Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15]>COCCOCCOC.C1COCC1>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: C1CCOC1
Product: OCCCCCCCCCCCBr
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Sodium Borohydride (28.8 g, 0.76 mole) was dissolved in diglyme (700 ml) and THF (300 ml) and the solution cooled to 20° (dissolution of the NaBH4 is slightly exothermic). BF3OEt2 (145 g, 1.02 mole) was then added dropwise, with external cooling, at such a rate to keep the temperature of the mixture below 15°. After the addition was complete the mixture was stirred for 0.5 hour at 10°. This reducing agent was then added slowly to a solution of 11-bromoundecanoic acid (200 g, 0.76 mole) in THF (400 ml) keeping the temperature below 20°. After the addition was complete, the reaction was stirred at room temperature for 1.5 hours then quenched by pouring onto water (3 L) and concentrated HCl (100 ml). The quenched mixture was stirred for 0.5 hour at room temperature then cooled to 5°. The crystalline product was filtered off, washed with water (3×1 L) and dried under vacuum to give 11-bromoundecanol (189.2 g, 99.2%).
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.[C:16]([Si:20]([CH3:28])([CH3:27])[O:21][CH2:22]/[CH:23]=[CH:24]/[C:25]#[CH:26])([CH3:19])([CH3:18])[CH3:17]>C(#N)C.C(N(CC)CC)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>[Si:20]([O:21][CH2:22]/[CH:23]=[CH:24]/[C:25]#[C:26][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:28])[CH3:27]
Reactant: C#C/C=C/CO[Si](C)(C)C(C)(C)C
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC/C=C/C#Cc1ncnc(Oc2ccccc2)c1N
Yield: 87.8 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (1.0 g) was dissolved in a mixed solvent of acetonitrile (53 mL)/triethylamine (39 mL), and tert-butyl(dimethyl)[(2E)-2-penten-4-ynyloxy]silane (753 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (112 mg) and copper(I) iodide (36.5 mg) were sequentially added. The title compound (1.07 g) was obtained as crystals by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[SH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:3][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ncc(Br)nc1Oc1ccccc1
Reactant: COC(=O)CCS
Product: COC(=O)CCSc1cnc(N)c(Oc2ccccc2)n1

Procedure:
Prepared according to the method of Example from 5-Bromo-3-phenoxypyrazin-2-amine and methyl 3-mercaptopropanoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16][C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:27])([F:26])[F:17])=[CH:20][CH:21]=3)[N:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: O=c1cc(-c2cccc(Br)c2)[nH]n1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 13 h

Procedure:
5-(3-Bromophenyl)-2-(2-hydroxyethyl)-1,2-dihydro-3H-pyrazol-3-one (21 g, 74 mmol), 4-trifluoromethyl-1-fluorobenzene (28 mL, 220 mmol), and K2CO3 (30.6 g, 220 mmol) were combined in 140 mL of dry DMA. The mixture was heated at 160° C. with stirring in a sealed vessel for 13 h. The reaction was cooled to ambient temperature and more 4-trifluoromethyl-1-fluorobenzene (5 mL, 39 mmol) was added. The mixture was heated at 160° C. with stirring in a sealed vessel for 18 h. The reaction was cooled to ambient temperature and diluted with EtOAc. The mixture was washed with water and brine, then dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The dark residue was chromatographed on a 330 g silica gel column using 0-40% EtOAc:hexanes over 70 min at 100 mL/min. The product-containing fractions were combined and the solvent was removed under reduced pressure to give 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}ethanol as an oil which solidified on standing. Calcd (M−1-1)+: 428.2. Found: 428.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:18]1(O[Si](C)(C)C)[CH2:20][CH2:19]1)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH:18]1[CH2:20][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C1CC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic acid tert-butyl ester (3.00 g, 15.13 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (3.96 g, 22.70 mmol) were dissolved in methanol (30 mL), and while stirring the solution at room temperature, acetic acid (0.87 mL, 5.13 mmol) and then sodium cyanoborohydride (1.06 g, 15.13 mmol) were added thereto. Then, the mixture was heated to reflux for 21 hours. The reaction liquor was left to cool naturally, then a saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added thereto, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [chloroform-methanol (10:1)], to obtain the title compound (3.61 g, 100%) as an oily matter.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5](N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(O)C>[CH2:14]([O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:5]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
Thionyl chloride (5.25 mL, 72 mmol, 3.6 equiv.) is added dropwise to a 0° C. solution of absolute ethyl alcohol (20 ml). Diisopropyl ethylamine (3.45 ml, 19. mmol, 1 equiv.) was added and then 4.8 g of N-CBZ-L-serine methyl ester was added as a solid. Stirring is continued for 16 hours at room temperature. The ethanol and thionyl chloride are then removed by rotary evaporation and the residue is dissolved in ethyl acetate (200 ml). The organic phase is washed with 1N hydrochloric acid (50 ml) and saturated sodium bicarbonate (50 ml) and brine (20 ml). The organic layer is dried with magnesium sulfate. Rotary evaporation of the product gives an oil which is chromatographed on silica gel with hexane/ethyl acetate (3:1) to give N-CBZ-L-serine ethyl ester.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][C:23]1([C:29]([O:31]CC)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH3:5]>C(O)C.O>[CH2:4]([O:6][CH2:7][C:8]1[N:21]([CH2:22][C:23]2([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH3:5]
Reactant: CCOCC(=O)Nc1cnc2ccccc2c1NCC1(C(=O)OCC)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)O)CCCCC1
Yield: 69 %

Procedure:
Sodium hydroxide (2.71 g, 67.7 mmol) was added to a solution of ethyl 1-[({3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)methyl]cyclohexanecarboxylate hydrochloride (10.15 g, 22.6 mmol) in 9:1 ethanol/water (30 mL), and the solution was heated at reflux for several hours. The ethanol was removed under reduced pressure, and the resulting solution was diluted with water and adjusted to pH 4 to 5 with the addition of 3 M hydrochloric acid. The mixture was then extracted several times with dichloromethane The aqueous fraction was adjusted to pH 7 and extracted several more times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 5.73 g of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanecarboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]2[C:10]([N:15]([CH3:22])[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.CC(C)([O-:32])C.[K+]>CS(C)=O.CC(O)(C)C>[CH3:22][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[C:9]([CH2:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[OH:32])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)[O-]
Reactant: CN(c1cccnc1)c1ncccc1CC(c1cccnc1)c1cccnc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CN(c1cccnc1)c1ncccc1CC(O)(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine (34 mg) in 1.2 mL of DMSO:t-BuOH (80:20) was added potassium tert-butoxide (21 mg). The reaction was stirred under an oxygen balloon at room temperature for 2 h, then quenched by adding 2 drops of water. Purification by reverse phase HPLC gave 26 mg of 2-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-1,1-dipyridin-3-ylethanol as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (d, J=1.9 Hz, 2H), 8.47 (dd, J=4.6, 1.7 Hz, 2H), 8.35 (dd, J=4.6, 1.7 Hz, 1H), 8.21 (dd, J=4.6, 1.2 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.59-7.57 (m, 2H), 7.24-7.15 (m, 4H), 7.08-7.05 (m, 1H), 6.99-6.95 (m, 1H), 4.57 (s, 1H), 3.55 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:45])[CH2:31][C@@H:32]([C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:45])[CH2:31][C@@H:32]([C:38]1[CH:39]=[CH:40][C:41]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)=[CH:42][CH:43]=1)[C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reaction time: 16 h
Yield: 96.2 %

Procedure:
To a solution of alcohol 27.1 (179 mg, 0.765 mmol) in THF (7 mL), was added phenol 7.5 (300 mg, 0.765 mmol), DIAD (0.155 mL, 0.803 mmol), and triphenylphosphine (211 mg, 0.803 mmol). The solution was stirred for 16 hours and then concentrated to a reduced volume. The residue was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 27.2 (440 mg). MS ESI (pos.) m/e 598.2 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (1 H, d, J=1.6 Hz), 7.38 (1 H, s), 7.08-7.29 (8 H, m), 7.00 (1 H, d), 6.82 (2 H, d, J=8.6 Hz), 6.54 (1 H, s), 6.33 (1 H, br. s.), 6.05 (1 H, d, J=1.6 Hz), 4.92 (2 H, s), 4.85-4.90 (1 H, m), 4.66 (1 H, dd, J=1.6 Hz), 4.49-4.58 (1 H, m), 4.01-4.04 (1 H, m), 3.93 (1 H, dd, J=17.6, 8.2 Hz), 3.45 (1 H, dd, J=17.6, 6.7 Hz), 3.11 (1 H, dd, J=13.5, 3.3 Hz), 2.68 (1 H, dd, J=13.3, 9.4 Hz), 1.43 (9 H, s).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[CH2:1]([N:8]([C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:21])([CH3:22])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)O)n1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.7 %

Procedure:
To a suspension of 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid resin (0.15 g) synthesized in Example 461-6 in acetonitrile (1.5 ml) were added triethylamine (0.16 ml) and 2-chloro-3-nitropyridine (0.089 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the mixture, washed three times with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried. Trifluoroacetic acid (2.0 mL) was added to the obtained resin, and the mixture was left standing at room temperature for 2 hr. Then the resin was removed by filtration from the reaction mixture, and the filtrate was concentrated by blowing a nitrogen gas, vacuum dried, and purified by preparative HPLC to give the title compound (1.5 mg) as a pale-brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:16][CH:15]=1
Reactant: Cc1nnnn1C
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 1,5-dimethyltetrazole (0.98 g, 10.0 mmoles) in tetrahydrofuran (20 mL) at -30° C. was added n-butyl lithium (4.7 mL of 2.14M solution, 10.0 mmoles). After stirring for 0.25 hour, the solution was cooled to -50° C. and 4,4'-difluorobenzophenone (1.74 g, 8.0 mmoles) was added. After stirring for 1 hour at -50° C. and 1 hour at -10° C., the reaction was quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 40% (v/v) ethyl acetate in hexane to give 2.0 g of the title compound; m.p.=116°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(F)cc32)cc1
Yield: 90.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.85 g) was obtained. This compound was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane was added. The precipitated solid was collected by filtration to give N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.85 g). melting point: 165.6° C.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[S:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1>>[S:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:12][CH2:11]1
Reactant: COC(=O)C(Br)CCBr
Reactant: NC1CCSCC1
Product: COC(=O)C1CCN1C1CCSCC1
Yield: 35 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with tetrahydro-thiopyran-4-ylamine 18J yielded methyl 1-(tetrahydro-2H-thiopyran-4-yl)azetidine-2-carboxylate as a light brown solid (35%). MS ISP (m/e): 216.3 (100) [(M+H)]+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([OH:10])[N:2]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:2]=1
Reactant: On1nnc2cccnc21
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1nnc2cccnc21)c1ccccc1

Procedure:
The title compound was prepared from [1,2,3]Triazolo[4,5-b]pyridin-3-ol and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, oil).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:16]=1[CH2:17]N1CCNCC1.C(N(C(C)C)CC)(C)C>CC(O)CC>[Cl:14][C:15]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Fc1cccc(Cl)c1CN1CCNCC1
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(N2CCN(Cc3c(F)cccc3Cl)CC2)nc[nH]1
Temperature: 80 °C
Reaction time: 40 h
Yield: 17.1 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (Intermediate 4; 100 mg, 0.77 mmol), 1-(2-chloro-6-fluorobenzyl)piperazine (Oakwood; 87 mg, 0.38 mmol), and diisopropylethylamine (200 μL, 1.1 mmol) in 2-butanol (5 mL) was heated in a sealed scintillation vial on a hot plate at about 80° C. for 8 hours and then allowed to cool to room temperature and stand at room temperature for 40 hours. The mixture was filtered. The solid was washed with 2-butanol and air-dried to give 6-[4-(2-chloro-6-fluorobenzyl)-piperazin-1-yl]-3H-pyrimidin-4-one (21 mg, 17%) as a white solid, mp 255-256° C. (dec). 1H NMR (d6-DMSO) δ 2.41-2.44 (m, 4H), 3.42-3.45 (m, 4H), 5.24 (s, 1H), 7.19-7.24 (m, 1H), 7.40-7.43 (m, 1H), 7.51-7.56 (m, 1H), 7.87 (s, 1H), 11.61 (br s, 1H). LRMS ES+M+H 323. HRMS Calcd. for C15H17ClFN4O (M+H), 323.1070. Found, 323.1069.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine yields 2-(pyrazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.I[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Ic1cnccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2cnccn2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 2-iodopyrazine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=312.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2].[NH3:29]>>[CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:29])=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2]
Reactant: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CNc1ccccc1CC
Reactant: N
Product: CCCC1=NN(c2ccc(C(N)=O)cc2)C(=O)C1=CNc1ccccc1CC

Procedure:
From the reaction of 4-(4-(2-ethylaniIinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid and diluted ammonia solution, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzamide is obtained, Mp 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:23])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:38])=[CH:18][C:17]=3[F:23])[CH:14]=2)=[CH:24][CH:25]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)cc3F)ncn2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of N-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (88 mg, 0.26 mmol) in THF (2 mL) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.72 mL, 0.26 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated with isopropyl ether to give the title compound (125 mg, 93%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.50 (s, 1H), 8.09 (s, 1H), 7.85 (br s, 0.5H), 7.66 (d, 1H, J=12.6 Hz), 7.36-7.15 (m, 9.5H), 6.88 (d, 1H, J=8.1 Hz), 5.91 (s, 1H), 4.42 (br s, 2H), 3.72 (s, 2H), 3.71 (s, 3H); MS (ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH3:16][C:6]1[CH:7]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:17]=[C:18]([NH2:20])[S:19][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(S(C)(=O)=O)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(S(C)(=O)=O)cc(C)c1-c1csc(N)n1
Yield: 46.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylsulfonyl)phenyl)ethanone (7.60 g, 24.9 mmol) and thiourea (1.90 g, 25.0 mmol) in 95% EtOH (35.6 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (20 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(methylsulfonyl)phenyl)thiazol-2-amine (3.28 g) as yellow solids in 47% yield: 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 2 H), 6.34 (s, 1 H), 5.19 (m, 1 H), 3.04 (s, 3 H), 2.26 (s, 6 H).