Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[OH-].[K+].[F:32][C:33](F)=[C:34]([F:39])[C:35]([F:38])([F:37])[F:36]>O1CCCC1.O>[F:32][C:33]([O:14][C:10]1[CH2:9][C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][CH:11]=1)=[C:34]([F:39])[C:35]([F:38])([F:37])[F:36]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: OC1=CC=CC(Oc2ccccc2)(Oc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: FC(OC1=CC=CC(Oc2ccccc2)(Oc2ccccc2)C1)=C(F)C(F)(F)F
Temperature: 25 °C
Yield: 75 %

Procedure:
Five g (0.018 mole) of 3-phenoxy-3-phenoxyphenol, 100 ml of xylene and 1.2 g of KOH are placed into a flask equipped with a Dean-Stark trap. This mixture is stirred at reflux until water of reaction ceases to evolve. The mixture is cooled and 100 ml of tetrahydrofuran (THF) are added and the mixture is further cooled in a dry ice/acetone bath while 15 g of perfluoropropene are bubbled into the reaction mixture. The mixture is stirred for three hours while warming to room temperature. Next, 100 ml of water are added and the mixture is stirred. The product phase is separated, dried over sodium sulfate, filtered and distilled. The product propene is an oil obtained in a yield of 75 percent. The oil has a pour point below -27° C., a boiling point of 150° C. at 1.0 mm Hg and a DSC of 373° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=1)[CH3:2].Cl>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)OC)nc2c(C3CC3)cccc12
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOc1cc(C(=O)O)nc2c(C3CC3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 mL of 5N NaOHaq was added to a solution of 1.10 g of methyl 4-ethoxy-8-cyclopropylquinoline-2-carboxylate in 5 mL of CHCl3/MeOH (1:1) and the mixture was stirred at room temperature for 3 hr. After the addition of 3.0 mL of 5N HCl aq, the mixture was extracted by CHCl3. The organic layer was washed by satd. brine, dried over NaSO4, then concentrated to afford 4-ethoxy-8-cyclopropylquinoline-2-carboxylic acid as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[N:31][N:30]=[N:29]4)=[CH:24][CH:23]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[CH3:19][C:17]1[N:18]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:15][C:16]=1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][CH:23]=1.[ClH:33]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(-n2cnnn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(C2CCNCC2)sc1COc1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 93) (500 mg, 1.10 mmol) in dichloromethane (5 mL) was treated with 1.5 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 5 hours and all the solvent were removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-chlorophenyl isocyanate (0.0733 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 43 as a colorless solid (0.050 g, 30%). LCMS m/z (%)=386 M+H+ (37Cl, 26), 385 M+H+ (35Cl, 94), 1H NMR (400 MHz, DMSO-d6) δ: 8.84 (bs, 1H), 8.77 (bs, 1H), 7.48 (d, J=1.91 Hz, 1H), 7.46 (d, J=1.84 Hz, 1H), 7.44 (d, J=3.65 Hz, 1H), 7.33 (t, 1H), 7.3 (s, 1H), 7.29 (d, J=7.68 Hz, 2H), 7.07 (d, J=8.9 Hz, 2H), 6.13 (d, J=1.83 Hz, 1H), 4.25 (m, 1H), 3.7 (s, 3H), 1.3 (d, J=6.76 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:13][O:12][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc2c(cc1Br)CCCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1Br)CCCC2
Temperature: 50 °C
Yield: 94.7 %

Procedure:
A 21 mL oven dried scintillation vial with a Teflon lined cap was charged with 3-bromo-5,6,7,8-tetrahydronaphthalen-2-ol (568 mg, 2.50 mmol), powdered K2CO3 (691 mg, 5.00 mmol), dry DMF (7 mL) and iodomethane (0.622 mL, 10.00 mmol). The flask was purged with N2 sealed and heated on the orbital shaker to 50° C. for 4 hours. After cooling the reaction to ambient temperature, it was concentrated under high vacuum to remove DMF, and then partitioned between brine:water (1:1) and ethyl acetate (2×). The organics were combined, dried with Na2SO4, filtered and concentrated to a crude paste. The crude was purified by Biotage MPLC (90 g column, 2.5% ethyl acetate in heptane) to give 571 mg (94%) of 3-bromo-5,6,7,8-tetrahydronaphthalen-2-yl methyl ether as a white solid. Rf 0.57 (10% ethyl acetate in heptane) 1H NMR shows ˜6% contamination with the 1-bromo regio-iosmer. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1 H), 6.59 (s, 1 H), 3.85 (s, 3 H), 2.69 (m, 4 H), 1.76 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 153.4, 137.4, 133.4, 130.8, 112.4, 108.3, 56.2, 29.5, 28.3, 23.1, 22.9.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18][CH2:19][S:20]([CH3:22])=[O:21].[OH-].[Na+]>O>[CH3:22][S:20]([C:19]([S:18][CH3:17])=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[O:21]
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Reactant: CSCS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSC(=Cc1cccc(C(=O)c2ccccc2)c1)S(C)=O
Temperature: 95 °C
Reaction time: 1.17 h

Procedure:
m-Benzoylbenzaldehyde (902 mg) was added to 1 ml of FAMSO, and 60 mg of sodium hydroxide was added. The mixture was stirred at 95° C. for 70 minutes in an atmosphere of argon. Water (20 ml) was added, and the reaction mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column using methylene chloride as an eluant to afford 1.035 g of 1-methylsulfinyl-1-methylthio-2-(m-benzoylphenyl)ethylene.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([O:20]C)=[O:19])=[CH:10]1>CO.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([OH:20])=[O:19])=[CH:10]1
Reactant: COC(=O)c1cn(-c2ccccn2)c2ncccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(-c2ccccn2)c2ncccc12
Temperature: 90 °C

Procedure:
Potassium hydroxide (11.30 mg, 0.201 mmol) was added to a solution of methyl 1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (10.2 mg, 0.040 mmol) in MeOH (67.1 μl) and water (67.1 μl) at RT. The mixture was heated at 90° C. for 2 h. The organic layer was extracted into ethyl acetate after acidifying the mixture with 0.5 N citric acid. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid, which was used without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:15][OH:16])=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: CC1(C)OB(O)c2ccc(C=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2ccc(C=NO)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
To a mixture of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (560 mg, 2.95 mmol) and NH2OH.HCl (246 mg, 3.54 mmol) in THF (6 mL) and H2O (1.5 mL) at rt was added NaOAc (339 mg, 4.13 mmol). The reaction mixture was stirred at rt for 16 h, diluted with H2O and extracted with EA (10 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (620 mg, 100% yield) as a white solid.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27][NH2:28]>>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[CH:24][CH:23]=2)[C:19]([CH2:25][CH2:26][CH2:27][NH:28][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:20]1
Reactant: ClCCOc1cccc2ccccc12
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Product: c1ccc2c(OCCNCCCc3c[nH]c4ccccc34)cccc2c1
Yield: 85 %

Procedure:
This compound was prepared in the manner described above for Example 13 by replacing 2-(indan-4-yloxy)-ethylchloride with 2-(napthalen-1 -yloxy)-ethylchloride (0.6 g, 2.8 mmol), and 3-(5-fluoro-1H-indol-3-yl)-propylamine with 3-(1H-indol-3-yl)-propylarmine (1.35 g, 7.2 mmol) in 85% yield (1.42 g) as a yellow solid: mp 119-120° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[CH2:40][OH:41])=[CH:34][CH:33]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:25][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:41][CH2:40]/[CH:39]=[CH:38]/[C:35]2[CH:36]=[CH:37][C:32]([CH2:31][C:27]3[NH:26][CH:30]=[CH:29][N:28]=3)=[CH:33][CH:34]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
346 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-caboxylic acid together with 215 mg (1 mM) of (E)-3-{4-(1-imidazolylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 474 mg (87.4%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[S:10][CH2:11][CH2:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:4].[OH-].[K+].CCO>CCO.O>[F:22][C:13]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:12][CH2:11][S:10][C:6]1[N:7]=[CH:8][S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
4-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid methyl ester (0.88 g, 2.54 mmol) is taken in EtOH/water (1:1) (4 ml) powdered KOH (0.36 g, 6.34 mmol) is added. The mixture is refluxed vigorously at 120° C. for 16 h. After completion of the reaction, EtOH is evaporated. The residue is diluted with water (20 ml), acidified with 2M hydrochloric acid to pH 3, and extracted with EtOAc (3×30 ml). The combined organic layers are dried over sodium sulfate, evaporated to dryness yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid (0.7 g, 2.09 mmol, 83%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH:14]([C:16]([OH:18])=[O:17])[CH3:15])[C:4]1=[O:19].[CH2:20]([CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[ClH:1].[C:16]([CH:14]([N:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][CH2:9][CH:3]([NH:2][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:4]1=[O:19])[CH3:15])([OH:18])=[O:17]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C(=O)O)N1C(=O)C(N)CCc2ccccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(C(C)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-1-(1-carboxyethyl)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one hydrochloride (3 g) and ethyl benzylpyruvate (6.5 g) in acetic acid (30 ml) and methanol (30 ml) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.8 g) in methanol (10 ml) was added over 4 hours. The reaction mixture was stirred at room temperature for 24 hours. Cencentrated hydrochloric acid (2 ml) was added and the mixture was stirred for 1 hour. The solvents were removed at reduced pressure and the residue was partitioned between water (50 ml) and ether (30 ml). The pH was adjusted to 9.4, the ether layer was separated and discarded. The aqueous solution was adjusted to pH 4.3 and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate solutions were dried over magnesium sulfate and the solvent removed under reduced pressure. Hydrogen chloride was bubbled into a solution of the crude product in methylene chloride (10 ml) for 2 minutes. The solution was evaporated to give 1-(1-carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one hydrochloride, as a mixture of diastereomers, m.p. 87°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11]([OH:13])=O)[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][CH:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CC(O)CC1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Product: C=CC1CC1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C

Procedure:
Reaction of compound the acid 23c (50 mg, 37 mmol) with (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert-butyl ester according to the method described in Example 1 step j, provided the title compound as a slightly yellow oil (50 mg, 38%). 1H-NMR (300 MHz, CDCl3): δ [(1.38 & 1.42) s, 9H], 1.75-1.83 (m, 1H), 2.00-2.21 (m, 3H), 3.55-3.63 (m, 1H), [(3.77 & 3.82) s, 3H], 4.20-4.38 (m, 1H), 4.65-4.80 (m, 1H), 5.13-5.20 (m, 1H), 5.22-5.38 (m, 1H), 5.60-5.82 (m, 1H), 6.95-6.96 (m, 2H). Inhibitors of the invention are achieved from the title compound by coupling of the afforded cyclopentenol derivative to a desired pyrimidinol for example as described in Example 3 step f, followed by hydrolysis of the methyl ester using a reagent like LiOH; coupling of a desired alkenylamine and macrocyclisation as described in Example 3 step h and i; hydrolysis of the tert. butyl ester by treatment with for example TFA and finally coupling of a desired sulphone amide derivative for example as described in Example 3, step k.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=[CH:30][C:29]([CH2:28][N:11]2[CH2:12][CH2:13][N:8]([CH2:14][C:15]3[N:16]=[N:17][C:18]4[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=4)[N:20]=3)[CH2:9][CH2:10]2)=[CH:34][CH:33]=1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(CN3CCN(Cc4ccc(-c5ccccc5)cc4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (30 mg; 0.05 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added 4-chloromethylbiphenyl (15 mg; 0.08 mmol) followed by potassium carbonate (28 mg; 0.20 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 20 mg of yellow colored 3-(4-Biphenyl4-ylmethyl-piperazin-1-ylmethyl)-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[CH2:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>>[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:3]([O:2][CH3:1])([CH3:5])[CH3:4]
Reactant: OCCCCl
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: COC(C)(C)OCCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a 1-liter, 4-necked round-bottomed flask, equipped with a mechanical stirrer, nitrogen inlet, internal thermometer, addition funnel and cooling bath (-20° to -25° C.), is added 288.4 g (4.0 mol) of 2-methoxypropene and 0.502 g (0.0002 mol) of the pyridinium salt of p-toluene sulfonic acid. To the cooled solution is then slowly added, under a nitrogen flow over a period of 1 hour, 189.0 g (2.0 mol) of 3-chloropropanol. The reaction mixture is then stirred at -20° to -25° C. for 1 hour and then warmed to 0° C. To the reactor is then added a mixture of 25 ml of a saturated aqueous sodium bicarbonate solution and 425 ml of a saturated aqueous sodium chloride solution. The resultant mixture is then transferred to a separatory funnel and the layers are separated. The organic layer is then concentrated in vacuo at 40° C. and the resultant clear light oil is dried at room temperature under high vacuum for 3 hours to yield the desired compound (97.4% yield; and 98.06% purity).
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][CH2:9][O:10][C:11](=[O:36])[C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])=[C:16]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[C:15]([CH3:34])=[N:14][C:13]=2[CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:43](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[C:1]1([CH:7]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:8][CH2:9][O:10][C:11](=[O:36])[C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])=[C:16]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:43])[CH2:30][CH2:29]3)=[O:27])[C:15]([CH3:34])=[N:14][C:13]=2[CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-c2c(C(=O)OCCC(c3ccccc3)c3ccccc3)c(C)nc(C)c2C(=O)N2CCNCC2)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C(=O)OCCC(c3ccccc3)c3ccccc3)c(C)nc(C)c2C(=O)N2CCN(C)CC2)c(C)c1
Reaction time: 0.5 h

Procedure:
169 mg (0.301 mmol) of 4-(2,4-dimethylphenyl)-2,6-dimethyl-5-(piperazine-1-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester was dissolved in 10 ml of DMF. 62.4 mg (01.301 mmol) of potassium carbonate was added and stirred for 30 minutes. 51.3 mg (0.361 mmol) of methyl iodide was added under cooling with ice and stirred at the same temperature for 1 hour. The reaction mixture was further stirred for 10 minutes after adding water. After evaporating DMF under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol =50/1 to 10/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([N:24]2[CH2:25][CH2:26][N:27]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:23]2=[O:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)cc3F)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A 0° C. mixture of 3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.528 mmol) and TEA (0.1 mL, 0.716 mmol) in DCM (5 mL) was treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with DCM, sonicated and allowed to evaporate overnight. The residue was treated with Et2O, sonicated and the resulting solid collected via filtration to afford N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (154 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 7.95 (s, 1 H), 7.74 (dd, J=12.9, 2.2 Hz, 1 H), 7.36-7.28 (m, 2 H), 7.22 (d, J=2.5 Hz, 1 H), 6.62 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.82 (m, 6 H), 3.79 (m, 2 H), 3.45 (m, 2 H), 3.37 (m, 2 H), 1.72 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: (M+H+): 481.2.