). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.10 (s, 6H), 0.92 (s, 12H), 3.85 (d, 1H, J=12.0 Hz), 4.07 (d, 1H, J=12.0 Hz), 4.35 (q, 1H, J=6.6 Hz), 6.77-6.79 (m, 1H), 6.93-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.O.[CH2:10](Cl)Cl>>[CH3:10][O:8][C:5]1[CH2:6][CH2:7][O:1][CH2:2][CH2:3][N:4]=1
Reactant: O=C1CCOCCN1
Reactant: ClCCl
Solvent: O
Product: COC1=NCCOCC1

Procedure:
A solution of 1,4-oxazepan-5-one (1 g, 8.7 mmol) and (CH3)3O+BF4− (1.9 g, 12.8 mmol) in DCM (30 mL) was stirred at room temperature for 20 h. The reaction mixture was then poured into water (60 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:22]OC)[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)[Br:26]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:22][Br:26])[CH:10]=1)=[O:5])[CH3:2]
Reactant: BrB(Br)Br
Reactant: CCOC(=O)c1cc(-c2sc(-c3ccccc3)nc2COC)n[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2sc(-c3ccccc3)nc2CBr)n[nH]1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
A −78° C. solution of the above-prepared 5-(4-methoxymethyl-2-phenyl-thiazol-5-yl)-2H-pyrazole-3-carboxylic acid ethyl ester (1.5 g, 4.37 mmole, 1.0 eq) in dry CH2Cl2 (20 ml) was treated with a solution of 1.0M BBr3 in CH2Cl2 (5.24 ml, 5.24 mmole, 1.2 eq) and the mixture stirred at −78° C. for 45 minutes, then allowed to warm to room temperature and stirred for one hour. The reaction mixture was quenched by adding saturated NaHCO3, stirred for 30 minutes then extracted twice with CH2Cl2. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid. Silica gel chromatography using a gradient elution of (3:2)-(1:1) hexanes-ethyl acetate provided 610 mg (36%) of the title compound as an off white solid. 1H NMR(CDCl3): δ 1.4 (t, 3H), 4.4 (q, 2H), 4.9 (s, 2H), 7.2 (s, 1H), 7.4 (m, 3H), 7.95 (m, 2H), 11.1 (bs, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9].[H-].[Na+].[NH2:12]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:12][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9]
Reactant: N#Cc1c[nH]c(C#N)c1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)n(N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of DMF (100 mL) was added 1H-pyrrole-2,4-dicarbonitrile (1.00 g, 8.54 mmol) followed by NaH, 60% dispersion in mineral oil (0.51 g, 12.8 mmol). The solution was stirred at rt for 15 min and then (aminooxy)(diphenyl)phosphine oxide (2.99 g, 12.8 mmol) was added, and the solution was heated to 80° C. for 2 h. Upon cooling to rt the solution was filtered washing with CH2Cl2. The solution was partially concentrated and a white precipitate formed which was filtered. The mother liquor was then evaporated under vacuum and subsequently purified by MPLC (Isco) 100% CH2Cl2 ramping to 9:1 v/v CH2Cl2-EtOAc. The resulting purified fractions were combined and concentrated in vacuo yielding 0.92 g of a white solid (6.98 mmol, yield 82%). 1H-NMR (DMSO-d6) (17.92 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 6.66 (s, 2H); MS [M+H]+=133.0; LCMS RT=0.96 min.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:31]([O:33]CC)=[CH2:32])[C:27](=[O:36])[N:26]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)(C)(C)C.Cl>C(Cl)(Cl)Cl>[C:31]([C:28]1[C:27](=[O:36])[N:26]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]4)=[CH:14][N:15]=3)[N:21]=[CH:22][C:23]=2[C:29]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
To a solution of (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (394 mg, 0.68 mmol) in chloroform (5 ml) was added hydrogen chloride (2 M ethereal solution, 2.0 ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (239 mg, 0.52 mmol). MS (APCI+) 487, 391, 279 (100); 1H NMR δ(400 MHz, DMSOd6) 8.98 (s, 1H), 8.34 (br, 2H), 7.78-7.73 (m, 2H), 7.51 (br, 1H), 5.89-5.80 (m, 1H), 3.98 (br, 2H), 3.62-3.51 (m, 4H), 2.40-3.23 (m, 2H), 2.44 (s, 3H), 3.34 (s, 3H), 2.25-2.20 (m, 2H), 2.16-2.13 (m, 1H), 1.93 (br, 2H), 1.80-1.78 (m, 2H), 1.61-1.58 (m, 2H); Anal. Calc'd for C24H29N7O2, 2.10 HCl, 2.85H2O, 0.45 C2H5OH: C, 50.16; H, 6.68; N, 16.45; Cl, 12.49. Found: C, 50.37; H, 6.90; N. 16.45; Cl, 12.61.