Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:26]([NH:28][C:29]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:30])[CH3:27]
Reactant: CCN=C=O
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
A solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) in THF (1.5 mL) was added with triethylamine (11 μL, 0.08 mmol) and ethyl isocyanate (40.3 μL, 0.51 mmol), followed by stirring at room temperature for 5 hours. Further, the reaction mixture was added with potassium carbonate, stirred for 30 minutes and added with water. The precipitated solid was collected by filtration and the solid was triturated in ethanol to obtain Compound 21 (53 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>C(C(C)=O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.5 g of 2-hydroxyphenylsulfonamide, 5.5 g of potassium carbonate and 1.7 ml of allyl bromide in 100 ml of methyl ethyl ketone is stirred, under nitrogen, for 1 hour at reflux temperature. The reaction mixture is cooled to room temperature, filtered, and evaporated to dryness. One recrystallisation from ethyl acetate yields 3.27 g of 2-allyloxyphenylsulfonamide with a melting point of 104°-105° C.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>CN(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:9][Si:10]([C:13]#[C:14][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CN(C)C
Product: C[Si](C)(C)C#Cc1ccc(N)cc1
Reaction time: 12 h
Yield: 94.8 %

Procedure:
As shown in the following Reaction 1, 300 mg (1.37 mmol) of 4-iodoaniline was melted in 5 mL of trimethylamine, and 0.20 mL (1.46 mmol, 1.07 eq) of trimethylsilylacetylene, 4 mg (0.0068 mmol, 0.5 mol %) of dichlorobis-(triphenylphosphine)palladium(II), and 2 mg (0.013 mmol, 1 mol %) of copper iodide were added thereto, and then the reaction solution was stirred under nitrogen atmosphere for 12 hours. Next, the reaction solution was filtered with ether, and was extracted with 10 mL of 2M ammonium chloride aqueous solution 2 times and with 1M sodium chloride aqueous solution 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase volume ratio; ethylacetate:n-hexane=1:4) to obtain 246 mg of 4-trimethylsilylethynylaniline with the yield of 98%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 0.24-0.27 (m, 9H), 3.81 (s, 2H), 6.58 (d, 2H), 7.29 (d, 2H)].
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:32][CH:33]([CH3:36])[CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:32]([N:28]1[CH2:29][CH2:30][CH:25]([C:15]2[C:14]([CH2:13][N:12]([CH3:31])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:18][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH2:26][CH2:27]1)[CH:33]([CH3:36])[CH3:34]
Reactant: CC(C)C=O
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN1CCC(c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of (R/S) tert-butyl N-methyl-N-[2-[methyl([[1-(oxan-2-yl)-3-(piperidin-4-yl)-1H-pyrazol-4-yl]methyl])amino]ethyl]carbamate (250 mg, 0.57 mmol, 1.00 equiv) and 2-methylpropanal (62 mg, 0.86 mmol, 1.50 equiv) in 1,2-dichloroethane (15 mL) was added NaBH(OAc)3 (364 mg, 3.00 equiv). The resulting solution was stirred at room temperature overnight and then concentrated under vacuum to give 160 mg of crude (R/S) tert-butyl 2-(((3-(1-isobutylpiperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl(methyl)carbamate as a light yellow oil. LCMS (method A, ESI): RT=1.52 min, m/z=492.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C@@H:7]1[NH2:12])=[O:5].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C@@H:7]1[NH:12][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)=[O:5]
Reactant: COC(=O)[C@@H]1CCC=C[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC=C[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 316.7 %

Procedure:
The crude cis-2-amino-cyclohex-3-enecarboxylic acid methyl ester hydrochloride (2.8 mmol) was dissolved in methanol (5 mL). 4-Fluoro-benzaldehyde (37.3 mg, 0.3 mmol) was added, followed by 4 Å molecular sieves (0.5 g) and sodium acetate (0.46 g, 5.6 mmol). After stirring at 25° C. for 15 min, sodium cyanoborohydride (0.37 g, 5.9 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL), followed by saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, cis-2-(4-fluoro-benzylamino)-cyclohex-3-enecarboxylic acid methyl ester (250 mg, 0.95 mmol, 34%), as a clear oil. LC-MS (ESI) calcd for C15H18FNO2 263.13, found 264.04 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=1)C.O.[OH-].[Na+].C(O)(=O)C>C(O)C>[CH3:15][O:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)c1ccc(C)c(OCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COCOc1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-methoxymethoxy-4-methyl-benzoic acid ethyl ester (4.5 g, 20 mmol) (from Example 3 supra) in a mixture of ethanol (50 mL), water (20 mL) and 1 N aqueous sodium hydroxide (30 mL) was stirred at room temperature for 18 hours. Mixture was concentrated to remove most of the ethanol. Resulting aqueous solution was acidified with acetic acid (2.5 g, 41.6 mmol). After standing for another 30 minutes, the precipitate formed was collected by filtration, washed with water and dried to give 3-methoxymethoxy-4-methyl-benzoic acid as a white powder. (Yield 3.82 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[CH:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
Reactant: COc1ncc(Cl)cc1NC1CN(C(=O)OC(C)(C)C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2ccnc(F)c2)cc1NC1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of tert-butyl 3-((5-chloro-2-methoxypyridin-3-yl)amino)azetidine-1-carboxylate (2.00 g, 6.37 mmol) in dioxane/water (5:1, 38 mL) was added 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.85 g 8.29 mmol), Xphos-Pd-G2 (125 mg, 0.159 mmol), and K3PO4 (2.90 g, 13.7 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 1 h. After cooling to RT, the reaction mixture was filtered and washed with ethyl acetate (100 mL). The organic layer was washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to obtain 2.4 g of tert-butyl 3-((2′-fluoro-6-methoxy-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate as a white yellow solid (100%): 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.3 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.24 (dt, J=5.5, 1.6 Hz, 1H), 6.96 (t, J=1.5 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 4.60 (d, J=6.5 Hz, 1H), 4.29 (dd, J=8.9, 7.1 Hz, 2H), 4.19 (qd, J=6.7, 5.7, 1.9 Hz, 1H), 3.99 (s, 3H), 3.75 (dd, J=9.1, 4.7 Hz, 2H), 1.38 (s, 9H); MS (ES) m/z 375 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Br)=[CH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c(Br)cn1
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: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)c1cc(C)c(C=C(C)C)cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
To a solution of 5-bromo-4-methyl-pyridine-2-carboxylic acid ethyl ester (4.03 g, 16.5 mmol) in DME (43 mL), 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (5.36 g, 16.5 mmol) followed by 2 N aq. K2CO3-solution (16 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (343 mg, 0.297 mmol) is added. The mixture is stirred at 80° C. for 6 h before it is cooled to rt, diluted with diethyl ether (50 mL), washed with sat. aq. NaHCO3-solution (3×30 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 4-methyl-5-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (1.33 g) as a yellow oil; LC-MS: tR=0.87 min, [M+1]+=220.08.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[CH:17])[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2].[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:29]=[CH:28][C:27](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:25]=[CH:26][C:27]([C:17]#[C:16][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]3[C:11](=[O:13])[CH2:10][CH2:9][C:8]([CH3:14])([CH3:15])[C:7]=3[CH:6]=2)=[CH:28][CH:29]=1)([CH3:23])[CH3:22]
Reactant: C#Cc1cc(CC)c2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C#Cc2ccc(C(C)(C)C(=O)OC)cc2)cc2c1C(=O)CCC2(C)C

Procedure:
Following General Procedure B and using 8-ethyl-6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 180, 0.09 g, 0.39 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.152 g, 0.5 mmol), triethyl amine (8 mL), copper(I)iodide (0.024 g, 0.12 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.087 g, 0.12 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 2–10% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.095 g, 59%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[C:24]([C:10]1[C:9]([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[N:11]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CC(C)(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2C(C)(C)C)C2CCCCC2)cc1
Yield: 16.3 %

Procedure:
Using cyclohexyl{3-tert-butyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.52 g) synthesized in Example 13(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.34 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.13 g, 16%) was obtained as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:27])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:7]=1)=O)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[O-]S([O-])(=O)=O.[Mg+2].[NH4+].[Cl-]>ClCCl.CO>[CH3:11][C:9]1[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:27])([F:28])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(CO)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a cold (0° C.) solution of ethyl-5-methyl-1-[2′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]1H-pyrazole-3-carboxylate (EXAMPLE 3) (1.1 g, 2.82 mmol) in anhydrous dichloromethane (10 mL) was added DIBAL-H in toluene solution (1.0M, 6.8 mL, 6.8 mmol). The reaction was stirred at 0° C. for 30 minutes, then 0.5 mL of methanol was added. The reaction was warmed up to room temperature, and stirred continuously for another 30 minutes. After the addition of 5 g of Celite and 5 g of anhydrous MgSO4, the saturated NH4Cl aqueous was added dropwise. The resulting slurry was stirred vigorously for an hour. Then the mixture was filtered and concentrated to give the crude product. The crude alcohol obtained was purified by flash-column chromatography on silica-gel to provide the pure titled product as a yellow oil (0.9 g, 93% yield).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5](S(C)(=O)=O)=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].[CH3:34][NH2:35].CCCCCC>CN(C1C=CN=CC=1)C.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5]([NH:35][CH3:34])=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CN
Reactant: COC(=O)c1ccc(C)c(-n2c(S(C)(=O)=O)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CNc1nc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)OC)ccc1C
Temperature: 25 °C

Procedure:
Methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylsulfonyl)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (0.35 g, 0.64 mmol), DMAP (0.01 g, 0.06 mmol), and methylamine (0.97 mL of a 2M solution in THF, 1.93 mmol) were combined and stirred at ambient temperature. Reaction complete after 4 h. Washed with 5% citric acid, extracted in DCM, dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a brown film. Dissolved in a small amount of DCM, added hexane, and cooled. Filtered precipitate and washed with a solution of cold 50% DCM/hexane. Dried resulting white solid in vacuo (0.22 g, 69%). 1H NMR (CD3OD/400 MHz) δ8.04 (m, 1H), 7.77 (s, 1H), 7.58 (q, 1H, J=8.8 Hz), 7.53 (d, 1H, J=8.4 Hz), 6.99 (m, 2H), 5.52 (s, 2H), 3.87 (s, 3H), 2.84 (s, 3H), 2.10 (s, 3H). ESHRMS m/z 494.0523 (M+H calculated for C2H19BrF2N3O4 requires 494.0522).
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:21][C@@H:22]([C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(O)(C)C>[C:16]([O:21][C@@H:22]([C:24]1[N:25]=[C:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[O:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:14]=4[N:15]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][N:29]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1cc2nc(N3CCNCC3)oc2cn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4ccncc4o3)CC2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 2-(1-piperazinyl)oxazolo[5,4-c]pyridine (775 mg, 3.8 mmol; J. Org. Chem. 1995, 60, 5721) in isopropanol (38 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2×; 3% methanol/chloroform then 6→8% methanol/ethyl acetate, where used herein, the arrow symbol, →, indicates a gradient) to give 1.2 g (79%) of the title compound of Example 2, Step A as a pale yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ 8.57 (s, 1H), 8.39 (d, 1H), 8.28 (d, 1H), 7.30 (d, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH3:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:26][CH:27]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Cc1ccc(Cn2cnc(N)n2)cc1
Product: Cc1ccc(Cn2cnc(NC3CCN(c4nc(C)ns4)CC3)n2)cc1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-methyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4](Cl)[N:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][CH3:17])=[O:15])[C:5]([C:8]#[N:9])=[CH:6][N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C#N

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-cyanopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave—20° C., 10 minutes) to afford 2-(2-chloro-5-cyano-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid. Mp: 228-32° C. (dec); MS: 288.26 (M+H); 1H NMR (chloroform-d): δ 12.49 (s, 1H), δ 8.69 (d, J=8 Hz, 1H), δ 8.50 (s, 1H), δ 7.57 (m, 2H), δ 7.22 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.08 (d, J=5 Hz, 3H).
Reaction SMILES: [CH2:1]([S:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:19])[C:14]([O:16]CC)=[O:15])[N:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[OH-].[Na+].Cl>>[CH2:1]([S:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:19])[C:14]([OH:16])=[O:15])[N:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)Nc1nc(C(=O)C(=O)OCC)cs1
Agent: CCCS(=O)(=O)N=c1[nH]c(C(=O)C(=O)OCC)cs1
Agent: Cl
Agent: [Na+]
Product: CCCS(=O)(=O)Nc1nc(C(=O)C(=O)O)cs1
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(2-propanesulfonylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (12.0 g.) and 1N sodium hydroxide aqueous solution (93 ml.) was stirred for 1 hour under ice-cooling. After the reaction, to the reaction mixture was added 1N hydrochloric acid (93 ml.) and the mixture was extracted with ethyl acetate under saturation with sodium chloride. The extract was washed with a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off from the extract, and the residue was washed in diethyl ether, collected by filtration and dried to give 2-(2-propanesulfonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (7.3 g.), mp. 148° to 150° C.
Reaction SMILES: [Li+].[Cl-].[CH2:3]([C:10]1[CH:11]=[C:12]([O:24][CH3:25])[CH:13]=[CH:14][C:15]=1OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH2:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:28]([C:15]1[CH:14]=[CH:13][C:12]([O:24][CH3:25])=[CH:11][C:10]=1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:27]=[CH2:26]
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1ccc(OC)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
LiCl (3.08 g, 72.8 mmol) in a roundbottom flask was flame-dried in high vacuum, and the system was allowed to cool to RT under argon. 3-Benzyl-4-(trifluoromethanesulfonyloxy)anisole (21.0 g, 60.6 mmol), bis(triphenylphosphine)palladium(II) chloride (2.13 g, 3.0 mmol), anhydrous DMF (150 mL), and allyltributyltin (22.6 mL, 72.8 mmol) were added, and the mixture was purged with argon through three evacuation/argon flush cycles. The mixture was heated in an oil bath preset at 95° C., affording a yellow, homogeneous solution. After 1.5 h, the dark mixture was concentrated on the rotavap (high vacuum), and the residue was reconcerntrated from xylenes. The resulting residue was taken up in Et2O (120 mL) and stirred briskly with 10% KF (120 mL) for 0.5 h. The layers were separated, and the aqueous layer was extracted with Et2O (2×120 mL). The combined organics were filtered through celite® to remove the insoluble solids, and the filtrate was washed sequentially with H2O (60 mL) and brine (60 mL). Drying (MgSO4) and concentration left a cloudy, yellow oil. Chromatography (silica gel, 5% EtOAc/hexanes) gave the title compound as a light yellow oil (14.21 g, 98%): TLC Rf (5% EtOAc/hexanes) 0.51; 1H NMR (250 MHz, CDCl3) δ 7.03-7.31 (m, 6H), 6.74 (dd, J=8.3, 2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 5.79-5.98 (m, 1H), 4.89-5.07 (m, 2H), 3.97 (s, 2H), 3.75 (s, 3H), 3.21-3.33 (m, 2H); FTIR (CCl4) 1610, 1496, 1256, 1046, 914 cm-1 ; MS (ES) m/e 239.2 (M+H)+.