Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[NH:14])OCC)=[CH:6][CH:5]=1.C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].NN.[N:24]([O-])=O.[Na+]>O.C(O)(=O)C>[N:20]1[CH:19]=[N:21][N:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)[N:24]=1
Reactant: CCOC(=N)c1ccc(CO)cc1
Reactant: N=CN
Reactant: O=N[O-]
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OCc1ccc(-c2nncnn2)cc1
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a mixture of 4-(hydroxymethyl)-benzenecarboximidic acid, ethyl ester, hydrochloride (1 mmol, 216 mg) and formamidine acetate (5 mmol, 521 mg) was added anhydrous hydrazine (20 mmol, 630 uL) the resulting viscous oil was allowed to stir. After 1 hour, acetic acid (3 mL) was added followed by sodium nitrite (690 mg, 10 mmol) as a finely divided powder. The now bright pink solution was allowed to stir for 15 minutes and then diluted with 15 mL of water. The aqueous crude reaction was subsequently extracted with methylene chloride (4×10 mL). The organic extracts were dried with MgSO4. After solvent removal, the crude pink product was purified by flash chromatography (silica gel) first washing with 100% methylene chloride, followed by methylene chloride with 1% methanol, giving (4-(1,2,4,5-tetrazin-3-yl)phenyl)methanol (40 mg, 21%) as a bright pink solid. LRMS-ESI [M+H]− calcd. for C9H9N4O−: 189.08, found: 188.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Cl[C:13]([F:19])([F:18])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:18][CH:13]([F:19])[O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1OC(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
5-Bromo-2-nitrophenol (1 g, 4.59 mmol) and methyl 2-chloro-2,2-difluoroacetate (991 mg, 6.9 mmol) were dissolved in dry DMF (3 mL). Potassium carbonate (1.27 g, 9.18 mmol) was added and the reaction was stirred at 120° C. for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% dichloromethane in hexanes to afford the title compound as a dark brown oil (375 mg, 30%).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[N:11][CH:12]=1>CC(O)=O.O1CCOCC1>[Br:6][C:7]1[CH:8]=[C:9]2[NH:14][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:13][C:10]2=[N:11][CH:12]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CC1CC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Brc1cnc2nc(C3CC3)[nH]c2c1
Yield: 20.9 %

Procedure:
A solution of cyclopropanecarbaldehyde (0.89 g, 12.76 mmol, 1.2 eq), 5-bromopyridine-2,3-diamine x167 (2 g, 10.63 mmol, 1 eq) in AcOH (20 ml) and 1,4-dioxane (40 ml) is heated at 110° C. during 24 hours. After cooling, the solvents are evaporated under reduced pressure. The resulting brown solid is recrystallized in CH2Cl2/hexane (1/1) to yield 0.53 g of 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168 as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH:28]1([CH:32]([NH2:35])[CH2:33][CH3:34])[CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:35][CH:32]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:33][CH3:34])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: CCC(N)C1CCC1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CCC1
Yield: 72.6 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.50 g, 1.21 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclobutyl-propylamine HCl (0.36 g, 2.42 mmol) were treated substantially as described in Part C of Example 19a to produce 0.33 g (73%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine: MS (AP) m/z 375.9 [(M+H)+, 100].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[NH:24]1[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[N:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O.CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29]([C:28]5[NH:24][N:25]=[CH:26][CH:27]=5)=[O:30])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccn[nH]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccn[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
To a mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), 1H-pyrazole-5-carboxylic acid (84 mg, 0.75 mmol), 1-hydroxybenzotriazole (101 mg, 0.75 mmol) and N,N-dimethylformamide (5 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol), triethylamine (0.279 mL, 2.0 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and crystallized from ethyl acetate to give the title compound (43 mg, yield 21%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](O)[CH:15]=[CH2:16].[C:18]1(C)[CH:23]=CC=C[CH:19]=1.S(=O)(=O)(O)O>COC1C=CC(O)=CC=1.O>[OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:23][CH:18]=[CH2:19])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:14][CH:15]=[CH2:16])=[O:8]
Reactant: Cc1ccccc1
Reactant: C=CCO
Reactant: O=C(O)c1cc(O)cc(C(=O)O)c1
Agent: COc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCOC(=O)c1cc(O)cc(C(=O)OCC=C)c1
Yield: 52 %

Procedure:
Into a reaction vessel equipped with a stirrer, condenser and thermometer was placed 0.2 mole of 5-hydroxy-isophthalic acid. Thereto were added 0.6 mole of allyl alcohol, 300 ml of toluene, 1.3 g of sulfuric acid and 0.2 g of p-methoxyphenol and the mixture was refluxed with heating. A mixture of toluene and water was distilled off and cooled with a condenser, and toluene was separated from water and returned contineously to the reaction vessel. The mixture was heated for 8 hours. and then allowed to cool. At this point, total of distilled water was 7 ml. After the reaction mixture was washed with a saturated aqueous solution of sodium chloride until the aqueous layer did not indicate acidic, toluene was distilled at a reduced pressure. The resulting concentrate was distilled at a reduced pressure to obtain 27 g (yield 52%) of diallyl 5-hydroxy-isophthalate. b.p. 202°~205° C./5 mmHg.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].NC1C=N[C:17]2[C:22](C=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2C(CN)=[CH:35][CH:34]=[C:33]([C:39]([F:42])([F:41])[F:40])[N:32]=2)[CH2:27][CH2:26]1>C(Cl)Cl>[CH3:24][CH:25]1[CH2:26][CH2:27][N:28]([C:31]2[C:11]([CH2:12][NH:8][C:1]([NH:3][C:7]3[CH:6]=[N:5][C:4]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:22][CH:21]=4)=[O:2])=[CH:35][CH:34]=[C:33]([C:39]([F:40])([F:41])[F:42])[N:32]=2)[CH2:29][CH2:30]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Solvent: ClCCl
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
1,1′-Carbonyldiimidazole (CU) (1.1 eq.) was added to 3-aminoquinoline (1 eq.) dissolved in methylene chloride. The mixture was stirred during 12 h at room temperature. After that (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (0.98 eq.) was added to the mixture. After 12 h the solvent was evaporated and the mixture was purified by column chromatography (silica gel: 100-200; eluent: 50% ethyl acetate in n-hexane) and give the desired 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(quinolin-3-yl)urea (example compound 12) (100 mg, 42%).
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C(=O)C2=CC=CC=C12.O.NN>C(Cl)Cl.CO>[NH2:5][O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)/C=C/CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/CON
Reaction time: 15 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl 4-phthalimidooxycrotonate (20.0 g) in methylene chloride (140 ml) was added a solution of hydrazine monohydrate (5.0 g) in methanol (10 ml) with stirring, and the stirring was continued at ambient temperature for 15 hours. The insoluble substance was collected by filtration and washed with methylene chloride. The washings and the filtrate were combined and then extracted three times with 5% hydrochloric acid. After the combined extracts were washed with diethyl ether, thereto was added methylene chloride, followed by adjusting to pH 7.5 with 28% aqueous ammonium hydroxide. The separated methylene chloride solution was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave an oil of tert-butyl 4-aminooxycrotonate (11.03 g).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-:26].[Na+].Cl>C(O)C>[CH2:14]([C:3]1[C:4](=[O:13])[C:5]2[C:10]([C:11](=[O:12])[C:2]=1[OH:26])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [OH-]
Reactant: CCCCCCCCCCCCC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 10 parts of 3-chloro-2-n-dodecyl-1,4-napthoquinone, 5 parts of 50% aqueous sodium hydroxide and 320 parts of 95% aqueous ethanol were heated at reflux for 15 minutes. The color of the mixture turned from yellow to dark red. The mixture was cooled to 25° C. and acidified with 10% aqueous hydrochloric acid. The color of the mixture was golden yellow after acidification. The product was filtered off and washed twice with water (25 parts) and twice with cold methanol (25 parts) to yield 8 parts of 2-n-dodecyl-3-hydroxy-1,4-naphthoquinone, m.p. 85°-87° C.
Reaction SMILES: N(C(C)(C)C#N)=N[C:3](C)(C)[C:4]#N.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>C1C=CC=CC=1>[CH2:3]=[CH2:4].[C:16]([O:18][CH:13]=[CH2:14])(=[O:17])[CH3:15].[C:16]1(=[O:17])[O:18][C:13](=[O:19])[CH:14]=[CH:15]1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: C=C
Product: C=COC(C)=O

Procedure:
A solution of azobis(isobutyronitrile) in benzene was simultaneously introduced at a rate sufficient to keep the reactor temperature at 170° C. (about 0.587 g./hr. corresponding to 0.86 kg. catalyst per 1000 kg. of terpolymer). The total benzene feed was 1.04 l kg./hr. The terpolymer produced was isolated by a procedure similar to that described in Procedure A. The weight percent of maleic anhydride was 1.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])C.[CH3:18][O-:19].[Na+]>CO>[CH3:1][O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:19][CH3:18])=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5]
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2ccc(I)cc2c1OC
Temperature: 100 °C
Reaction time: 10 h
Yield: 89.7 %

Procedure:
To the suspension of 4-chloro-6-iodo-quinoline-3-carboxylic acid ethyl ester (14 g, 0.039 mol) in anhydrous methanol (180 mL) was added sodium methoxide (4.16 g, 0.07 mol). The mixture was heated to 100° C. under a pressure tube and stirred for 10 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (12 g, 92%) as a yellow solid. LC-MS m/e 344 (MH+)
Reaction SMILES: [S:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].S(Cl)([Cl:19])=O>CCCCCC>[S:1]([NH:11][C@H:12]([C:14]([Cl:19])=[O:16])[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Temperature: 50 °C
Yield: 93 %

Procedure:
A mixture of N-tosyl-L-alanine (3.1 g; 13 mmol) and thionyl chloride (6 mL) was heated for 1.5 hours at 50° C. then diluted with dry hexane (50 mmL). The mixture was stirred rapidly, chilled and the solid was collected by filtration to obtain 3.15 g (93%) of N-tosyl-L-alaninyl chloride (35) having a melting point of 99°-100° C. The IR spectrum of this material was identical to that of the recrystallized material prepared according to method (i).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][C:18](O)=[O:19].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:18](=[O:19])[CH2:17][Cl:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)aniline (3.74 g, 16.3 mmol) in DCM (60 mL) was added chloroacetic acid (2.31 g, 24.4 mmol), EDC (5.0 g, 32.6 mmol) and DMAP (cat.). The reaction mixture was stirred at RT overnight. The contents were transferred to a separatory funnel and DCM layer was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography using 3:1 Pet. Ether:DCM in. Purified product was isolated as a white solid weighing 3.67 g (yield: 74%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH2:22])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:8]=2[N:7]=1)[CH3:2].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:3][CH2:4][CH:5]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2)[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:8]=2[N:7]=1)[CH3:2]
Reactant: CCOC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 22.3 %

Procedure:
A mixture of (R)-2-ethoxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (510 mg, 1.7 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (410 mg, 1.7 mmol) and DIPEA (1.5 mL, 8.5 mmol) in n-butanol (6 mL) was heated at 90° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 200 as a white solid (158 mg, 22%). LCMS (Method K): RT 3.80 min [M+H]+ 418.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.60 (1H, s), δ 8.22-8.05 (2H, m), 7.87 (1H, br s), 7.75-7.49 (6H, m), 7.11 (1H, td, J=9.32, 2.48 Hz), 6.89 (1H, dd, J=8.92, 2.50 Hz), 5.63 (1H, br s), 3.88 (2H, br d, J=6.76 Hz), 3.40-3.33 (2H, m), 1.01-0.91 (3H, m)
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]([CH3:24])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[CH3:24][C:16](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCc2c[nH]c(N)n2)nn1
Yield: 43.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.062 g, 0.362) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.075 g, 0.434 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.054 g, 43%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.39 (s, 1H), δ 7.12-7.07 (m, 5H), δ 6.54 (s, 1H), δ 6.36 (s, 1H), δ 5.09 (s, 2H), δ 3.01 (t, 2H), δ 2.76 (t, 2H), δ 1.60 (s, 3H) ppm; 13C; 147.7, 143.1, 136.3, 132.7, 129.9, 128.9, 128.6, 128.5, 128.2, 127.4, 127.1, 124.9, 109.9, 61.2, 23.0, 22.3, 14.7 ppm; HRMS (ESI) calcd for C16H20N6 (M+) 308.1749. found 308.1742.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C1COCC1>[CH3:39][O:38][C:36](=[O:37])[NH:25][C@H:23]([C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:2][CH3:3])=[CH:10][CH:9]=3)[CH2:16][CH2:15]2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 36.1 mg (0.10 mmol) (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) and 42.7 μL (0.250 mmol) DIPEA in 2 mL THF are added 11.64 (0.150 mmol) methyl chloroformate at 0° C. The mixture is stirred for 12 h at rt. The solvent is removed under reduced pressure, the residue is taken up in DMF and purified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol) to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>CC(C)=O>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCC2CO2)cc1
Yield: 60.7 %

Procedure:
A mixture of 16.7 gm (0.10 mole) of ethyl 4-hydroxybenzoate, 20.7 gm (0.15 mole) of potassium carbonate and 24 mL (0.30 mole) of epichlorohydrin in 250 mL acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated. The resulting oil was taken up in 100 mL toluene and washed with 100 mL 1.0N sodium hydroxide and 2×100 mL water. The toluene phase was then dried over magnesium sulfate and evaporated to give 13.5 gm (61%) of a clear oil. The NMR spectrum of this oil was consistent with the assigned structure and the oil was used in the next reaction step without further purification.
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][C:22]#N)[C:17]=3[CH:24]=2)[C:3]1=[O:25].[CH2:26]([OH:28])[CH3:27].O.S(=O)(=O)(O)[OH:31]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[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][C:22]([O:28][CH2:26][CH3:27])=[O:31])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: O=S(=O)(O)O
Reactant: CCO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC#N)c3c2)c1=O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetonitrile (1.00 g), ethanol (20.0 mL) and water (1.00 mL) is treated with concentrated sulfuric acid (10.0 mL), refluxed for 15 minutes, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an orange foam. Column chromatography of the foam using silica gel and a 10% ethyl acetate in methylene chloride solution gives the title product as a solid which is identified by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: OC1CCOCC1
Product: Fc1cc(OC2CCOCC2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28])[NH2:24]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:24][C:23]3[CH:25]=[C:26]([CH3:29])[C:27]([OH:28])=[C:21]([Cl:20])[CH:22]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Cc1cc(N)cc(Cl)c1O
Product: Cc1cc(Nc2ncc(F)c(Nc3cccc(C(C)(C)C)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine with 3-chloro-4-hydroxy-5-methylaniline gave N4-(3-tert-butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 25.46 min.; purity: 100%; MS (m/e): 400 (M+); 1H NMR (DMSO-d6): δ 9.63 (1H, s), 9.30 (1H, s), 8.82 (1H, s), 8.20 (1H, d, J=3.9 Hz), 7.92 (1H, d, J=8,8 Hz), 7.58 (2H, m), 7.40–7.20 (3H, m) 2.22 (3H, s), 1.35 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][O:14][CH2:15][C:16]([CH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1)=[O:17].N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[C:18]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1)[C:16](=[O:17])[CH2:15][O:14][CH3:13])[C:7]#[N:8]
Reactant: COCC(=O)Cc1nc(C)cs1
Reactant: COc1cc(C#N)ccc1C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1

Procedure:
500 mg (3.10 mmol) of the compound from example 3A and 632 mg (3.41 mmol) of the compound from example 13A are dissolved in 15 ml of dichloromethane, and 0.307 ml (3.10 mmol) of piperidine and 0.178 ml (3.10 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 200 mg (20% of theory) of the title compound are obtained as a mixture of the E/Z isomers.