Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:3]([O:7][C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[N:4][O:5][CH3:6].[P:22]([O-:30])([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23].[K+].[I-].[K+]>C(C(C)=O)C>[P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])([O:30][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:3]([O:7][C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[N:4][O:5][CH3:6])=[O:23]
Reactant: CCOP(=O)([O-])OCC
Reactant: CCN(CC)C(=O)OC(=NOC)C(Cl)c1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(OCC)OC(C(=NOC)OC(=O)N(CC)CC)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-Chloro-1-(4-chlorophenyl)-2-(N,N-diethylcarbamoyloxy)-2-methoxyiminoethane (16.6 grams; 0.05 mole), methyl ethyl ketone (100 ml), potassium O,O-diethyl phosphate (9.6 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvents in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[1-(4-chlorophenyl)-2-(N,N-diethylcarbamoyloxy)-2-methoxyiminoethyl] O,O-diethyl phosphate.
Reaction SMILES: [Na].O=[C:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:25]2[NH:24]C(=O)[O:22][C:21](=O)[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:21]2[OH:22]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(Cl)cccc2c(O)c1C(=O)OCC
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a stirred mixture of diethyl oxosuccinate sodium salt (2.31 g, 11.0 mM) in dimethylformamide (20 mL) under a nitrogen atmosphere was added 8-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (2.17 g, 11.0 mM). The resulting mixture was heated slowly to 130° C. and maintained at this temperature for 2.5 hr. After cooling, the reaction mixture was poured into water and the resulting mixture was then extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to obtain an oily solid (1.55 g). This material was chromatographed (eluant: CH2C12 /CH3OH; 98/2) over silica gel to provide the title compound as an oil which slowly crystallized to a tan solid (0.700 g, 19.7%). A 0.150 g portion of this material was recrystallized from toluene/hexane to provide an analytical sample (0.050 g) of the title compound as a tan solid, mp 98°-99° C.; MS(CI): 324 (M+H). Analysis for C15H14NO5Cl·0.1 C6H14Calculated: C, 56.38; H, 4.67; N, 4.21 Found: C, 56.38; H, 4.83; N, 4.19
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26].ClC1C=C(C=CC=1)C(OO)=[O:32].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])(=[O:32])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-methyl-3-{3-[(methylsulfinyl)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.480 g, 1.24 mmol) and 3-chloroperoxybenzoic acid (0.600 g, 60%, 2.10 mmol) in methylene chloride is stirred at room temperature for four hours, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% diethyl ether in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)cnc1Cl
Reaction time: 3 h

Procedure:
Fe powder (9.75 g, 0.174 mol, Sigma-Aldrich) was added in portions over a period of 2 h to a stirred solution of 2-chloro-3-methyl-5-nitropyridine (10 g, 0.058 mol, Combi-blocks) in acetic acid/water (29 mL: 88 mL). After 3 h, the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 6-chloro-5-methylpyridine-3-amine as a brown solid (8.0 g; 97%). MS m/z=142.03 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)[CH2:2][CH3:3].[C:14]([O:18][C:19]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33]Br)=[C:29]([F:35])[CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:11][C:9]([C:7]1[CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])=[CH:28][C:29]=2[F:35])[N:6]=1)=[O:10])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 65 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
Ethyl 3-n-propylpyrazole-5-carboxylate (1.05 g, 5.8 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (2.0 g, 5.8 mmol), and potassium carbonate (1.6 g, 11.5 mmol) were dissolved in DMF (10 mL). The mixture was stirred at 65° C. for 16 hours, then diluted with EtOAc. The organic layer was washed with saturated NaHCO3 and saturated aqueous NaCl, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography (EtOAc in hexanes) to yield 1-(2′-t-butoxycarbonyl-3-fluorobiphenyl-4-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:67]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)(=[O:69])[CH3:68]>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([N:73]3[CH2:74][CH2:75][N:70]([C:67](=[O:69])[CH3:68])[CH2:71][CH2:72]3)=[O:11])=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCN(C(C)=O)CC3)cc2)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
The hydrogenated compound 4 (2.0 g, 4.6 mmol) was dissolved in CH2Cl2 (20 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (0.75 mL, 5.4 mmol) and BOP reagent (2.19 g, 4.96 mmol) were added and the reaction mixture was stirred for 15 min. 1-Acetylpiperazine (1.16 g, 9.02 mmol) was added and the resulting solution was stirred at room temperature for about 2 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (75 mL). The organic layer was extracted with 1.0 N NaOH (1×10 mL), water (2×30 mL) and brine (1×30 mL). Drying and concentration of the organic layer gave the desired amide 18 (2.4 g, ˜96%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 6.87 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.58 (m, 1H), 3.50 (s, 3H), 3.27-3.46 (m, 8H), 3.08-3.13 (m, 1H), 2.77-2.83 (m, 3H), 2.61 (t, J=7.2 Hz, 2H), 1.99 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)n1
Temperature: 75 °C
Yield: 12.1 %

Procedure:
To a solution of 5-chloro-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(6-methyl-pyridin-2-ylmethoxy)-3H-pyrimidin-4-one of Step C (67 mg, 0.16 mmol) in acetonitrile (2 mL) was added 2-hydroxy-2-methylpropionamidine HCl (34 mg, 0.25 mmol) and potassium carbonate (68 mg, 0.49 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (9.5 mg, 12% yield). MS (M+H): 492; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.14 (s, 3H), 2.21 (s, 3H), 2.60 (s, 3H), 4.79 (s, 1H), 5.61-5.74 (m, 2H), 7.13 (d, J=7.43 Hz, 1H), 7.40 (d, J=7.04 Hz, 1H), 7.54-7.58 (m, 2H), 7.68 (s, 1H), 7.93 (s, 1H), 8.14 (d, J=7.83 Hz, 1H), 8.77 (d, J=5.09 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1nccnc1C
Solvent: CC(=O)O
Product: Cc1ncc[n+]([O-])c1C
Temperature: 35 °C
Reaction time: 48 h
Yield: 94.6 %

Procedure:
A mixture of 2,3-dimethylpyrazine (L1) (25 g, 0.23 mol) and 30% H2O2 (52.4 g, 0.46 mol) in acetic acid (74 mL) was stirred for two days at 35° C. The solvent was removed under vacuum. Water was added and the mixture evaporated again. The residue was basified with aqueous K2CO3 and extracted with EtOAc. The organic phases were dried over Na2SO4 and concentrated. The resulting solid combined from two batches was recrystallized from cyclohexane to give 2,3-dimethylpyrazine 1-oxide (L2) (27 g). 1HNMR (CDCl3, 300 MHz) δ 8.18 (d, J=3.9 Hz, 1H), 8.02 (d, J=4.2 Hz, 1H), 2.58 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)Nc1cc(NC(C)(C)C)nc(Cl)n1
Reactant: C1CNCCN1
Product: CC(C)(C)Nc1cc(NC(C)(C)C)nc(N2CCNCC2)n1
Yield: 76.5 %

Procedure:
By reacting 2-chloro-4,6-bis(1,1-dimethylethylamino) -pyrimidine with piperazine as described in Example 4, the title product is obtained in a yield of 76.5%, m.p.: 135°-138° C.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1.[C:18](#[N:20])[CH3:19]>>[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:19][C:18]#[N:20])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(C(=CC#N)c2ccccc2)cc1
Yield: 78 %

Procedure:
To a solution of 6.5 g (0.114 mol) of KOH in 70 mL of acetonitrile was added dropwise under argon a solution of 4-methylbenzophenone (22.5 g, 0.114 mol) in acetonitrile (45 mL). After the addition was complete, the reaction mixture was heated at reflux overnight. It was then allowed to cool, poured into ice and extracted with dichloromethane. The organic phase was dried and the solvent was removed to afford 30 g of a crude product that was chromatographed on silica gel (hexane-ethyl acetate mixtures of increasing polarity) to give 19.5 g of the desired product (yield: 78%).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[N:7](=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)[OH:8]>CCOCC.C(N(CC)CC)C>[CH2:1]([NH:4][C:5]([O:8][N:7]=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN=C=O
Reactant: CC1OCSC1=NO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 3 ml of allyl isocyanate was caused to react with 3 grams of 4-oximino-5-methyl-1,3-oxathiolane dissolved in 50 ml of ether containing 2 drops of triethylamine over a period of 20 hours at room temperature. Conventional workup and recrystallization from isopropyl ether afforded 3 grams of product, mp 66.0°-67.5°, structure confirmed by spectral analysis.
Reaction SMILES: [CH3:1][C:2]#[N:3].CC([O-])(C)C.[K+].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]([OH:15])[CH2:1][C:2]#[N:3])[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(Br)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of THF (200 mL) and CH3CN (7.8 mL, 148 mmol) cooled to −50° C., was added KOtBu (18.16 g, 162 mmol) in portions by maintaining the temperature at −50° C. After stirring for 30 min, 3-bromobenzaldehyde (25 g, 135 mmol) was charged maintaining the same internal temperature. After stirring for 30 min, the reaction mixture was warmed to 0° C. and stirred for additional 3 h. This was recooled to −10° C. and quenched with excess water. Extraction with ethyl acetate yielded the crude product, which was purified by flash chromatography (0 to 20% EtOAc-hexanes gradient) to give 23 as light yellow oil. Yield (21 g, 69%): 1H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.49 (bd, J=7.8 Hz, 1H), 7.47 (bd, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 6.09 (d, J=4.4 Hz, 1H), 4.92 (m, 1H), 2.81-2.95 (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1>C(O)(=O)C>[CH3:1][C:2]1[NH:8][C:9]2=[N:10][CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[C:14]2[N:15]=1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
2.3 mL (24.33 mol) of acetic anhydride are added to a solution, stirred at 15° C., of 1.5 g (9.73 mmol) of 2,3-diamino-5-nitropyridine in 15 mL of acetic acid. After stirring for 15 minutes at room temperature, the mixture is heated at 110° C. for 2 hours and then at 140° C. for 7 hours. The resulting mixture is concentrated under reduced pressure and taken up in 100 mL of water. A precipitate is collected by filtration. After purification by chromatography on a column of silica, 0.4 g of the expected product is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:15][CH:14]([F:16])[C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=3)[CH:7]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.10) (0.19 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.021 g, 9%). MS (ISP) 444.4 [(M+H)+]; mp 210° C.
Reaction SMILES: C[O:2][C:3]([CH:5]([O:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[N:30]=1)[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:3]([CH:5]([O:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[N:30]=1)[C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])([OH:4])=[O:2]
Reactant: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C)nc(OC(C(=O)O)C(OCC(C)(C)C(=O)O)(c2ccccc2)c2ccccc2)n1
Yield: 42.7 %

Procedure:
10.1 g (20 mmol) of methyl 3-[2-methoxycarbonyl-2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-1,1-diphenylethoxy]-2,2-di-methylpropionate were dissolved in 50 ml of dioxane and 50 ml of 2N NaOH solution and stirred at 80° C. for 4 h. The solution was diluted with 300 ml of H2O and extracted with 100 ml of ethyl acetate. The aqueous phase was neutralized with 1N HCl and extracted with ethyl acetate, and the organic phase was dried over MgSO4, filtered and concentrated. The oily residue was crystallized from diethyl ether/hexane to result in 4.1 g (42%) of colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][CH:21]([F:39])[O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1>>[F:39][CH:21]([F:20])[O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: CC1(C)OB(c2ccc(F)cc2OC(F)F)OC1(C)C
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC(F)F)n2)c1

Procedure:
Example 15 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 2-[2-(difluoromethoxy)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Focus Synthesis LLC). The batch was purified by preparative HPLC:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[C:16]2[CH:17]=[N:18][C:19]([NH:21][C:22]([NH:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:23])=[CH:20][C:15]=2[N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:13]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[C:16]2[CH:17]=[N:18][C:19]([NH:21][C:22]([NH:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:23])=[CH:20][C:15]=2[NH:14][N:13]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N1C(=O)c3ccccc3C1=O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(3-(1,3-Dioxoisoindolin-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (229 mg, 0.342 mmol) was dissolved in DCM (2 mL), charged with TFA (660 μL, 8.56 mmol) and triethylsilane (54.7 μL, 0.342 mmol), and stirred at room temperature for 30 min. The solvents were concentrated in vacuo and the residue was treated with triethylamine (1 mL). Purification via flash chromotagraphy (10-100% EtOAc/DCM) afforded (R)-1-(3-(1,3-dioxoisoindolin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C23H18N6O3 [M+1]+ 427. found 427.
Reaction SMILES: [CH3:1][N:2]1CCN(C2C=CC3C(C=2)=CC=C2C=3OC(C(NC3C=CC(N4CCOCC4)=CC=3)=O)=CC2=O)CC1.C(O[C:41]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:44](OCC)=[CH:43][C:42]=1[NH:56][C:57]([C:59]1[O:60][C:61]2[C:66]([C:67](=[O:69])[CH:68]=1)=[CH:65][CH:64]=[CH:63][C:62]=2[N:70]1[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]1)=[O:58])C>>[C:1]([C:44]1[CH:43]=[C:42]([NH:56][C:57]([C:59]2[O:60][C:61]3[C:66]([C:67](=[O:69])[CH:68]=2)=[CH:65][CH:64]=[CH:63][C:62]=3[N:70]2[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]2)=[O:58])[CH:41]=[CH:46][C:45]=1[N:47]1[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)#[N:2]
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1NC(=O)c1cc(=O)c2cccc(N3CCN(C)CC3)c2o1
Reactant: CN1CCN(c2ccc3c(ccc4c(=O)cc(C(=O)Nc5ccc(N6CCOCC6)cc5)oc43)c2)CC1
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCOCC5)c(C#N)c4)oc23)CC1

Procedure:
This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as prepared in Example 12, yielding a yellow solid. (120 mg=82%), LCMS−m/z=474.5.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:31]1[N:32]=[CH:33][C:34]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)=[N:35][CH:36]=1)#[N:30]>CN(C)C=O>[Cl:28][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:34]2[CH:33]=[N:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=2)=[O:39])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(N)cc1Cl)Cc1ccc(F)cc1F
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1ccc(NC(=O)Nc2cnc(C#N)cn2)cc1Cl)Cc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To a solution of tert-butyl 2-(4-amino-2-chlorophenoxy)ethyl(2,4-difluorobenzyl)-carbamate (1.6 g, 3.87 mmol) in N,N-dimethylformamide (4 mL) at RT were phenyl 5-cyanopyrazin-2-ylcarbamate (1.39 g, 5.81 mmol) (Example 10) and N,N,N-diisopropylethylamine (0.751 g, 5.81 mmol) added. The reaction mixture was heated at 60° C. for 1.5 hours then the reaction mixture was poured into ice-water (100 mL) and allowed to stand for 30 minutes. The resulting precipitate was collected, washed with water and air dried. The crude product was purified by column chromatography on neutral silica gel using 0-2% methanol in DCM to give the title compound (0.53 g, 26% yield).