Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Yield: 84.5 %

Procedure:
4-Cyanophenol (95.2 g), benzyl chloride (127 g) and potassium carbonate (138 g) are refluxed in acetone (160 ml) for 5 hours. The product is separated by filtration, concentrated under reduced pressure, and thereto is added benzene. The mixture is washed with water, and benzene is distilled off under reduced pressure to give 4-benzyloxybenzonitrile (141.38 g). The 4-benzyloxybenzonitrile (141 g) is dissolved in benzene (338 ml) and thereto is added ethanol (270 ml), and the mixture is cooled to 0° C. Into the resulting slurry is bubbled hydrogen chloride gas (36 liters) with stirring, and thereafter, the temperature is raised to 25° C., and the mixture is allowed to stand for 2 days. The reaction mixture is concentrated under reduced pressure until 1/3 volume, and to the concentrated mixture is added ether. The precipitated crystals are separated by suction filtration to give an imide ester (183 g).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1I.C([Li])CCC.CN(C)[CH:17]=[O:18]>C(OCC)C>[Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:17]=[O:18]
Reactant: Cc1c(I)sc(I)c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(I)sc(C=O)c1Br
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
A suspension of 3-bromo-2,5-diiodo-4-methylthiophene (43 g, 100 mmol) in diethyl ether (300 mL) was treated with an etheral solution of 2.5 M butyllithium (40 mL, 100 mmol) during 5 min at −70 to −60° C. After 10 min, the mixture was treated with N,N-dimethylformamide (11 mL, 140 mmol) and the cooling bath was removed. Upon warming to 23° C., the mixture was quenched with 10% aqueous NH4Cl (500 mL) and extracted with ethyl acetate (3×500 mL). The combined extracts were washed with water and brine (500 mL each), dried (MgSO4) and concentrated in vacuo to give the crude product (31 g) as a rust-colored solid which was recrystallized from hot ethyl acetate. Vacuum filtration gave the title compound (25 g, 76%, m.p. 152-53° C.) as rust-colored needles.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:31])([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:12]([N:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[O:13]>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:13][C:12]([C:11]([F:10])([F:31])[C:24]([F:29])([F:30])[C:25]([F:27])([F:28])[F:26])=[N:14][C:15]([C:20]([F:23])([F:22])[F:21])([C:16]([F:19])([F:18])[F:17])[N:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(Br)cc1
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)C(F)(F)C1=NC(C(F)(F)F)(C(F)(F)F)N=C(c2ccc(Br)cc2)O1
Temperature: 60 °C
Yield: 100.4 %

Procedure:
4-Bromobenzonitrile (0.3 g, 1.65 mmol) and 2,2,3,3,4,4,4-heptafluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl)ethylidene}butanamide (1.2 g, 3.3 mmol) were dissolved in diethyl ether (4.0 mL) and heated in a sealed glass tube to 60° C. for 17 hours. The solvent and excess reagent were distilled off to give a colorless liquid (0.9 g, 100 percent yield). EIMS (m/z): 543 (M+), 524 (M-F), 474 (M-CF3).
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH3:3].[CH:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:12]([CH:15]1[O:10][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:7])[O:8]1)([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(O)CCC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CCC(C)(C)OC(C(C)(C)C)O1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 730 g (5 mol) of 2,5-dimethylhexane-2,5-diol, 3 g of p-toluenesulfonic acid, 430 g (5 mol) of pivalaldehyde and 1 l of toluene was refluxed for 4 hours (h) during which the water of reaction produced (90 ml) was removed. The reaction mixture was then cooled down to room temperature (RT) and stirred up with 10 ml of 25% strength aqueous sodium hydroxide solution, the phases were separated, the organic phase was washed with a little water until neutral, and the toluene was then removed at 50°-60° C. The residue obtained was fractionated under reduced pressure affording 909 g (4.25 mol) of 2-tert.-butyl-4,4,7,7,-tetramethyl-1,3-dioxacycloheptane (boiling point 54° C./0.2 mbar). This corresponds to a yield of 85% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][N:23]2[C:31](=[O:32])C3C(=CC=CC=3)C2=O)[C:19](C(OCC)=O)=[C:18]([NH:39][C:40]2[CH:41]=[C:42]([CH3:46])[CH:43]=[CH:44][CH:45]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[O:32]=[C:31]1[C:19]2[C:18]([NH:39][C:40]3[CH:41]=[C:42]([CH3:46])[CH:43]=[CH:44][CH:45]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:21][C:20]=2[CH2:22][NH:23]1
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Temperature: 65 °C
Reaction time: 12 h
Yield: 44.2 %

Procedure:
A mixture of ethyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-((1,3-dioxoisoindolin-2-yl)methyl)-6-(m-tolylamino)pyrimidine-5-carboxylate (109 mg, 0.174 mmol) and hydrazine hydrate (36.5 mg, 0.729 mmol) in EtOH (2 mL) was stirred at 65° C. for 12 h. After cooling, the mixture was concentrated under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3, water, and brine, were filtered through SiO2, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOAc/hexanes and filtered to give the title compound (34.8 mg). The filtrate was concentrated and triturated with IPE to give a second batch (20.3 mg) of the title compound (total 65.1 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.79 (m, 17H), 2.32 (s, 3H), 3.84 (br s, 1H), 4.06 (br s, 1H), 4.14 (s, 2H), 6.55-6.70 (m, 1H), 6.87-7.04 (m, 2H), 7.20-7.24 (m, 1H), 7.40-7.48 (m, 1H), 7.68-7.80 (m, 1H), 8.01-8.06 (m, 1H), 8.56-8.59 (m, 1H). [M+H] calc'd for C24H33N6O3, 453; found, 453.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:17]=[N+:18]=[N-:19])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Agent: [Na+]
Product: COc1ccc(CCCN=[N+]=[N-])cc1
Yield: 75 %

Procedure:
Azide 12 was prepared according to procedure C from 11 (8.8 g, 0.036 mol) and sodium azide (3 g, 0.045 mol) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.90 (m, 2H), 2.65 (t, 2H), 3.28 (m, 2H), 3.80 (s, 3H), 6.85 (d, 2H), 7.10 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27]([OH:29])[CH3:28]>>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:29][CH2:27][CH3:28])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(N)=O)c1ccc2c(c1)Oc1ccccc1CC2=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc2c(c1)Oc1ccccc1CC2=O
Reaction time: 5 h

Procedure:
To 50 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-3-yl)-propionamide in 2 ml of ethanol was added 0.2 ml of conc. sulfuric acid and the mixture was refluxed with stirring for 5 hours. The solvent was distilled off to obtain the residue, which was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow oil, which was chromatographed over silica gel, eluted with chloroform and there was obtained 55 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-3-yl)-propionate as pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(NCCC[CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=O>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:33][C@H:32]([C:34]([OH:36])=[O:35])[CH3:31])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
N-Benzyloxycaronbyl-L-phenylalanyl-Nε -trifluoroacetyl-L-lysine (m.p. 143°-147° C.) from N-benzyloxycarbonyl-L-phenylalanine and Nε -trifluoroacetyl-L-lysine (A. T. Moore, et al., J. Chem. Soc. (C), 2349-2359 (1966)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.N[C:21]1N=C(C2C=C(Br)C=CC=2O)C=[C:23](Cl)[N:22]=1.CN(C)CCCO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][N:22]([CH3:23])[CH3:21])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Agent: CN(C)CCCO
Product: CN(C)CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 43 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 3-dimethylamino-propan-1-ol provided 4-[5-bromo-2-(3-dimethylamino-propoxy)-phenyl]-6-chloro-pyrimidin-2-ylamine (43% yield).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH3:25])[CH:19]=1)=O>CC(C)=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][C:20]=1[CH3:25]
Reactant: Cc1cc(C(=O)CBr)ccc1Cl
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(Cl)c(C)c3)cs2)c(C)s1
Yield: 70.5 %

Procedure:
155 mg (0.627 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 10 mL of reagent grade acetone. 2-Bromo-1-(4-chloro-3-methylphenyl)ethan-1-one (0.658 mmol; 163 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the reaction mixture was concentrated and dissolved in 50 mL of CH2Cl2. The organic layer was washed with 50 mL of 1N HCl (aq.), dried over sodium sulfate and concentrated. The crude product was purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 168 mg (68% yield) of methyl 4-[4-(4-chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[OH:31][C@@H:27]([CH2:26][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[C:28]([OH:30])=[O:29]
Reactant: COC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: NC[C@H](O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NC[C@H](O)C(=O)O)ncc3c2)cc1
Yield: 45.2 %

Procedure:
A mixture of 4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-2-(S)-hydroxy-propionic acid (97 mg, 0.92 mmol) in 0.5 M NaOMe/MeOH solution (1.23 mL, 0.62 mmol) was microwaved at 120° C. for 2 h. After cooled, solid precipitate was collected and rinsed with cold MeOH (1 mL). Solid was dissolved in water (40 mL), acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was dried over MgSO4, filtered and concentrated to provide the title compound 54 mg (0.14 mmol) in 15% yield. LC-MS ESI−: 397.02 (M−1)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][N:5]=1)[CH3:2].[Br:12]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][Br:12])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1cc(CO)ccn1
Solvent: ClCCl
Product: CCOc1cc(CBr)ccn1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 0.31 g of 2-ethoxy-4-(hydroxymethyl)pyridine in 6 ml of dichloromethane is added dropwise to a solution of 1.025 g of dibromotriphenylphosphorane in 12 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for about 1 hour. The reaction medium is taken up in 100 ml of dichloromethane and then washed with 3×100 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography, using a cartridge 27 mm in diameter packed with 20 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate)(9/1)(v/v) at a flow rate of 8 ml/minute. The fractions between 80 and 180 ml are concentrated under reduced pressure. 0.37 g of 2-ethoxy-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]([O:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:9]([F:33])[CH:8]=1)[CH3:5].COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([O:23][C:18]3[C:17]([C:15]([NH:14][CH2:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:34])=[O:2])=[CH:8][C:9]=4[F:33])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: COC(=O)[C@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: C[C@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.9) was prepared in a manner analogous to that described in Example 1, substituting (S)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid methyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][C:14](OCC)=[N:13][CH2:12][CH2:11]1)=[O:9].O.[NH2:20][NH2:21]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:11][CH2:12][NH:13][CH:14]([NH:20][NH2:21])[CH2:15]1)=[O:9]
Reactant: NN
Reactant: CCOC1=NCCN(C(=O)c2ccccc2Cl)C1
Solvent: O
Solvent: ClCCl
Product: NNC1CN(C(=O)c2ccccc2Cl)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[(2-chlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (I39) (0.755 g, 2.83 mmol) dissolved in Dichloromethane (DCM) (10 mL) was added to hydrazine hydrate (0.220 mL, 7.08 mmol, commercially available from e.g. Alfa Aesar, Acros or Fluka) dissolved in Dichloromethane (DCM) (5 mL) and stirred at 25° C. for 4 hr. The solvents were removed in vacuo and the residue azeotroped with toluene (3×25 mL), to afford product in 715 mg that was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=[O:14]>C1COCC1>[CH3:22][S:21][C:17]1[N:16]=[C:15]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)c1ccnc(SC)n1
Solvent: C1CCOC1
Product: CSc1nccc(C(=O)Cc2ccccc2)n1
Temperature: -78 °C

Procedure:
A solution of benzylmagnesium chloride (4.7 mL, 9.38 mmol, 2 equiv) was added to a solution of N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (1–2, 1.0 g, 4.7 mmol, 1 equiv) in THF (25 mL) cooled to −78° C. The reaction solution was allowed to warm to 0° C. and partitioned between ethyl acetate (2×100 mL) and brine. The organic extracts were combined, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with CH2Cl2 to 15% EtOAc/CH2Cl2 provided 1-[2-(methylthio)pyrimidin-4-yl]-2-phenylethanone (3-1) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, 1H, J=5 Hz), 7.52 (d, 1H, J=5 Hz), 7.25–7.37 (m, 5H), 4.48 (s, 2H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:9]N2C(=O)CCC2=O)=O)[NH:5][CH:6]=1.[Cl-].[C:18]([C:20]1[CH:21]=[C:22]([C:27]#[C:28][CH2:29][NH2+:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])[CH:23]=[CH:24][C:25]=1[F:26])#[N:19].C([O-])(O)=O.[Na+]>CC#N.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N:30]([CH2:29][C:28]#[C:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([C:18]#[N:19])[CH:21]=2)[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])=[O:9])[NH:5][CH:6]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Cl)c[nH]1
Reactant: COc1ccc(C[NH2+]CC#Cc2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN(CC#Cc2ccc(F)c(C#N)c2)C(=O)c2cc(Cl)c[nH]2)c(OC)c1

Procedure:
A solution of F1 (1.5 eq), F2 (1 eq) and NaHCO3 (2.5 eq) in a mixture of CH3CN and H2O (20:1) was heated at reflux for 12 hrs and then the MeCN was removed under reduced pressure. The resulting residue was diluted with DCM, washed with 1N HCl solution (2×) and then with brine; dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by Biotage system eluting with EtOAc/petrol ether to obtain the desired compound. MS (ES) C24H19ClFN3O3 requires: 451, found: 452 (M+H)+. 1H NMR (400 MHz, DMSOd6) δ: 11.92 (1H, br. S), 7.91 (1H, dd, J=6.2, 1.9 Hz), 7.78-7.71 (1H, m), 7.54 (1H, t, J=9.0 Hz), 7.17-7.11 (1H, m), 7.07-7.04 (1H, m), 6.62-6.57 (1H, m), 6.56-6.20 (2H, m), 4.75 (2H, br. S), 4.46 (2H, br. S), 3.81-3.72 (6H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:35][O:34][C:5]2([CH2:33][CH2:32][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4][CH2:3]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[CH3:36][C:2]1([CH3:1])[CH2:3][O:4][C:5]2([CH2:6][CH2:7][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20]([C:38]5[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:32][CH2:33]2)[O:34][CH2:35]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Yield: 71 %

Procedure:
The title compound is prepared from 12,12-dimethyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one and 4-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 7. Yield: 71% of theory; LC (method 3): tR=3.40 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[CH:14]=[N:13][NH:12][C:11]=1[NH2:15].CN1[CH:22]=[CH:21][C:20](=[O:23])N(C)C1=O.[Cl-].[NH4+]>C(O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[CH:14]=[N:13][N:12]2[CH:22]=[CH:21][C:20](=[O:23])[NH:15][C:11]=12
Reactant: Nc1[nH]ncc1-c1cccs1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=c1ccn2ncc(-c3cccs3)c2[nH]1

Procedure:
A 21 wt % solution of sodium ethoxide in ethanol (32.7 mL, 87.6 mmol) was slowly added to an ambient temperature, stirred suspension of 4-thiophen-2-yl-2H-pyrazol-3-ylamine (4.1 g, 25.0 mmol) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione [874-14-6] (3.9 g, 27.5 mmol) in ethanol (217 mL). As addition progressed the solid dissolved to give a clear brown solution. The solution was heated to reflux for 2 d, cooled, then poured into 5% (w/v) aqueous ammonium chloride. Ethanol was evaporated out and the reduced volume product solution chilled, with stirring, in an ice bath to precipitate 3-thiophen-2-yl-4H-pyrazolo[1,5-a]pyrimidin-5-one as 3.2 g of red-brown fine crystalline powder, mp. 231-232° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.13 (br. s., 1 H) 7.10 (dd, J=5.05, 3.54 Hz, 1 H) 7.38-7.46 (m, 2 H) 8.07 (br. s., 1 H) 8.51-8.73 (m, 1 H) 12.06 (br. s., 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 123.66, 127.71, 138.70, 142.47. LRMS (ESI) m/z 218.0 [(M+H)]+, calc'd for C10H7N3OS: 217.25.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCN3CCOCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-morpholin-4-yl-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (30 mg, 0.08 mmol). 8-Cyclohexyl-5-oxo-2-(2-morpholin-4-yl-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (25 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H31N5O4: 430.24 (M+H). Found: 430.2.
Reaction SMILES: [NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([CH2:9][CH2:10][O:11][P:12](=[O:15])([O-:14])[O-:13])#[N:8].[NH+]1C=CC=CC=1.C(CCOP([O-])([O-])=O)#N.[Ba+2].N1C=CC=CC=1>O>[NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([CH2:9][CH2:10][O:11][P:12](=[O:13])([OH:15])[OH:14])#[N:8]
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: [Ba+2]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: N#CCCOP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
According to the method of Tenor (J. Am. Chem. Soc., p. 159-168, 1961), 2-cyanoethylphosphoric acid pyridinium salt was prepared. Namely, 1.61 g of barium 2-cyanoethylphosphate and 10 g of an ion exchange resin (Dowex 50 (hydrogen ion form)) were suspended in water, stirred at room temperature for 30 minutes, 2 ml of pyridine was added to the supernatant, the mixture was washed with water, and the mixture then concentrated to dryness under a reduced pressure, followed by an addition of pyridine to give 1 mmol/ml of 2-cyanoethylphosphoric acid pyridinium solution.