Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][CH2:12][C@H:11]([NH:14]C(OC(C)(C)C)=O)[CH2:10]1)=[O:8]>CO>[ClH:4].[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]1)=[O:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](N)C1
Product: Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Acetyl chloride (3.5 mL, 49.3 mmol) was added dropwise at 0° C. to 100 mL of MeOH. The resulting mixture was stirred at 0° C. for 5 minutes before adding (1S,3S)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid methyl ester (1.192 g, 5.2 mmol). The reaction mixture was allowed to warm up to RT and stirred for 48 h before being evaporated to give crude (1S,3S)-3-amino-cyclopentanecarboxylic acid methyl ester hydrochloride which was used as is in the following step.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])[CH2:6][CH2:5]1)(=O)C.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[O:14]([CH:12]([CH3:13])[CH2:11][O:10][CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCC(OCC(C)O)CC1
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(COC1CCNCC1)Oc1ccccc1
Reaction time: 3 h
Yield: 3.6 %

Procedure:
N-Acetyl-4-(2-hydroxy-n-propoxy)piperidine (12 g.) in dry D.M.F. (50 ml.) was added dropwise to a stirred suspension of sodium hydride (5.0 g., 50% dispersion in mineral oil) in D.M.F. (50 ml.) at 60°-70° C. under an atmosphere of nitrogen. The suspension was stirred for 3 hours, then fluorobenzene (6.4 g.) in D.M.F. (50 ml.) added dropwise and the suspension stirred at 100° C. for 50 hours. The cooled solution was treated with isopropanol (20 ml.) then water (200 ml.), extracted with petroleum ether (3×200 ml.) and chloroform (3×200 ml.). The combined chloroform extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue (9.0 g.) in sodium hydroxide solution (20 ml., 5N) and methanol (20 ml.) to bring about solution was heated under reflux for 5 hours. The methanol was evaporated, the residue diluted with water then extracted with chloroform (3×50 ml.). The combined chloroform extracts were washed with 2N HCl (3×30 ml.), the combined aqueous extracts basified to pH 12 with sodium hydroxide solution and extracted with chloroform (3×50 ml.). The combined chloroform layers were dried (Na2SO4), solvent evaporated in vacuo, then the residue triturated with ether and filtered. The filtrate was concentrated then distilled to give 4-(2-phenoxy-n-propoxy)piperidine (0.5 g.), b.p. 118°-122° C./0.3 mm., characterized spectroscopically.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([OH:28])=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH2:35]>CN(C=O)C>[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH:35][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:29])=[O:28]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)O)s2)cc1C
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)NCC(=O)OC)s2)cc1C
Yield: 97 %

Procedure:
Using a procedure analogous to Example 38, 5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 51) (0.3 g, 0.72 mmol), glycine methyl ester hydrochloride, and DMF (2 mL) as reaction solvent to give the title compound (0.34 g, 0.69 mmol, 97%). 1H NMR (CDC3), δ 0.71 (t, J=7.1 Hz, 6H), 0.95 (t, J=7.1 Hz, 6H), 1.63-1.72 (m, 4H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 4.15 (d, J=5.2 Hz, 2H), 6.20 (t, J=5.2 Hz, 1H), 6.63 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.98-7.01 (m, 1H), 7.01-7.06 (m, 1H). LC/MS (m/z): calcd. for C27H38NO5S (M−H)−: 488.7; found: 488.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([C:25]2[N:26]=[CH:27][O:28][CH:29]=2)[O:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH:17]=[C:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH2:12]2)=[C:6]([CH3:8])[CH:7]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([C:25]2[N:26]=[CH:27][O:28][CH:29]=2)[O:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH2:12]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(C(O[C@@H]2CCC[C@H](C=C3SC(=O)NC3=O)C2)c2cocn2)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C(O[C@@H]2CCC[C@H](CC3SC(=O)NC3=O)C2)c2cocn2)c(C)c1
Yield: 85.3 %

Procedure:
0.35 g of 5-[1-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]-methylidene]thiazolidine-2,4-dione is dissolved in 12 ml of a solvent mixture of ethyl acetate and methanol (3:1), and 20 mg of palladium-on-carbon are added. The mixture is then hydrogenated at room temperature under a hydrogen pressure of 3 bar for 2 hours. The catalyst is filtered off and the solvent is then removed under reduced pressure and the residue is taken up in acetonitrile. The product can be filtered off, giving 0.3 g of 5-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dione as a white solid. C22H26N2O4S (414.52), MS (ESI): 415 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[C:10]([F:26])=[C:11]([C:19]3[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=3)[CH:12]=[CH:13][C:14]=2[CH:15]2[CH2:18][CH2:17][CH2:16]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O.O1CCOCC1>[NH2:25][C:22]1[N:23]=[CH:24][C:19]([C:11]2[C:10]([F:26])=[C:9]([C:14]([CH:15]3[CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=2)[O:8][C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=3)=[CH:7][N:6]=2)=[N:20][CH:21]=1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(Oc3ncc(Br)cn3)c2F)cn1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(C3CCC3)c(Oc3ncc(-c4cnc(N)nc4)cn3)c2F)cn1
Temperature: 25 °C

Procedure:
5-(3-((5-Bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine (60 mg, 0.14 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (32 mg, 0.14 mmol) were added to a sealable microwave vial equipped with a stir-bar. 1,4-Dioxane (0.58 mL) and Na2CO3 (2 M, 0.14 mL) were added And the mixture sparged with Ar for 10 min before adding Pd(dppf)Cl2.CH2Cl2 (5 mg, 0.007 mmol) and heating the reaction mixture at 80° Celsius for 15 hours. The reaction was then cooled to rt, diluted with water (5 mL), and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C22H19FN8O, 430.17; m/z found, 431.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.83 (s, 2H), 8.67 (s, 2H), 8.23 (s, 1H), 8.16 (s, 1H), 7.82-7.74 (m, 1H), 7.30 (d, J=8.3, 1H), 3.68 (p, J=8.9, 1H), 2.31-2.08 (m, 4H), 2.07-1.92 (m, 1H), 1.92-1.76 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.C([Mg]Cl)(C)C.[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[C:8]([OH:11])=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[CH:10]=3)[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2cc(O)ccc2o1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
To a cooled (0° C.) suspension of 2-methyl-1,3-benzoxazol-5-ol (Fujita, et al., Synthesis (1982):62-9) (10.3 g, 68.9 mmol) in anhydrous tetrahydrofuran (150 mL) was added isopropylmagnesium chloride (34.4 mL, 2.0 M solution in tetrahydrofuran, 68.9 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, and 1-benzhydrylindoline-2,3-dione (18.8 g, 59.9 mmol) and anhydrous dichloromethane (150 mL) were added. The reaction mixture was heated at reflux for 6 days and was allowed to cool to ambient temperature. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (200 mL) and ethyl acetate (200 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL) and the combined organic solution was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/ethyl acetate (3/1), followed by recrystallization from hexanes/ethyl acetate to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one (3.10 g, 10%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ8.41 (br s, 1H), 7.63-7.60 (m, 2H), 7.47-7.32 (m, 10H), 7.15 (s, 1H), 7.04-6.96 (m, 1H), 6.96-6.88 (m, 1H), 6.87 (d, J=9.0 Hz, 1H), 6.41 (d, 7.8 Hz, 1H), 4.58 (br s, 1H), 2.44 (s, 3H); MS (ES+) m/z 445.2 (M−17).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([C:12]([N:17]2[CH:20]([N+:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:19][C:18]2=[O:28])=[C:13]([O-:16])[CH2:14][CH3:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:31]>O>[Cl-:31].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]([N:17]2[CH:20]([N+:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:19][C:18]2=[O:28])=[C:13]([OH:16])[CH2:14][CH3:15])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: CCC([O-])=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1[N+](CC)(CC)CC
Reactant: Cl
Solvent: O
Product: CCC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1[N+](CC)(CC)CC
Product: [Cl-]

Procedure:
A mixture of 1-(4-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate (210 mg) in water (10 ml) and 0.1 N hydrochloric acid (5 ml) was lyophilised and the residue triturated with ether to afford the title salt (220 mg), νmax (Nujol) 1790 cm-1 (β-lactam), τ (DMSO-d6) values for mixture of isomers include 4.50 (m, azetidinyl C--4H), 6.3-6.8 (m, NCH2), 6.7-7.3 (m, ##STR7##
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[C:20]([NH2:24])(=[S:23])[CH2:21][CH3:22].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:21]([C:20]1[S:23][C:3]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=2)=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[N:24]=1)[CH3:22]
Reactant: CCC(N)=S
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(F)c2)s1
Yield: 38.1 %

Procedure:
A solution of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide (11 g, 29 mmol) and thiopropionamide (2.7 g, 30 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 14 hrs. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to give the title compound (3.3 g, yield 38%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:6]1.Cl.[CH3:31][O:32][NH2:33]>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:33][O:32][CH3:31])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[CH:6]1
Reactant: CN1CCN(Cc2cn(Cc3ccc(F)cc3F)c3cnc(C(=O)O)cc23)CC1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2c(CN3CCN(C)CC3)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-3-[(4-methylpiperazin-1-yl)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methylhydroxylamine hydrochloride in analogy to step 2 of example 17. 1H NMR (MeOH-d4) δ 8.77 (s, 1H), 8.43 (s, 1H), 7.59 (s, 1H), 7.27-7.03 (m, 1H) 7.01-6.93 (m, 2H), 5.55 (s, 2H), 3.82 (s, 5H), 2.82 (m, 4H), 2.66 (m, 4H), 2.50 (s, 3H). LCMS (APCI, M+H+): 430.2. Anal. (C22H22F2N5O3×1.5H2O×0.8AcOH)C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)[C@H](N)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](COCc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 22.1 %

Procedure:
To a solution of O-benzyl-D-serine methyl ester (3,13 g, 14.96 mmol) in MeOH, was added 2-fluoronitrobenzene (1.6 mL, 15.08 mmol) and NaHCO3 (1.3 g, 15.48 mmol), and the resulting solution was brought to a reflux for approximately one day. The reaction mixture was then cooled, filtered, concentrated and chased with benzene (4×50 ml). The residue was re-dissolved in EtOAc, cooled to 0° C. and HCl gas was bubbled into the resulting solution until it reached a pH of ˜4. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. Upon completion, the reaction mixture was washed with saturated NaHCO3 (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography eluting with 8%-30% EtOAc in Hexanes to give 1.09 g (3.30 mmol) of N-(2-nitrophenyl)-O-benzyl-D-serine methyl ester.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:20])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8]>>[F:20][C:6]([F:5])([O:12][C:13]1[CH:14]=[C:15]([F:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:17][CH:18]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CN(C)C(=O)C(F)(F)Oc1cccc(F)c1
Product: CN(C)C(=O)C(F)(F)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Nitric acid (100%, 200 mL, 4.8 mol) was cooled to −5° C. 2,2-Difluoro-2-(3-fluoro-phenoxy)-N,N-dimethyl-acetamide (19.0 g, 81.5 mmol) was added at rate to keep the temperature below −2° C. Upon complete addition stirring was continued for 30 min. The reaction mixture was then poured on 450 mg ice-water. The aqueous phase was extracted with TBME (3×100 mL); the combined organic phases were washed with water (100 mL) and brine (100 mL) and dried over MgSO4. Evaporation of the solvent gave the crude product that was purified by preparative HPLC. The product (6.5 g, >98% by HPLC, 28% yield) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>CC(CC(C)C)=O>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:23])[CH:21]=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 60 °C
Yield: 92 %

Procedure:
166 g of 2-Methyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 60° C. While stirring, 136 g of acrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for six more hours. Then, extraction and distillation were conducted to obtain 2-methyl-2-adamantyl acrylate at the yield of 92%.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CC(CC)=O>[CH2:22]([O:1][C:2]1[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Cc1cc(=O)n2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C=CCOc1cccn2c(=O)cc(C)nc12

Procedure:
To 3.52 g of 9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one in 100 ml of pure ethyl methyl ketone is added 3.31 g of micronized anhydrous potassium carbonate and 2.90 g of allyl bromide. The mixture is stirred and heated under reflux for about 6 hours and then cooled. To the mixture is added 20 ml of water and the whole stirred vigorously, filtered with suction, the water layer separated, the organic layer washed with saturated aqueous sodium chloride, dried, and concentrated. The residue is recrystallized from heptane to give 9-[ (allyl)oxy]-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, m.p. 113°-115°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1B(O)O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:28]4[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=4[F:33])[N:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Reactant: OB(O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(F)c1-c1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Yield: 74 %

Procedure:
A solution of 4-(benzyloxy)-6-(6-bromopyridin-2-yl)quinoline (1.0 equiv.), 2,6 difluorophenylboronic acid (3.0 equiv.), diisopropylethylamine (3.0 equiv) and tetrakis(triphenylphospine)palladium (0.1 equiv.) in 1:1 toluene/ethanol was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (60-75 EtOAc/hexanes eluant) to yield 4-(benzyloxy)-6-(6-(2,6-difluorophenyl)pyridin-2-yl)quinoline (74%). LC/MS=425.1 (M+H), LC=3.59 min.
Reaction SMILES: [C:1]1([O:7][C:8](=[NH:10])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:18]([NH:10][C:8](=[NH:9])[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(N)Oc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N=C(NC(=O)c1ccccc1)Oc1ccccc1
Reaction time: 1 h
Yield: 73.1 %

Procedure:
O-phenylisourea (1 g) was dissolved in chloroform (50 ml) and triethylamine (1.2 g) and thereafter benzoylchloride (0.8 g) were added at 0° to 5° C. After stirring for one hour at 0° to 5° C., the mixture was washed with water and the chloroform was evaporated off under reduced pressure to give N-benzoyl-O-phenylisourea (1 g), m.p. 125.1° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Cl[C:15]1[N:24]=[C:23]2[C:18]([C:19](=[O:32])[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:22]2C=C)=[CH:17][C:16]=1[F:33].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][NH:22]3)=[CH:17][C:16]=2[F:33])[CH2:3]1
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)nc21
Reactant: NC1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c[nH]c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 87 %

Procedure:
To a cooled solution of 3-aminopyrrolidine (3.6 g) and triethylamine (4.2 g) in 100 ml of chloroform was added a solution of ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate (4.15 g) in 50 ml of chloroform over a period of 40 minutes with stirring. The reaction mixture was kept under ice-cooling for one hour and then stirred for 4 hours at room temperature. To this mixture was added a mixture of water (50 ml) and 2 N sodium hydroxide (20 ml). The chloroform layer was separated from the reaction mixture, washed with water, and dried over anhydrous sodium sulfate. The chloroform was distilled off and the residue was triturated with ethyl acetate (20 ml). The resulting solid was collected and recrystallized from ethyl acetate to give 3.9 g of ethyl 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (ethyl ester of the compound 1) m.p. 139°-141° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[Cl:13][C:14]1[C:23]2[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=1.[Cl:13][C:14]1[C:23]2[C:18](=[C:19]([O:12][CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=3)[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CCOc2cccc3c(Cl)ccnc23)cc1
Product: Cc1ccc(CCOc2ccnc3c(F)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %
Yield: 52.8 %

Procedure:
To a solution of 1.2 g of sodium hydride in 50 ml of DMF was added 3.4 g of 2-(4-methylphenyl)ethanol, and the mixture was stirred for one hour at room temperature. Then 4.5 g of 4-chloro-8-fluoroquinoline were added, the mixture was heated to reflux for five hours, and then cooled to room temperature, and poured into a mixture of ice in water. The solid phase was collected and dried. TLC showed three products. These were separated by HPLC (silica gel, 70% pentane/30% EtOAc) giving 1.84 g of 8-fluoro-4-[2-(4-methylphenyl)ethoxy]quinoline (Yield: 26.3%; M.P. 89°-90° C.) 0.610 g of 4-chloro-8-[2-(4-methylphenyl)ethoxy]quinoline (Yield: 8.7%; M.P. 74°-75° C.); and 0.450 g of 4,8-bis[2-(4-methylphenyl)ethoxy]quinoline (Yield: 6.4%; M.P. 142°-143° C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[C:5]#N.[OH-:12].[Na+].C[OH:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[C:5]([OH:15])=[O:12]
Reactant: CO
Reactant: COc1cc(F)cc(C#N)c1
Reactant: [OH-]
Agent: [Na+]
Product: COc1cc(F)cc(C(=O)O)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
In a 50 ml round bottom flask equipped with stir bar and reflux condensor added 3-Fluoro-5-methoxybenzonitrile (0.62 g, 4.10 mmol), methanol (6.2 ml) and sodium hydroxide (6.2 ml, 6N aqueous). Stirred the resulting reaction mixture at 100° C. overnight. Reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted with dichloromethane (100 ml) and acidified using hydrochloric acid (1N aqueous). The organic phase was separated, sequentially washed with water (100 ml) and brine (100 ml), dried (sodium sulfate) and concentrated in-vacuo, to yield the title compound (0.64g, 91%) as a white solid.