Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:28])[N:13]([CH2:15][C:16]3[CH:17]=[N:18][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:20][CH:21]=3)[CH:14]=2)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:22]([C:19]1[N:18]=[CH:17][C:16]([CH2:15][N:13]2[CH:14]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]=[CH:11][C:12]2=[O:28])=[CH:21][CH:20]=1)#[CH:23]
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(C#C[Si](C)(C)C)nc3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-1-((6-(2-(trimethylsilyl)ethynyl)pyridin-3-yl)methyl)pyridin-2(1H)-one (0.60 mmol, 240 mg), tetrabutylammonium fluoride (1.20 mmol, 1.2 mL) in THF (5 mL) and H2O (1 mL) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was taken up in CH2Cl2, washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 3%. The fractions were collected and evaporated. The residue thus obtained was triturated with diisopropyl ether. The precipitated solid was filtered off and dried. Further purification by circular chromatography-TLC CH2Cl2/MeOH(NH3)sat. 3% yielding 1-((6-ethynylpyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (68 mg, 35%).
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][C:9]([C:12]1[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(O)C.[O-][C:23]#[N:24].[K+]>O>[C:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:23]#[N:24])[CH:13]=1)([CH3:11])([CH3:10])[CH3:8]
Reactant: N#C[O-]
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Agent: [K+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC(C)(C)c1ccnc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To stirred dimethyl sulfate (6.70 g) was added slowly 4-tert-butyl-1-oxypyridine (8.0 g) at ca. 10° C. in an ice-water bath and the mixture was stirred for 3 hours at 80° C. After cooling to room temperature, to the mixture was added a mixture of ethanol and water (1:1, 60 ml) under stirring. To the mixture was added dropwise an aqueous solution of potassium cyanate (6.9 g in 20 ml of water) below 10° C. and stirring for 1 hour under the same condition, and then overnight at room temperature. To the resultant mixture was added 150 ml of water and the resultant mixture was extracted with CHCl3. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. A crude compound was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane to give 4-tert-butyl-2-cyanopyridine (4.6 g) as a yellow oil.
Reaction SMILES: OC(C)(C)[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])C)([CH3:5])[CH3:4].CC([O-])(C)C.[K+]>C1COCC1>[CH3:5][C:3]1([CH3:4])[C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[NH:6]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1(C)C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To tert-butyl 3-hydroxy-2,3-dimethylbutan-2-ylcarbamate (10.02 g, 46.1 mmol) in THF (300 ml) was added portion wise potassium 2-methylpropan-2-olate (7.24 g, 64.6 mmol). The reaction was stirred for five hours and quenched with HCl (1 M, 66 mL) to pH=2. The reaction mixture was then concentrated under vacuum to about one third of the volume, and diluted with water (50 mL). The aqueous layer was then extracted with DCM (3×100 mL). The combined organic was washed with brine (50 mL), dried (Na2SO4) and concentrated to give crude product as a light tan oil (6.25 g). LCMS m/z 144.1 (M+H)+, Rt 0.42 min.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl.O>[CH2:32]([O:31][C:29]([NH:28][C@@H:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([NH:20][C@H:8]([CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[CH2:7][C:6]([OH:40])=[O:5])=[O:39])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN1CCc2cc(F)ccc21
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)O)CN1CCc2cc(F)ccc21
Reaction time: 8 h

Procedure:
The title compound of example 158 (46 mg, 83 μmol) was dissolved in a mixture of TFA, dichloromethane and water in a ratio of 45:45:10 (1 mL) and stirred overnight. The solvent was removed and the reaction was lyophilized to afford 58.1 mg (114% of theory) of material that likely had some water or multiple TFA salts included; 1H NMR (MeOD, 400 MHz) δ 0.91 (s, 9H), 1.49 (dd, 1H, J1=9.3, J2=14.4), 1.67 (dd, 1H, J1=3.1, J2=14.5), 2.63 (d, 1H, J=6.5), 2.98 (dd, 1H, J1=J2=8.1), 3.17 (dd, 1H, J1=5.5, J2=13.6), 3.26-3.34 (m, 1H), 3.47 (dd, 1H, J1=8.6, J2=17.3), 3.58 (dd, 1H, J1=8.4, J2=16.6), 4.13 (dd, 1H, J1=3.0, J2=9.3), 4.46-4.55 (m, 1H), 4.98-5.11 (m, 2H), 6.68 (dd, 1H, J1=4.1, J2=8.6), 6.77-6.84 (m, 1H), 6.86-6.91 (m, 1H), 7.24-7:33 (m, 5H); HPLC-MS calcd. for C27H34FN3O5 (M+H+) 500.2, found 500.5.
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][C:11]2([C:16](=[O:17])[N:15]([C:18]3[C:19]([CH3:35])=[N:20][C:21]([N:24]4[CH2:28][CH2:27][C@@H:26]([N:29]5[CH2:33][CH2:32][CH2:31][C@@H:30]5[CH3:34])[CH2:25]4)=[CH:22][CH:23]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>CO.CCO>[ClH:38].[CH3:35][C:19]1[C:18]([N:15]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:37][CH2:36]3)[C:16]2=[O:17])=[CH:23][CH:22]=[C:21]([N:24]2[CH2:28][CH2:27][C@@H:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3[CH3:34])[CH2:25]2)[N:20]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCCC2(CCNCC2)C1=O
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of 2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester (20 mg, 0.04 mmol) in methanol (2 mL) was added a saturated solution of HCl in EtOH (2 mL) and stirred the resulting mixture for 20 hours. Concentrated the reaction mixture and dried under high vacuum to afford 20 mg (100% yield) of the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH2:19]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:20]([CH3:22])[CH3:21]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CNCC(C)C
Solvent: CCO
Product: CC(C)CN(CC(C)C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
A mixture of 26 g of 3-nitro-4-chloro-benzophenone, 20 ml. of ethanol and 35 ml. of diisobutylamine is heated to 80° to 85° C. under stirring, and the reaction mixture is kept at this temperature for 6 hours. When the reaction is over, the ethanol is distilled off under reduced pressure, and 260 ml. of petroleum ether (b.p.: 40° to 100° C.) are added to the solid residue. The separated diisobutylamine hydrochloride is removed by filtration, the filtrate is evaporated, and the residue is recrystallized from ethanol. 32.7 g of 3-nitro-4-(N,N-diisobutylamino)-benzophenone are obtained, m.p. 80°-81° C. (compound B9 supra)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: BrCCCBr
Reactant: Oc1c(F)cccc1F
Product: Fc1cccc(F)c1OCCCBr

Procedure:
Analogously to Example 91b, 2.00 g of 2,6-difluorophenol and 30.7 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.70 (1:6 EtOAc-heptane); Rt=4.97.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O-:11])=[O:10].[Na+]>>[C:1]([O:10][C:9](=[O:11])[CH:8]([NH2:7])[CH:12]([CH3:14])[CH3:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(N)C(=O)[O-]
Reactant: CCCC(=O)Cl
Agent: [Na+]
Product: CCCC(=O)OC(=O)C(N)C(C)C
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 6.39 g (60 mmol) of the prepared butyryl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 9.18 g (66 mmol) of sodium 2-amino-3-methylbutanoate. The round bottomed flask is placed in an ice bath and the butyryl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-3-methylbutanoic butyric anhydride.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH:13]([C:33]#[N:34])[C:12]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=N[OH:54])C>CO.[Cu](Cl)Cl>[CH2:1]([O:8][N:9]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH:13]([C:33](=[O:54])[NH2:34])[C:12]([CH2:35][O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=NO
Reactant: CC(C)(C)OC(=O)N(OCc1ccccc1)[C@@H]1C=C(CO[Si](C)(C)C(C)(C)C)C(C#N)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl[Cu]Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(OCc1ccccc1)[C@@H]1C=C(CO[Si](C)(C)C(C)(C)C)C(C(N)=O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A mixture of (5R)-(9H-fluoren-9-yl)methyl 5-((benzyloxy)(tert-butoxycarbonyl)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyano-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 160, 1.3 g, 1.87 mmol), acetaldehyde oxime (0.569 mL, 9.34 mmol) and newly activated copper(II) chloride on 4 Å MS (187 mg, 0.15 mmol) (used 100 mg CuCl2/mol sieves per 1 mmol substrate) in MeOH (5 mL) was stirred under nitrogen at 65° C. for 6 h. The mixture was filtered and evaporated. The residue was purified on silica gel column (0-60%, EtOAc/hexanes). The two diastereomers were combined together to afford the title compound (1.190 g, 89%) as a pale yellow foamy solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Br:26])=[CH:13][CH:14]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:7]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Br:26])=[CH:13][CH:14]=2)[CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1cc2cc(Br)ccc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cc2cc(Br)ccc2cc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (3-benzyloxy-7-bromonaphthalen-2-yl)-carbamic acid tert-butyl ester (38.65 g, 90.2 mmol) in DMF (300 mL) at 0° C. is added NaH (3.79 g, 99.3 mmol). To the solution is added methyl bromoacetate (10.3 mL, 108.2 mmol). The mixture is stirred for 10 min and then quenched with 1 N HCl. The solution is extracted with EtOAc and washed with 1 N HCl (3×) and sat. NaCl. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is recrystallized from EtOAc to afford [(3-benzyloxy-7-bromonaphthalen-2-yl)-tert-butoxycarbony-amino]-acetic acid methyl ester.
Reaction SMILES: [Cl-].[Cl-].[C:3]1([N:9](B)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>>[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]([OH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BN(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Product: OC(c1ccccc1)c1ccccc1Nc1ccccc1
Yield: 22.4 %

Procedure:
Using diphenylaminoborane dichloride (200 mg), benzaldehyde (85 mg) and tri-n-butylamine (147 mg), the reaction is effected as in Example 7, whereby 2-phenylaminobenzhydrol (49 mg) is obtained. This substance is recrystallized from benzene-hexane to give crystals melting at 111° to 112° C. Anal. Calcd. for C19H17ON: C, 82.88; H, 6.62; N, 5.09. Found: C, 82.67; H, 6.28; N, 5.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(=O)c1cnc(OCC(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)F)c(Cl)c1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (3.56 g, white solid) from 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (2.88 g, 12.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[NH2:17])=[O:10])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]#[N:17])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(N)=O
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C#N
Temperature: -35 °C
Yield: 84.8 %

Procedure:
In a dry three-necked flask, 286 mL of pyridine, (S)-[2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (13.5 g, 49.8 mmol) and imidazole (7.11 g, 104.6 mmol) were added successively under nitrogen atmosphere. Then the reaction system was cooled to −35° C. followed by dropwise addition of phosphorus oxychloride (19 mL, 204.2 mmol) with stirring. The reaction mixture was stirred for 1 hour at the same temperature. After warmed up to room temperature, the reaction mixture was stirred for another 30 minutes. The mixture was evaporated to remove pyridine and the resulting mixture was diluted with ethyl acetate followed by addition of water. The mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (S)-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1c (10.7 g, yield 84.9%) as a white powder.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([O:44][CH2:45][C:46]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:28]=[CH:29][N:30]=[CH:31][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:47])(=[O:43])[CH3:42]
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (174 uL, 1.0 mmol) and acetoxyacetyl chloride (65 uL, 0.60 mmol) and the resulted mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to give compound 189 as a yellow solid which was used in next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 514.2, Calculated 514.2.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Br)cc1Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Br)CCC1

Procedure:
using isopropyl 2,4-dibromo-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2,4-dibromo-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 157°-158° C.,
Reaction SMILES: Br[C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.Cl.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])(=O)C.[Na+]>CN(C=O)C>[CH3:9][S:8][C:5]1[N:6]=[CH:7][C:2]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]=3[NH:15][C:10](=[O:12])[C:3]=2[N:4]=1
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1nc(SC)ncc12
Temperature: 120 °C
Yield: 79.6 %

Procedure:
In a microwave vessel, methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (1.0 eq, 274 mg, 1.18 mmol), 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (1.2 eq, 329 mg, 1.42 mmol), and sodium acetate (3.0 eq, 291 mg, 3.55 mmol) were mixed in anhydrous DMF (2 ml). The mixture was degassed by bubbling nitrogen gas in the solution for 10 min and the reaction heated under microwaves at 120° C. for 30 min. After cooling down the expected material crashed out of NMP. The solid was filtered, suspended in water filtered and dried. The material was triturated in AcOEt and filtered give a yellow solid. The same procedure was repeated 9 times using the same amounts of materials to provide methyl 3-(methylthio)-5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (283 mg, 10% yield). LCMS (ES): >95% pure, m/z 302 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 2.71 (s, 3H), 3.89 (s, 3H), 7.80 (dd, J=1.6, J=8.4, 1H), 7.97 (d, J=1.6, 1H), 8.59 (d, J=8.8, 1H), 9.98 (s, 1H), 12.34 (s, 1H) ppm.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10])(=O)C.[H-].[OH-].[Li+]>O1CCCC1.O>[OH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10]
Reactant: CC(=O)Oc1cc(F)ccc1OCCO
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccc(F)cc1O
Temperature: 90 °C

Procedure:
2-(2-Acetoxy-4-fluorophenoxy)ethanol 1.53 g was dissolved in a mixed solvent of tetrahydrofuran 10 ml and water 5 ml, then lithium hydroxide monohydride 294 mg was added thereto, and the mixture was stirred at 90° C. After stirred for 10 hours, the reaction mixture was cooled and partitioned by adding water and ethyl acetate. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (1.07 g, 80%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([NH:16][CH2:17][CH2:18][NH2:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C>C(O)C>[C:12]([O:11][C:9](=[O:10])[NH:16][CH2:17][CH2:18][NH:19][C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1ncc(Br)cn1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (500 mg), N-Boc-ethylenediamine (496 mg), and triethylamine (1 mL) in ethanol (10 mL) was heated at 80° C. for 4 hours. The reaction was then concentrated in vacuo and the residue purified by preparative HPLC (hexanes:EtOAc; 60:40) to afford compound 10 (700 mg) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[I:14]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[C:8]=1[I:14]
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(CCl)nc2ccccn12
Solvent: CC#N
Product: O=c1c(I)c(CCl)nc2ccccn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
A mixture of 21.9 g (112.5 mmol) of the product from Step 1 (11) and 38.9 g (168.8 mmol) of N-iodosuccinimide in 660 mL of acetonitrile was stirred at 80° C. under nitrogen for 16 hours. The reaction mixture was then allowed to cool to ambient temperature and the acetonitrile was removed in vacuo. The resulting solid was washed with water, saturated Na2O3S2, saturated NaHCO3, brine, and filtered. Drying under reduced pressure at 40° C. overnight yielded 29.8 g (92.9 mmol, 83%) of 2-(chloromethyl)-3-iodo-4H-pyrido[1,2-a]pyrimidin-4-one (12) as a light brown solid.
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:37]=[C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][N:34]=3)=[CH:27][CH:26]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.C(O)C>[C:4]1(/[C:10](=[N:22]/[O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]3[N:37]=[C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][N:34]=3)=[CH:29][CH:30]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Lithium hydroxide monohydrate (54.9 mg) was added to a solution of ethyl E-8-phenyl-8-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]octanoate (236 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (1.4 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-phenyl-8-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]octanoic acid (208 mg, yield 93%) as colorless crystals. m.p. 76-77° C.