Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[NH:2][C@H:3]([C:12](N)=[O:13])[CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(Cl)(Cl)=[O:16]>C1COCC1>[NH2:2][C@H:3]([C:12]([OH:13])=[O:16])[CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)C[C@H](NO)C(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
HO-Asp(But)-NH2 (20.0 g, 105.7 mmol) was suspended in 300 mL of anhydrous THF and heated to 50° C. Phosgene (20% in toluene) (105 mL, 211.4 mmol) was added to the amino acid suspension, and the amino acid dissolved over the course of approx. 1 hr, forming a clear solution. The solution was concentrated on by rotary evaporation, transferred to a beaker, and hexane was added to precipitate the product. The white solid was isolated by filtration and dissolved in anhydrous THF. The solution was filtered over a bed of Celite to remove any insoluble material. An excess of hexane was added on the top of the filtrate and the bilayer solution was left in the freezer overnight. The NCA was isolated by filtration and dried in vacuo. 15.0 g (66% yield) of Asp(But) NCA was isolated as a white, crystalline solid. 1H NMR (d6-DMSO) δ 8.99 (1H), 4.61 (1H), 2.93 (1H), 2.69 (1H), 1.38 (9H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:18]([S:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:18]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CSc1cncnc1-c1ccc(C#N)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(-c2ncncc2SCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of methyl 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetate (22 mg, 0.065 mmol), aqueous sodium hydroxide solution (1M, 0.5 mL) and methanol (1 mL) was stirred at room temperature for 2 hours. Methanol was removed and aqueous sodium hydroxide solution (1M, 1 mL) and ethyl acetate (3 mL) were added. The aqueous layer was removed, acidified and extracted with ethyl acetate. The second organic layer was concentrated to dryness to yield 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetic acid (19 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(Br)c1O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cccc1Br
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-bromo-6-methylphenol (0.520 g, 2.78 mmol) in 15 ML of acetone was added iodomethane (0.338 mL, 5.42 mmol) and potassium carbonate (0.768 g, 5.56 mmol). The reaction was heated to reflux and stirred overnight. Ammonium chloride (sat.) was added and the mixture was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford 456 mg of 1-bromo-2-methoxy-3-methylbenzene as a clear oil. To a solution of 1-bromo-2-methoxy-3-methylbenzene (0.123 g, 0.61 mmol) in 3 mL of THF at −70° C. was added n-butyllithium (1.6 M in hexanes, 0.46 mL, 0.73 mmol) dropwise. The reaction stirred at −70° C. for 30 minutes and was then allowed to warm up to −20° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate, dried over sodium sulfate and filter to give 96 mg crude material. The crude material was purified by column chromatography (3/1 hexanes/ethyl acetate) to afford 40 mg of 2-methoxy-3-methylphenylboronic acid as a white solid. MS(ES+): 167.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:19][N:18]=1)=[O:16].CC1CCCO1>COC.O>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](=[O:35])[NH:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:25]=2)=[CH:19][N:18]=1)=[O:16]
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Reactant: Cc1cnc(N)cn1
Agent: COC
Agent: C[Al](C)Cl
Solvent: O
Solvent: CC1CCCO1
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)cn1
Temperature: 25 °C

Procedure:
To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 mL) in a 3-neck flask equipped with overhead stirring and a condensor at 0° C. was added Me2AlCl (1 M solution in hexanes) (715 mL). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a: 52.6 g, 142.5 mmol) was dissolved in dimethylether (210 mL). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2-methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide (2): (49.98 g, 81%)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.137 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.366 g, 0.88 mmol) and methylamine (0.273 g, 8.80 mmol). mp 156-160° C.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH3:12][N:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16](=[O:23])[N:15]([C:24]2[CH:25]=[CH:26][C:27]3[S:31][N:30]=[C:29]([CH:32]=[O:33])[C:28]=3[CH:34]=2)[C:14]1=[O:35]>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH3:12][N:13]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:16](=[O:23])[N:15]([C:24]2[CH:25]=[CH:26][C:27]3[S:31][N:30]=[C:29]([C:32]([OH:2])=[O:33])[C:28]=3[CH:34]=2)[C:14]1=[O:35]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0° C., treated dropwise with a solution of a 2:3 mixture of 3-[3-(hydromethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a white solid (8.50 g, mp 149-152° C.).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:16][C:15]1[CH:14]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH:12]=[C:11]([F:31])[C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 56.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.14 g, 0.23 mmol) prepared in Example 63a, triethylsilane (0.15 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (60 mg, 40%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.O1CCOCC1>O>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:38]4[CH:37]=[CH:36][N:35]=[C:34]([O:33][CH3:32])[CH:39]=4)=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH3:25]
Reactant: COc1cc(B(O)O)ccn1
Reactant: CCN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3ccc(-c4ccnc(OC)c4)n4ncnc34)cc2)CC1
Temperature: 107.5 °C
Yield: 69.8 %

Procedure:
To a reaction vial (40 mL), is added 5-chloro-N-(4-(4-ethylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (110 mg, 0.3 mmol), potassium carbonate (207 mg, 1.5 mmol, 5 eq.), 2-methoxypyridin-4-ylboronic acid (70 mg, 0.45 mmol, 1.5 eq), PddppfCl2 (44 mg, 20%), dioxane (4.0 mL) and water (1.0 mL). The reaction mixture is degassed and filled with argon. The reaction is heated at 105-110° C. for 20 h. After cooling to rt, ethyl acetate (10 mL) is added to each reaction vial. The organic phase is filtered through a pat of celite and then is evaporated to give a residue that is purified by silica gel column chromatography (1-3% 2N NH3 in MeOH/DCM) to give the title compound as a light yellow solid (90 mg, yield, 69.8%). 1H NMR (300 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.60 (d, J=4.8 Hz), 7.58 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.12 (m, 4H), 2.50 (m, 4H), 2.36 (q, J=6.9, 2H), 1.04 (t, J=6.9 Hz, 3H); LCMS-ESI (m/z): calcd for C24H27N7O, 429; [M+H]+ found, 430.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10]([O:15]C)(=[O:14])[C:11]([CH3:13])=[CH2:12].C(OOC([O-])=O)(OC(C)C)=O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OC
Agent: C=CCOC(=O)C(=C)C
Agent: CC(C)OC(=O)OOC(=O)[O-]
Solvent: ClCCl
Product: C=C(C)C(=O)[O-]

Procedure:
The copolymer of allyl methacrylate and methacrylate was prepared by placing 5 grams of allyl methacrylate, 95 grams of methyl methacrylate, 300 milliliters of methylene chloride, and 1.0 gram of isopropyl peroxydicarbonate in a 28 ounce round bottle. The bottle was sealed. The bottle was then heated at 50 degrees Centigrade in a water bath for 18 hours. The bottle was then removed from the water bath, and the polymer isolated by extraction with methanol to precipitate polymer. The polymer was then dried under vacuum. Thereafter, the molecular weight was determined by inherent viscosity in methylene chloride versus poly(methyl methacrylate), and was found to be in excess of 500,000.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=O)C.C1(S([O-])(=O)=O)C=CC=CC=1.[Na+].[CH3:24][O-:25].[Na+]>CO>[CH3:1][O:4][CH:5]([O:25][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc(F)cc1
Reactant: C[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(F)cc1

Procedure:
Electrolyte: 250 g (1.488 mol) of 4-fluorobenzyl acetate, 12.5 g of sodium benzenesulfonate, 12.5 g of sodium methylate and 2225 g of methanol
Reaction SMILES: [ClH:1].N1(CCNC2N=C([C@@H](N)CC3C=C(F)C=C(F)C=3)C(C3C=CC(F)=C(C=3)C(N)=O)=CN=2)C=CN=N1.[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C@H:46]([NH:68]C(=O)OC(C)(C)C)[C:47]2[C:52]([C:53]3[CH:54]=[C:55]4[C:59](=[CH:60][CH:61]=3)[CH2:58][NH:57][C:56]4=[O:62])=[CH:51][N:50]=[C:49]([N:63]3[CH:67]=[N:66][CH:65]=[N:64]3)[N:48]=2)[CH:41]=[C:42]([F:44])[CH:43]=1>>[ClH:1].[NH2:68][C@H:46]([C:47]1[C:52]([C:53]2[CH:54]=[C:55]3[C:59]([CH2:58][NH:57][C:56]3=[O:62])=[CH:60][CH:61]=2)=[CH:51][N:50]=[C:49]([N:63]2[CH:67]=[N:66][CH:65]=[N:64]2)[N:48]=1)[CH2:45][C:40]1[CH:41]=[C:42]([F:44])[CH:43]=[C:38]([F:37])[CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(-n2cncn2)ncc1-c1ccc2c(c1)C(=O)NC2
Agent: Cl
Agent: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1nc(-n2cncn2)ncc1-c1ccc2c(c1)C(=O)NC2

Procedure:
The title compound (29C) was prepared according to the method presented for the synthesis of compound 23E of Example 23 utilizing 29B. MS (m/z) 434.11[M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: ClCCOCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1cccc(N2CCOCC2)c1
Yield: 77.1 %

Procedure:
A solution of m-anisidine (11.2 mL, 0.1 mol), chloroethyl ether (11.7 mL, 0.1 mol), and diisopropylethylamine (35 mL, 0.2 mol) in toluene (100 mL) was stirred at reflux for 72 h. The precipitate was removed by filtration and washed with toluene (100 mL). The combined toluene solutions were concentrated in vacuo and purified by distillation (120-130° C., 0.2 Torr) to afford the intermediate 4-(3-methoxyphenyl)-morpholine (14.9 g, 77%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[CH:5][C:6](=[NH:17])[N:7]([CH:9]([CH3:16])[C:10](=O)[C:11]([O:13][CH3:14])=[O:12])[CH:8]=1>CO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:17]=2)[CH:8]=1
Reactant: COC(=O)C(=O)C(C)n1cc(Cl)ccc1=N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1nc2ccc(Cl)cn2c1C
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of methyl 3-(5-chloro-2-iminopyridin-1(2H)-yl)-2-oxobutanoate hydrobromide (8.51 g, 26.3 mmol) in MeOH (50 mL) was heated to reflux for 16 h, cooled to room temperature, and concentrated to give a white solid. The solid was dissolved in a mixture of EtOAc and saturated NaHCO3, the aqueous phase was discarded and the organic phase was washed with saturated NaHCO3 (1×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated to give methyl 6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylate (5.68 g, 25.3 mmol, 96% yield) as an off white solid.
Reaction SMILES: COC(CCC([O:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20](OC)=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25])=O)=O.[NH3:28]>CO>[OH:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20]([NH2:28])=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25]
Reactant: N
Reactant: COC(=O)CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CCC(=O)OC)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)SC(CCC(N)=O)O2

Procedure:
4.9 g of methyl 3-[5-(3-methoxycarbonylpropionyloxy)-4,6,7-trimethyl-1,3-benzoxathiole-2-yl]propionate (prepared as described in Example 31) was dissolved in 60 ml of methanol, and 17 g of 28% w/v aqueous ammonia was added to the solution. The reaction mixture was then allowed to react for 5 days at room temperature. At the end of this time, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography, and the title compound, melting at 160°-161° C., was obtained from the fraction eluted with a 3:7 by volume mixture of benzene and ethyl acetate. Mass spectrum (m/e): 267 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[N:13]2)=[N:6][CH:7]=1.Cl.Cl[CH2:34][CH2:35][N:36](CCCl)[CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C:5]4[N:4]=[CH:3][C:2]([N:1]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:7][N:6]=4)[CH:9]=3)[N:13]=2)=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N)cn4)c3)n2)cc1
Reactant: CCN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)n2)cc1
Temperature: 130 °C
Reaction time: 120 h

Procedure:
53.3 1.4 g (3.23 mmol) of 2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(4-methanesulfonylphenyl)-2H-pyridazin-3-one are dissolved in 30 ml of NMP, and 1.59 g (8.72 mmol) of bis(2-chloroethyl)ethylamine hydrochloride and 1.22 g (8.72 mmol) of potassium carbonate are added. The suspension is stirred at 130° C. for 5 days under an argon atmosphere. The reaction mixture is filtered, and the filtrate is stirred into 200 ml of diethyl ether. An oily residue deposits in the process. The residue is purified by means of column chromatography on silica gel. The resultant product is purified by means of preparative HPLC; yield: 41 mg of “A289” trifluoroacetate; HPLC: Rt=2.19 min (method C); LC-MS: 503 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CS(C)=O.[Cl-].[Na+].O>[CH3:14][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:24]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccn[nH]2)nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To the mixture of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine prepared in Referential Example 1 (25.5 mg) and (R)-3-(tert-butoxycarbonylamino)piperidine (50.9 mg) in DMSO (5 ml) was added DIEA (210.0 μL). And the mixture was heated to 110° C. under stirring for overnight. The resulting mixture was cooled to room temperature, poured into brine and extracted with EtOAc. The extract was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4 and concentrated in vacuo. And the residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=99/1˜0/100) to give tert-butyl {(3R)-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]piperidin-3-yl}carbamate (26.0 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Br)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(Nc2ccc(C(F)(F)F)cc2)c1
Yield: 55.8 %

Procedure:
To a solution of 2-bromo-6-chloro-4-methylpyridine (415 mg, 2.0 mmol) in toluene (10 mL) was added 4-trifluoromethylaniline (325 mg, 2.0 mL), Pd2(dba)3 (50 mg, XANTPHOS (50 mg), and t-BuOK (350 mg). The mixture was microwaved 30 minutes at 120° C., filtered through Celite and washed with CH2Cl2 (3×). The combined organic layers were concentrated. The residue was purified by chromatography on silica gel (20-40% CH2Cl2 heptane) to give the product as a white solid (320 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.53-7.63 (m, 2H), 7.41-7.49 (m, 2H), 6.70 (s, 1H), 6.61 (s, 2H), 2.28 (s, 3H). MS m/e 287.1 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][C:5]=1C=O)([O-:3])=[O:2].[C:30](O)(=O)[CH2:31][C:32]([OH:34])=[O:33].N1CCCCC1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][C:5]=1[CH:30]=[CH:31][C:32]([OH:34])=[O:33])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=O)c3)CC2)cc1OC
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=CC(=O)O)c3)CC2)cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
2-Nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde (4 g) was dissolved in 20 ml of pyridine followed by adding 2.1 g of malonic acid and 0.4 ml of piperidine, and the mixture was stirred at 80° C. for 4 hours. After evaporating pyridine and piperidine the reaction mixture was poured in a dilute aqueous hydrogen chloride solution and extracted with methylene chloride. After washing the methylene chloride layer with water the solvent was distilled off and methanol was added to the residue. After cooling, crystals which formed were collected by filtration to give 3.7 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-cinnamic acid, m.p. 197°-202° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[S:12][CH2:11][CH2:10][C:9]2=[O:17])=[O:5])[CH3:2].[Br:19]Br>C(O)C>[Br:19][CH:10]1[C:9](=[O:17])[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]=2[CH3:18])[S:12][CH2:11]1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C)c2c(c1C)C(=O)CCS2
Solvent: CCO
Product: CCOC(=O)c1cc(C)c2c(c1C)C(=O)C(Br)CS2
Reaction time: 1 h
Yield: 97.1 %

Procedure:
1.9 Grams (7.2 mmol) of 6-ethoxycarbonyl-5,8-dimethylthiochroman-4-one was dissolved in 28 ml of ethanol. Then, 1.2 g (7.5 mmol) of bromine was dropwise added with an ice bath cooling, and the mixture was stirred at the same temperature for 1 hour, then the ice bath was removed and further stirred for 1 hour. Water was added to the reaction mixture, and the reaction mixture was extracted with chloroform three times. An organic layer was washed with a saturated sodium chloride aqueous solution three times, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 2.4 g (yield 97%) of the titled compound.