Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([O:20]C)=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>C(O)C>[OH:20][C:18]1[NH:24][N:23]=[C:16]([C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[CH:17]=1
Reactant: NN
Reactant: COC(=O)C#Cc1c(-c2ccccc2)nn2ccccc12
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Yield: 42.7 %

Procedure:
A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propiolate (1.50 g), hydrazine monohydrate (0.544 g) and ethanol (15 ml) was heated under reflux for 2 hours. Ethanol was evaporated in vacuo. Water (50 ml) was added to the residue and the mixture was acidified with 1N hydrochloric acid. The resultant precipitates were collected by filtration and washed with water. Recrystallization from a mixture of N,N-dimethylformamide and water gave crystals of 3-(5-hydroxypyrazol-3-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.64 g).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26]>>[CH2:18]([N:26]([CH2:25][CH2:24][O:23][C:22]1[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=1[O:20][CH3:19])[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[C:17]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Product: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12

Procedure:
reaction of 4-oxiranylmethoxy-9H-carbazole with benzyl-[2-(2-methoxy-phenoxy]-ethylamine to give a 1-{benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amino}-3-(9H-carbazol-4-yloxy)propan-2-ol;
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[CH2:30][N:29]([CH3:35])[CH2:28][CH:27]2[C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH:27]2[C:26]3[C:31](=[C:32]([Cl:34])[CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH2:30][N:29]([CH3:35])[CH2:28]2)[CH:37]=1)(=[O:44])=[O:43])=[N+:2]=[N-:3]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (1.5 g, 6.87 mmol, 1.79 equiv) in DCM (20 mL) was added triethylamine (1.5 g, 14.82 mmol, 3.86 equiv) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (1.5 g, 3.84 mmol, 1.00 equiv). The reaction was stirred overnight at room temperature at which time the resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of ethyl acetate and then was washed with 2×20 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.8 g (85%) of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:24][C:25](=[O:27])[CH3:26])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:24][C:25](=[O:27])[CH3:26])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCOC1CCCCO1)COc1cccc(C(F)(F)F)c1

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-(3-trifluoromethylphenoxy)-2-pentyne (40.18 g.; 0.104 mole) is dissolved in ethyl acetate (200 ml.). 5% Palladium on carbon (5 g.) is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 45 lbs./in2 and 25°. When 0.208 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil, yield 40.60 g.; pmr (CDCl3) δ 2.13 (3H, s CH3COO), 4.10 (2H, d CH2O), 5.20 (1H, m CHOCO), 7.22 (4H, m Aryl H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][CH2:3][CH3:4].Cl.C([N:41]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[NH2:41][C:21]([C:19]1[N:20]=[C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:7]([CH2:29][NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:6]3[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[S:17][CH:18]=1)=[O:22]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(N)=O)cs3)cc12
Yield: 93.3 %

Procedure:
A solution of 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.79 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl [6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.74 g, 93.7%) as crystals.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23]Cl)[CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][N:12]2[C@H:8]([C:7]([CH3:15])([CH3:14])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][C:11]2=[O:13])[CH:20]=[N:19][CH:18]=1
Reactant: ClCc1cncc(Br)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as colorless oil. MS: 399.2, 401.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=4)=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:27]([NH:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[CH:35][CH:36]=4)=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)C(c2ccc(Cn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)cc2)C2CCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(CNC(=O)C(c2ccc(Cn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
270 mg (0.435 mmol) of methyl 4-({[(4-{[4-(4-chlorophenyl)-1-oxophthalazin-2(1H)-yl]methyl}phenyl)(cyclopentyl)acetyl]amino}methyl)benzenecarboxylate (Example 112A) were dissolved in 10 ml of dioxane/water (3:1 v/v), and 0.652 ml (0.652 mmol) of 1 N aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature overnight. The reaction mixture was then acidified with 1 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 269 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[CH3:14][O:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:5][C:2]([NH:1][S:18]([CH2:17][CH2:16][O:15][CH3:14])(=[O:20])=[O:19])([CH3:6])[C:3]#[N:4]
Reactant: COCCS(=O)(=O)Cl
Reactant: CC(C)(N)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a stirred mixture of 10 g (0.12 mole) 2-amino-2-methyl-propionitrile and 12.1 g (0.12 mole) triethylamine in about 200 ml methylene chloride cooled by an ice bath, 18.8 g (0.12 moles) 2-methoxyethane sulfonyl chloride (the product of Example 19) in 15 ml methylene chloride were added dropwise. The reaction mixture was then stirred at room temperature over the weekend. The reaction mixture was washed three times with equal amounts (about 200 ml) water, dried over magnesium sulfate, filtered and stripped to give an oil. The oil was recrystallized from ethyl ether/petroleum ether to give 15.0 g of the above-identified product, melting point 58°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([NH:13][C:14](=O)[CH2:15][Cl:16])[C:5]2([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[C:7]([CH3:12])=[N:6][N:13]=[C:14]2[CH2:15][Cl:16])=[C:4]([CH:3]=1)[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: CC1=Nc2ccc(Cl)cc2C(O)(c2ccccc2)N1NC(=O)CCl
Solvent: O=CO
Product: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 86 %

Procedure:
A solution of 33 parts of 6-chloro-3-chloroacetylamino-3,4-dihydro-4-hydroxy-2-methyl-4-phenylquinazoline in 500 volume parts of formic acid is refluxed for 2.5 hours, followed by subjecting to distillation to remove the excess formic acid. The resulting residue is neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethylacetate. The ethyl acetate layer is washed with water and dried over sodium sulfate, followed by distilling off the solvent. The resulting product is recovered by filtration and washed with ether and then dried, whereby 5-chloro-2-(3-chloromethyl-5-methyl-s-triazol-4-yl) benzophenone are obtained as crystals. Recrystallization from acetoneether gives colorless granules melting at 140° to 142° C. Yield: 86%.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([O:24][CH3:34])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(C)(C)CC(=O)O)cc2)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(C)(C)CC(=O)OC)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from Step C (250 mg), 4-(3-bromopropyl)-2-hydroxy-3-propylacetophenone (315 mg), and potassium carbonate (410 mg) in methyl ethyl ketone (10 ml) was refluxed under N2 for 4 hours then stirred at ambient temperature for 18 hours. The mixture was filtered, washed with brine, evaporated to dryness and the resulting oil was Purified by chromatography on silica gel to provide the title compound as an oil. NMR (CDCl3) 0.90 (3H, t), 1.43 (6H, s), 1.52 (2H, m), 2.30 (2H, m), 2.50 (3H, s), 2.55 (2H, m), 2.75 (2H, s), 3.57 (3H, s), 4.18 (4H, m), 6.41 (1H, d), 6.88 (2H, d), 7.53 (1H, d), 7.72 (2H, d).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:26])[CH:17]=1>CCO.Cl>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:9][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([CH3:26])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1ccc(N)cc1OCCN(C)C
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C)c(OCCN(C)C)c2)c2ccccc2n1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 9 (0.25 g, 1.29 mmol) and 5 (0.29 ml, 1.44 mmol) in EtOH (8 mL) were added 2 drops of conc. HCl. The mixture was heated under reflux overnight. After cooling to room temperature, EtOH was removed under reduced pressure. The residue was partitioned between sat. NaHCO3 (aq.) and EtOAc (100 mL each) and the aquous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on Florisil® (50% EtOAc/Hexanes to 15% MeOH/EtOAc) to yield the title compound as a light yellow solid (0.25 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.28 g (10.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.7 ml (12.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed at 0° C. with 1.1 ml (12.0 mmol) of 4-amino-butanol. The reaction mixture is slowly heated to room temperature while being stirred by removal of the ice bath. After 16 hours, the precipitate that is formed is filtered off. The filtrate is completely concentrated by evaporation and digested with diisopropyl ether. 2.74 g (9.8 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@H:10]([C:12]1C=CC=CC=1)C)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=S.C([OH:20])C>[Ni]>[OH:1][C@@H:2]([CH2:10][CH3:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:20]
Reactant: CCO
Reactant: CCCCOC(=S)[C@@H](O)[C@@H](C)c1ccccc1
Agent: [Ni]
Product: CCCCOC(=O)[C@@H](O)CC
Temperature: 80 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
n-Butyl(S)-2-hydroxy-(S)-3-phenylthiobutyrate (60 mg) was dissolved in ethanol (2.0 mL). Celite (240 mg) and an ethanol solution (3.0 mL) of Raney nickel (360 mg) were sequentially added at room temperature to the solution, and the mixture was stirred at 80° C. for 10 hours. The reaction mixture was filtered through Celite, and the filtrate was added to water (20 mL), followed by extraction with diethyl ether (20 mL×3). The organic layers were combined, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (methylene chloride), to thereby yield colorless oil (36 mg, 100%).
Reaction SMILES: Cl.Cl.[CH2:3]1[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][O:4]1.[Cl:13][C:14]1[C:19]([F:20])=[C:18](Cl)[N:17]=[C:16]([CH3:22])[N:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:13][C:14]1[N:15]=[C:16]([CH3:22])[N:17]=[C:18]([N:10]2[CH2:11][CH2:12][N:7]3[C@H:8]([CH2:3][O:4][CH2:5][CH2:6]3)[CH2:9]2)[C:19]=1[F:20]
Reactant: C1CN2CCOC[C@@H]2CN1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Reaction time: 2 h

Procedure:
To a mixture of (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (23.28 g, 108.2 mmol) in DCM (360 mL) was added 4,6-dichloro-5-fluoro-2-methylpyrimidine (19.59 g, 108.2 mmol) and N,N-diisopropylethylamine (68 mL, 390.4 mmol). The mixture was stirred for 2 h, and the resulting solution was diluted with DCM (100 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (9aS)-8-(6-chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine as a light yellow oil that was used without further purification. LCMS: (M+H)+: 287.1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[N:8][CH:9]=1.[CH3:17]I>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:17])[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: Brc1cncc(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 143.3 %

Procedure:
NaH (17 mg, 0.71 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (1.2 mL) was added. The slurry was cooled to 0° C. and compound 10 (164 mg, 0.653 mmol, 1.00 eq) was added as a solution in THF (1.2 mL). After stirring at 0° C. for 30 minutes methyl iodide (44.8 μL, 0.708 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 248 mg (93%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.62 (s, 2H), 8.35 (d, J=2.4 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.78 (t, J=2.2 Hz, 1H), 3.36 (s, 3H); [M+1]+: 265.0.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=2)=[CH:14][C:13]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH2:39][OH:40].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:28]([O:27][C:25]([C:21]1[CH:20]=[C:19]([C:18](=[N:39][OH:40])[C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:14]=2)[CH:24]=[CH:23][CH:22]=1)=[O:26])[CH3:29]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CCC(=O)OCC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccc(C(=NO)c2cccc(C(=O)OCC)c2)cc1CCC(=O)OCC
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of 1.1 g of 2-(decyloxy)-5-[3(ethyloxycarbonyl)benzoyl]benzenepropanoic acid, ethyl ester and 220 mg of hydroxylamine hydrochloride in 25 ml of pyridine was heated at 70° C. for approximately 18 hours. The reaction was allowed to cool to ambient temperature, ethyl acetate was added, and the solution was washed several times with lN hydrochloric acid and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1.04 g of the desired title product as an oil. NMR.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C-:13]#[N:14].[K+]>CN(C=O)C.[I-].[K+]>[C:3]1([CH2:2][C:13]#[N:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
1-Chloromethylnaphthalene (5.00 ml, 33 mmol) was dissolved in N,N'-dimethylformamide (50 ml) and potassium cyanide (4.31 g, 66 mmol) and potassium iodide (0.1 g) were added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water (150 ml) and diethyl ether (2×100 ml). The combined organic phases were washed with water (100 ml), dried (MgSO4), filtered and concentrated in vacuo affording 5.41 g (98%) of 1-naphtylacetonitrile as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][CH2:13][CH2:14][NH2:15].C(N(C(C)C)CC)(C)C>C(O)C>[F:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: NCCF
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCF)nc1
Yield: 45 %

Procedure:
A stirred mixture of 2-chloro-5-nitropyridine (2.4 g, 0.015 mol), 2-fluoroethylamine hydrochloride (1.75 g, 0.0175 mol) and diisopropylethylamine (7.0 ml, 0.040 mol) in absolute ethanol (50 ml) was kept under nitrogen at ambient temperature (24° C.) for 22 hours, warmed slowly to the reflux temperature during 6 hours and refluxed for 18 hours. It was then concentrated in vacuo. The residue was mixed with saturated NaHCO3 and extracted with EtOAc. The extract was washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with CH2 cl2. The product was crystallized from methyl tert butyl ether to give 1.25 g of the titled product, mp 126°-127° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.[CH2:22]([Sn]12CCCN(CCC1)CCC2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.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>[CH2:22]([C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1C2
Reactant: c1ccc(C[Sn]23CCCN(CCC2)CCC3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C(Cc3ccccc3)=C1c1ccc(OC)cc1C2
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (29.6 mg, 0.0847 mmol), 5-benzyl-1-aza-5-stanna-bicyclo[3.3.3]undecane (38.5 mg, 85% weight pure, 0.0935 mmol), and Pd(PPh3)4 (9.8 mg, 0.00848 mmol) in anhydrous toluene (1.3 mL) was degassed, placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 100° C. After heating 4 hours, the cloudy, dark brown reaction mixture was cooled in an ice bath and filtered through a pad of celite. The filtrate was evaporated under vacuum to an orange gum (57 mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, using 9:1 hexanes-EtOAc as developing solvent. The major UV visible band at Rf 0.18-0.26 was removed and eluted with EtOAc to afford 4-benzyl-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (29 mg) as a pale yellow gum.