Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:62]>C1COCC1.O1CCOCC1>[ClH:62].[O:15]([C:22]1[CH:23]=[CH:24][C:25]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidine carboxylate (1.0 g, 5.0 mmol) in anhydrous THF (5 mL) was added 4-phenoxyphenol (1.21 g, 6.5 mmol) in THF (5 mL) and triphenyl phosphine (1.57 g, 6 mmol) in THF (5 mL). The resulting mixture was cooled to 0° C. using ice-water bath and purged with nitrogen. Diisopropyl azodicarboxylate (1.21 g, 6 mmol) was dissolved in 5 mL of THF and added to above solution drop wise over period of 20 min under nitrogen. Reaction then was heated at rt for 3 h and 70° C. for 48 h. THF was removed in vacuo and crude mixture was purified by silica gel flash chromatography (10% EtOAc/Hexane) to obtain the product. To a solution of the product in dioxane (4 mL) was added 4M HCl in dioxane (10 mL) at rt and the resulting mixture was stirred for 3 h at that temperature. The solvent was removed in vacuo and residue was triturated with ether to obtain a white crystalline solid (918 mg, 68%): MS; m/z 270.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.81-1.87 (m, 2H), 2.07-2.12 (m, 2H), 3.02-3.08 (m, 2H), 3.19-3.25 (m, 2H), 3.56 (s, 1H), 4.57-4.61 (m, 1H), 6.92-7.10 (m, 7H), 7.33-7.37 (m, 2H), 8.91 (s, 2H); HPLC (UV); 96%. Elemental analysis. Calc C 66.77 H 6.59 N 4.58. Found C 65.82 H 6.70 N 4.77.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:20])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][C:8](=[O:20])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[C:16]2[O:17][CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: COc1cccc2c(O)c(-c3ccccc3)c(=O)oc12
Product: COc1cccc2c(OCCN3CCOCC3)c(-c3ccccc3)c(=O)oc12
Yield: 74 %

Procedure:
This compound is prepared according to the method of Example 8 from 45.6 g. (0.17 mol) of 3-phenyl-4-hydroxy-8-methoxy-coumarin and 30.5 g. (0.24 mol) of 2-morpholino-1-chlorethane. After recrystallisation from isopropanol, 48 g. are isolated; M.P. 90°-91° C. Yield 74% (theoretical yield 65.0 g.).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1>O1CCCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOc1ccc(Br)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 114.7 %

Procedure:
To a solution of NaH (0.160 g, 6.68 mmol) in anhydrous tetrahydrofuran (20 mL) was added diethyl malonate (1.07 g, 6.68 mmol) dropwise at 0° C. The resulting colorless solution was stirred at 0° C. for 15 minutes, then at room temperature for 30 minutes before cooling again to 0° C. A solution of 1-bromo-4-(2-bromoethoxy)benzene (1.70 g, 6.07 mmol) in anhydrous tetrahydrofuran (10 mL) was added over 5 minutes. The resulting mixture was heated at reflux until complete as judged by TLC. The mixture was cooled to room temperature and carefully quenched with water and then extracted with ethyl acetate (4×50 mL). The combined organic phases were dried over sodium sulfate filtered and concentrated under reduced pressure to give the title compound (2.5 g) as a colorless oil which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) ppm 7.43-7.32 (m, 2H), 6.84-6.68 (m, 2H), 4.32-4.14 (m, 4H), 4.01 (m, 2H), 3.64 (m, 1H), 2.43-2.32 (m, 2H), 1.33-1.18 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH3:34])[CH2:26][CH2:25]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:16][C:7]1[CH:6]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=3)[CH3:34])[CH2:28][CH2:29]2)=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCN(CCOC(C)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC=CC(=O)N2CCN(CCOC(C)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc(OC)c1O
Yield: 82.5 %

Procedure:
To a solution of 618 mg (0.929 mmol) of the amide compound in methanol (10 ml) was added 181 (0.952 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 15 hours. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate, and then extracted with chloroform. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was sujected to silica gel column chromatography, eluted with chloroform-methanol (100:1), to give 422 mg (0.766 mmol) of N-[5-(3,5-dimethoxy-4-hydroxyphenyl]-2,4-pentadienoyl]-N'-[2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine. Spectrophotometric data of the product support the structure shown below. ##STR126##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)[CH2:3][CH2:2]1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][OH:17].[H-].[Na+]>O1CCCC1>[CH2:20]([O:19][C:15](=[O:18])[CH2:16][O:17][C:11]1[CH:10]=[C:9]([Cl:14])[N:8]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:12]=1)[CH3:21]
Reactant: CCOC(=O)CO
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
2-Morpholino-4,6-dichloropyrimidine (2.34 g; 10 mmol) and ethyl glycolate (1.3 g; 12 mmol) were dissolved in tetrahydrofuran (100 mL), and chilled in an ice bath. To the solution was added sodium hydride (300 mg; 12 mmol), and it was stirred overnight at ambient temperature. The solvents were evaporated, and the solid was dissolved in ethyl acetate (200 mL) which was then washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, and evaporated to give (6-chloro-2-morpholin-4-yl-pyrimidin-4-yloxy)-acetic acid ethyl ester (3.16 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[O:13][C:12](=[O:22])[NH:11]2)[C:6]([F:9])=[N:7][CH:8]=1)#[CH:2].Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([F:30])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(N(CC)CC)C.[Cu]I.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>[F:9][C:6]1[C:5]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[O:13][C:12](=[O:22])[NH:11]2)=[CH:4][C:3]([C:1]#[C:2][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([F:30])[CH:25]=2)=[CH:8][N:7]=1
Reactant: C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Reactant: Fc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1N[C@H](c2cc(C#Cc3ccnc(F)c3)cnc2F)[C@@H](c2cccc(F)c2)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a 15 ml sealable vial was added (4R,5R)-4-(5-ethynyl-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (20 mg, 0.067 mmol) in triethylamine (2 mL). To this suspension was added 4-bromo-2-fluoropyridine (15.24 mg, 0.087 mmol), triphenylphosphine (5.24 mg, 0.020 mmol) and copper(I) iodide (0.254 mg, 1.332 μmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (0.935 mg, 1.332 μmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromotagraphy eluting first with 100% CH2Cl2 then 1% MeOH/99% CH2Cl2 affording (4R,5R)-4-(2-fluoro-5-((2-fluoropyridin-4-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (9.1 mg, 0.021 mmol, 31.4% yield) as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.51 (d, J=4.0, 1H), 8.45 (s, 1H), 8.14 (dd, J=8.0, 4.0, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.50-7.43 (m, 1H), 7.21-7.13 (m, 2H), 6.05 (brs, 1H), 5.39 (d, J=4.0, 1H), 5.04 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.01 min. Mass=396.20 (MH)+.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([OH:39])=[O:38])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(CC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(CC(=O)O)cc1
Yield: 63.8 %

Procedure:
Next, 1.25 g (1.94 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[4-(benzyloxycarbonylmethyl)phenyl] (methyl)phosphono}butanoate was dissolved in 20 mL of acetic acid and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced at room temperature for 3.5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was purified by medium pressure reversed-phase chromatography (ODS-S-50B). The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions of the compound eluted with 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying from water were carried out to obtain 2-amino-4-{[4-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid (0.41 g, yield 64%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]4[C:21]([CH:22]=3)=[N:20][N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=4)[CH:9]=[C:10]([CH2:11][CH2:12]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C1COCC1>[CH2:23]([N:19]1[CH:18]=[C:17]2[C:21]([CH:22]=[C:14]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][Br:31])[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:15]=[CH:16]2)=[N:20]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ncnn2c(CCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of 2-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-ethanol (210 mg, 0.55 mmol) in anhydrous THF (5.5 mL) at 0° C. was added carbon tetrabromide (235.5 mg, 0.71 mmol, 1.3 eq) and triphenylphosphine (157.6 mg, 0.60 mmol, 1.1 eq), and the reaction mixture was stirred at rt for 16 h. The reaction was poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by MPLC (Biotage®) eluted with 15% acetone/DCM to give 222.6 mg (91%) of desired product as a white solid. 1H-NMR (300 MHz, DMSO-d6) 8.55 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.58 (s, 1H), 7.36 to 7.15 (m, 5H), 7.13 (d, 1H), 6.73 (s, 1H), 5.65 (s, 2H), 3.82 (t, 2H), 3.46 (t, 2H); ES-MS m/z 447.3/449.2 [M+H]+, RT (min) 2.91.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[S:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])=[O:38])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
L-prolyl-L-proline benzylester hydrochloride (1.69 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C., and next for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-benzenesulfonyl-L-prolyl-L-proline benzylester(yield: 2.17 g, 98.1%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:10]=O>C(O)=O>[CH3:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1CCCCN1
Reactant: C=O
Solvent: O=CO
Product: CN1CCCCC1C(=O)O
Reaction time: 5 h

Procedure:
Into a 25 ml 3-necked round bottom flask, was placed piperidine-2-carboxylic acid (975 mg, 7.56 mmol), HCHO (2.0 ml) and HCOOH (2.6 ml). The resulting solution was allowed to react, with stirring, for 5 hours while the temperature was maintained at reflux. The reaction progress was monitored by LCMS. The mixture was then concentrated by evaporation under vacuum using a rotary evaporator. The residue was triturated with 30 ml of Et2O to provide 1-methylpiperidine-2-carboxylic acid of as a white solid (0.5 g, 41%).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.COCCOC.[NH3:50]>N.CO>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:50])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: N
Solvent: COCCOC
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 67 %

Procedure:
A solution of 9 (1.00 g) in DME/NH3 (50 ml) was heated at 80° C. in a steel bomb for 24 hours. After cooling, the solvent was evaporated and the solid obtained was stirred in NH3 /MeOH (100 ml) overnight. After the evaporation of the solvent, the residue was dissolved in water (50 ml), washed with CHCl3 (2×25 ml) and ether (2×25 ml). The water layer was evaporated and the residue crystallized from water to give pure 10 (0.30 g, 67%) as white crystals: m.p. 225° C. (dec).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[C:11]2[O:12][CH:13]([CH3:17])[C:14](=[O:16])[NH:15][C:10]=2[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][CH:2]([F:4])[O:5][C:6]1[C:11]2[O:12][CH:13]([CH3:17])[C:14](=[O:16])[NH:15][C:10]=2[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=1
Reactant: FC(F)Cl
Reactant: CC1Oc2c(O)cc(C=O)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 65.1 %

Procedure:
A 40 mL vial cooled in a dry ice/acetone bath was charged with chlorodifluoromethane (0.209 g, 2.413 mmol) followed by the addition of 8-hydroxy-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 398A (0.5 g, 2.413 mmol), Cs2CO3 (0.786 g, 2.413 mmol) and DMF (4.83 mL). The dry ice/acetone bath was removed; and with continued stirring, the reaction was slowly warmed to 23° C. After 2.5 hr, the reaction was transferred to a sand bath and stirred at 70° C. for 72 hr. The crude material was purified by prep HPLC-MS (30-55% MeCN in water, basic mode). The fractions were collected and concentrated in vacuo to give the title compound as a white solid (0.404 g, 57% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.51 (m, 3H) 4.93 (q, J=6.82 Hz, 1H) 7.08-7.28 (m, 1H) 7.32 (d, J=1.77 Hz, 1H) 7.46 (d, J=1.01 Hz, 1H) 9.83-9.88 (m, 1H) 11.14 (s, 1H). ESI-MS: m/z 258.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@@H:43](OS(C)(=O)=O)[CH:44]([CH3:46])[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1.[C:52](#[N:54])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:52]#[N:54])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC#N
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](OS(C)(=O)=O)C(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C#N)C(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 19c, 370 mg of methanesulfonic acid (R)-1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-ylmethyl]-2-methyl-propyl ester in the presence of 275 mg of tetrabutylammonium cyanide in acetonitrile are used to afford the title compound as a yellow oil. Rf=0.30 (EtOAc-heptane 1:1); Rt=5.38.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[CH:5]2.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]#[N:14])[CH:3]=2)[N:8]=1
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2nc(Cl)ccc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 6-bromo-2-chloroquinoline (0.90 g, 3.7 mmol), CuCN (0.50 g, 5.6 mmol) followed by addition of DMF (10 mL). The resulting mixture was then refluxed at 150° C. overnight. When the reaction appeared complete by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, redissolved in DCM, absorbed onto silica gel, and purified by flash chromatography to provide the title product.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:12][CH2:11][O:10][CH3:9])=[CH:6][N:7]=1
Reactant: COCCBr
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)nc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
To a 20 mL microwave vial, 6-fluoropyridin-3-ol (Alfa Aesar, 1.04 g, 9.24 mmol), 2-bromoethyl methyl ether (Aldrich, 1.04 mL, 11.1 mmol) and potassium carbonate (1.97 g, 14.2 mmol) were mixed into DMF (8 mL). The suspention was stirred at 45° C. for 1 h. The temperature was raised to 55° C. for 45 min. 2-Bromoethyl methyl ether (0.50 mL) was added and the mixture was stirred at 40° C. for overnight. The reaction mixture was poured into about 50 mL water and the aqueous phase was extracted with diethyl ether (2×40 mL). The aqueous phase was saturated with solid NaCl and extracted with diethyl ether (2×40 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The light brown oil was placed under an air stream for 30 min to remove residual ether to afford 2-fluoro-5-(2-methoxyethoxy)pyridine (1.64 g, 100% yield) as an amber oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.84-7.87 (m, 1H) 7.37 (ddd, J=9.05, 6.21, 3.13 Hz, 1H) 6.85 (dd, J=8.80, 3.52 Hz, 1H) 4.13-4.17 (m, 2H) 3.74-3.78 (m, 2H) 3.45 (s, 3H). m/z (ESI, positive ion): 172.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[I:32])[C:27]#[N:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:24]1[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][C:31]=1[I:32])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1I)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.16 g (32.8 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of toluene. 10.5 g (42.7 mmol) of 3-hydroxy-4-iodobenzonitrile, 11.2 g (42.7 mmol) of triphenylphosphine and 7.4 g (42.7 mmol) of N,N,N′,N′-tetramethylazodicarboxyamide were added to the solution under cooling with ice, and they were stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by the silica gel column chromatography (volume ratio of hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: [CH:1](=[N:8][CH:9]=[CH:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]=[CH:13][CH:14]=[CH2:15]>>[CH3:11][CH:10]1[CH2:4][CH:3]=[CH:2][CH2:1][CH2:15][CH:14]=[CH:13][CH2:12][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9]1
Reactant: C=CC=C
Reactant: CC=CN=Cc1ccccc1
Product: CC1C=NC(c2ccccc2)CC=CCCC=CC1

Procedure:
In a manner analogous to that described in Example 1(a), 495 g (3.41 mols) of N-benzylidene-propenylamine is reacted with 1,3-butadiene. The reaction mixture is distilled to yield 750 g (2.97 mols) of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene as a cis-trans isomeric mixture (cis:trans=65:35); b.p. 112°-113° C./1 Pa; nD20 =1.5505; m.p. (cis isomer)=57°-58° C.