Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:15]Br>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Br:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(O)c(Br)c1
Reaction time: 0.08 h

Procedure:
To a solution of (4-hydroxy-phenoxy)-acetic acid ethyl ester (0.59 g, 3 mmol) in acetic acid (1.5 mL) is added bromine (0.48 g, 9 mmol) in acetic acid (0.5 mL) at room temperature. After 5 min, solvent is evaporated and purified by column chromatography on silica gel giving the title compound (0.6 g).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]([CH3:23])[C:19]2=[O:22])=[CH:14][CH:13]=1>C1CCCCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH:3]=[O:4])=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]([CH3:23])[C:19]2=[O:22])=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cn1c(-c2ccccc2)cc2ccc(Cl)cc2c1=O
Solvent: C1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccccc2)c(C=O)c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 ml of dry N,N-dimethylformamide are cooled to 0° C., under an argon atmosphere, 12 ml (128 mmol) of phosphorus oxychloride are added dropwise and the mixture is stirred at room temperature for 1 h. 13.7 g (51 mmol) of 7-chloro-2-methyl-3-phenylisoquinol-1(2 H)-one are added and the mixture is gradually heated to 110° C. and is maintained at this temperature for 4 h. It is cooled to room temperature, the solvent is evaporated under reduced pressure, 200 ml of diethyl ether and ice are added to the residue, 1N sodium hydroxide is added, the organic phase is separated and the aqueous phase is extracted with 200 ml of dichloromethane. The two organic phases are combined, dried over sodium sulphate and filtered and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of cyclohexane and dichloromethane ranging from 80/20 to 50/50 and then with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30. After recrystallizing from cyclohexane, 7.68 g (26 mmol) of white solid are obtained. Melting point: 172°-173° C.
Reaction SMILES: [Br:1][C:2]1N=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(Br)nc1N1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: O=c1[nH]cc(Br)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3-morpholinopyrazin-2(1H)-one (1.0 equiv.) in DMF (0.1 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.0 equiv.) at 0° C. and the solution was allowed to warm to room temperature and stirred for 2 hours. Upon completion, the reaction was partitioned between water and ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude material was used for the next step without further purification. Isolated 5-bromo-1-methyl-3-morpholinopyrazin-2(1H)-one in 91% yield. LCMS m/z (M+H)=274/276, Rt=0.60 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.42 (s, 3H) 3.66-3.83 (m, 4H) 3.85-4.00 (m, 4H), 6.77 (s, 1H).
Reaction SMILES: O=C1C(=[C:11]([C:14]#[N:15])[C:12]#[N:13])C2C(=CC=C(S(N3CCCC3COC3C=CC=CC=3)(=O)=O)C=2)N1.[OH:32][C:33]1[CH:66]=[CH:65][C:36]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([S:47]([N:50]4[CH2:54][CH2:53][CH2:52][CH:51]4[CH2:55][O:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)(=[O:49])=[O:48])=[CH:44][CH:45]=3)[C:40](=O)[C:39]2=[O:64])=[CH:35][CH:34]=1>>[OH:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([S:47]([N:50]4[CH2:54][CH2:53][CH2:52][CH:51]4[CH2:55][O:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)(=[O:49])=[O:48])=[CH:44][CH:45]=3)[C:40](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[C:39]2=[O:64])=[CH:65][CH:66]=1
Reactant: O=C1C(=O)N(Cc2ccc(O)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc21
Reactant: N#CC(C#N)=C1C(=O)Nc2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Product: N#CC(C#N)=C1C(=O)N(Cc2ccc(O)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc21
Yield: 85 %

Procedure:
2-{1-(4-Hydroxy-benzyl)-2-oxo-5-[2-(pyridine-3-yloxymethyl)-pyrrolidine-1-sulfonyl]-1,2-dihydro-indol-3-yl-idene}-malononitrile (30b) was prepared according to the same procedure for compound 26 except using 28b, to afford 46 mg (85%) of 30b as a purple solid, mp 203.3° C. (decomp). 1H NMR (300 MHz, DMSO) δ 9.50 (s, 1H), 8.31 (s, 1H), 8.25 (d, J=2.7 Hz, 1H), 8.17 (dd, J=4.5 Hz, J=1.5 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.34 (m, 3H), 7.24 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.88 (s, 2H), 4.16 (m, 1H), 4.08 (m, 1H), 3.96 (m, 1H), 3.41 (m, 1H), 3.18 (m, 1H), 1.91 (m, 2H), 1.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[C:33]#[CH:34].CN(C=O)C>N(CC)CC.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>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][N:35]4[CH2:36][CH2:37][S:38](=[O:42])(=[O:41])[CH2:39][CH2:40]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCN3CCS(=O)(=O)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-propargylthiomorpholine-1,1-dioxide (103.8 mg). Anhydrous DMF (18 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and further purified by HPLC. The product is recrystallized from hot acetonitrile to afford 86.1 mg (27%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14][Li].[NH4+].[Cl-]>C(OCC)C>[CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10](=[O:12])[CH3:14])[S:8][CH:9]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1scc(CC(C)C)c1C
Reaction time: 0.5 h

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (2.44 g, 12.3 mmol) in diethyl ether (50 mL), a solution of methyllithium (23.1 mL, 1.6 M solution in diethyl ether) is slowly added at 20-23° C. The resulting suspension is stirred at rt for 30 min before another portion of methyllithium (2.3 mL) is added. Stirring is continued for further 30 min before the mixture is poured into vigorously stirred 1 N. aq. NH4Cl (400 mL). The organic phase is separated and the aq. phase is extracted again with diethyl ether. The combined organic extracts are dried over Na2SO4, filtered and evaporated to leave 1-(4-isobutyl-3-methyl-thiophen-2-yl)ethanone (2.34 g) as pale yellow oil; LC-MS: tR=1.03 min, [M+1]=197.20; 1H NMR (CDCl3): δ7.08 (s, 1H), 2.52 (s, 3H), 2.46 (s, 3H), 2.42 (d, J=7.0 Hz, 2H), 1.82 (m, J=7.0 Hz, 1H), 0.92 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[O:9]1[C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[C:19](OCC)=[O:20])[O:12][CH2:11][CH2:10]1>C1COCC1>[C:1]([CH2:2][C:19]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]21[O:9][CH2:10][CH2:11][O:12]2)=[O:20])#[N:3]
Reactant: CCOC(=O)C1CCCCC12OCCO2
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC12OCCO2
Yield: 47.9 %

Procedure:
To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at −78° C. Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.
Reaction SMILES: Cl[CH:2]([OH:5])[CH2:3][CH3:4].[N+:6]([C:9]1([N+:13]([O-:15])=[O:14])[CH2:12][NH:11][CH2:10]1)([O-:8])=[O:7].[OH-].[Na+]>>[CH2:4]([N:11]1[CH2:12][C:9]([N+:13]([O-:15])=[O:14])([N+:6]([O-:8])=[O:7])[CH2:10]1)[CH:3]1[O:5][CH2:2]1
Reactant: CCC(O)Cl
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1([N+](=O)[O-])CN(CC2CO2)C1

Procedure:
reacting 1-chloropropanol-3,3-dinitroazetidine of Formula IV prepared in step (1) with aqueous solution of NaOH to obtain 1-glycidyl-3,3-dinitroazetidine of Formula I, as shown in the following reaction scheme 2-2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][CH:25]=[C:24]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])=[CH:18][C:19]=1[F:37])[CH3:44]
Reactant: CCN(CC)CCCO
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCCOc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (0.12 g, 0.23 mmol), hydroxypropyldiethylamine (0.090 mL, 0.61 mmol), triphenylphosphine (0.20 g, 0.76 mmol) in DCM (10 mL) was added DIAD (0.17 mL, 0.86 mmol). The resulting mixture was stirred at room temperature for 12 hours, after which time, the solvent was removed under reduced pressure. The residue was extracted with EtOAc and 1N HCl (6×) and brine (1×) followed by drying with Na2SO4. Concentration of the organic fraction in vacuo afforded ‘N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide as a yellow oil (0.18 g, wet, ca 95% purity by analytical HPLC). Further purification by preparatory HPLC using ammonium acetate afforded the product in 99% purity by analytical HPLC. LCMS: m/z 619 (M+H)+. 1H NMR (DMSO-d6) δ 10.37 (br s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([NH2:22])[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.ON1C2C=CC=CC=2N=N1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH2:11][C:12]2[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=2)=[O:8])=[CH:4][N:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1ccc(Br)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2ccc(Br)nc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture consisting of 6-bromonicotinic acid (Sigma-Aldrich, 1.5 g), N,N-dicyclohexylcarbodiimide (1.60 g), and dichloromethane (10 mL) was added a solution consisting of veratrylamine (1.24 g) in dichloromethane (10 mL) followed by addition of 1-hydroxybenzotriazole (100 mg). The reaction mixture was stirred overnight at room temperature. The crude reaction mixture was diluted with added dichloromethane (200 mL) and the diluted mixture was washed twice with water (2×100 mL) and once with brine solution (100 mL). The organic phase was subsequently dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a white solid. The product was triturated in ethyl acetate and collected by filtration to afford the title intermediate as a white solid (2.22 g, 85% yield); Rf 0.35 with 3:2 v/v hexanes-ethyl acetate; MS (ESI−) m/z 349, 351.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].CCN(CC)CC.[CH3:22][NH:23][CH2:24][CH:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([O:4][C:5]([C:7]1[C:8]([N:23]([CH3:22])[CH2:24][CH:25]2[CH2:32][CH2:31][C:28]3([CH2:29][CH2:30]3)[CH2:27][CH2:26]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: CNCC1CCC2(CC1)CC2
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCOC(=O)c1cnc(Cl)nc1N(C)CC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of the 2,4-dichloropyrimidine-5-carboxylic acid allyl ester (1.6 mmol) in dioxane (6 mL) is added Et3N (2.4 mmol) at room temperature. A solution of methyl-spiro[2.5]oct-6-ylmethylamine (1.6 mmol) in dioxane (2.0 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and the reaction is quenched by the addition of water. The mixture is extracted with CH2Cl2. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound (370 mg); 1H NMR (CDCl3) δ 0.15-0.19 (m, 2H), 0.25-0.29 (m, 2H), 0.87-0.91 (m, 2H), 1.08-1.20 (m, 2H), 1.60-1.85 (m, 5H), 2.95 (s, 3H), 3.59 (d, 2H), 4.77-4.78 (m, 2H), 5.29-6.08 (m, 1H), 8.48 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH3:35])[C:22]=3[NH:23][C:24]([O:26][C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])=[O:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:35][N:21]1[C:22]([NH:23][C:24]([O:26][C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])=[O:25])=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:36])=[O:3])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)[N:19]=[N:20]1
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3nnn(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(C3CCC(CC(=O)O)CC3)cc2)nnn1C)c1ccccc1
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a solution of (4-{4-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-phenyl}-cyclohexyl)-acetic acid ethyl ester (15 mg, 0.031 mmol) in THF (2 mL) and ethanol (2 mL) was added a 1.0 M solution of sodium hydroxide (310 μL, 0.31 mmol) at room temperature. The resulting colorless solution was stirred for 15 h at which time TLC analysis indicated the absence of the starting material. Then, the solvent was removed under vacuum and the basic aqueous layer was neutralized with 1 N HCl. The resulting solids were collected by filtration and washed with water and hexanes. After air drying, (4-{4-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-phenyl}-cyclohexyl)-acetic acid (10 mg, 71% yield) was isolated as a white solid. 1H NMR (DMSO-d6) δ ppm 12.04 (br. s., 1H), 9.85 (br. s., 1H), 7.62 (d, J=7.3 Hz, 2H), 6.84-7.54 (m, 7H), 5.78 (br. s., 1H), 3.83 (s, 3H), 2.16 (d, J=6.8 Hz, 2H), 1.65-1.93 (m, 5H), 1.39-1.64 (m, 5H), 1.01-1.35 (m, 3H). LC/MS calcd. for C26H30N4O4 (m/e) 462, obsd. 463.3 [M+H, ES+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([CH:47]=[O:48])=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([N:24]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:4]1[C:5]([CH3:23])=[C:6]([CH:22]=[C:2]([C:41]2[CH:46]=[N:45][C:44]([CH:47]=[O:48])=[CH:43][CH:42]=2)[CH:3]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:32]
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 66.5 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.4 g, 0.793 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (0.28 g, 1.19 mmol) and tetrakis (0.091 g, 0.079 mmol) in dioxane (5 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.301 g, 2.83 mmol) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.28 g, 66.50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:23][NH2:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([NH:24][NH:23][C:21]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:22])=[O:40])=[CH:34][CH:33]=1
Reactant: Cc1ccc2nc(C(=O)NN)c(OCc3ccccc3)c(=O)n2c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2nc(C(=O)NNC(=O)Cc3ccc(F)cc3)c(OCc3ccccc3)c(=O)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The product from Example 9.1 (160 mg, 0.524 mmol) and sodium carbonate (106 mg, 1 mmol) were mixed with anhydrous tetrahydrofuran (25 mL) and then cooled in ice bath. To this stirred solution was added 4-fluorophenylacetyl chloride (90 mg, 0.55 mmol) dropwise. The mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was portioned between ethyl acetate and water and the organic phase washed with water, dried (Na2SO4) and concentrated in vacuo. Short column chromatography afforded the desired compound (210 mg, yield 86%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])=[CH:5]1)[N:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2cc(-n3ccc(CNC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of the compound (200 mg, 519 μmol) of Example 5 in N,N-dimethylformamide (5 ml) were added phenyl isocyanate (67.6 μl, 622 μmol) and successively triethylamine (108 μl, 778 μmol), and the mixture was stirred for 1 hour at 60° C. Triethylamine (723 μl, 5.19 mmol) was added to the reaction mixture, which was stirred for 4 hours at 100° C. The residue obtained by concentrating the reaction mixture under reduced pressure was submitted to silica gel column chromatography [dichloromethane-ethanol=20:1] to obtain 64.1 mg of title compound as yellow powder. Yield 26%.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C(Cl)Cl>[F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)nc1F
Temperature: 25 °C

Procedure:
2,6 difluoronicotinic acid, (0.479 g, 3.012 mmol) was suspended in 30 mL dry methylene chloride and treated with thionyl chloride (2.5 mL, 34.27 mmol), under reflux for 90 minutes. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure on a rotary evaporator, the residue obtained was further dried under high vacuum to give 2,6 difluoronicotinoyl chloride. 2,6 difluoronicotinoyl chloride was suspended in 30 mL acetonitrile, to this was added 2-fluoro-5-chlorobenzamidine (0.52 g, 3.012 mmol) and di-isopropylehylamine (1.04 mL, 6/024 mmol). The reaction mixture was allowed to stir at room temperature for one hour, at this time the formation of the acyl amidine intermediate was confirmed by LCMS as set forth below. The reaction mixture was then heated to reflux for three hours and cooled to room temperature. The reaction mixture was concentrated to dryness on a rotary evaporator and the residue was taken up in water. The suspension obtained was placed in an ice bath and acidified with 10% aq. hydrochloric acid to pH 4. The solid precipitate that formed was filtered and washed with water and anhydrous ether and dried to give 0.611 g of 2-(2-fluoro, 5-chloro) phenyl-7-fluoro-pyrido-8-pyrimidone. ESIMS M+obsd. 294.3 M+cald. 293.66. 1H NMR d6 DMSO. δ13.15, bs, 1H; δ8.7, t, 1H; δ7.9, m, 1H; δ7.75, m, 1H; δ7.5, t, 1H; δ7.4, dd, 1H;