Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.ClCCl.[CH3:25][CH:26]([CH3:33])[C:27]([O:29][CH2:30][CH2:31][OH:32])=[O:28]>O>[C:27]([O:29][CH2:30][CH2:31][O:32][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)(=[O:28])[CH:26]([CH3:33])[CH3:25]
Reactant: CC(C)C(=O)OCCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)OCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
83 g ((0.36 mol) of 3,5-dinitrobenzoyl chloride (compound 2) and 28 g (0.36 mol) of pyridine were placed in a 1-l four-necked flask equipped with a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added 100 ml of dichloromethane for dissolution. The flask was cooled to 10° C. with ice water. Thereto was dropwise added, in 20 minutes with the temperature (10° C.) being maintained, 62 g (0.47 mol) of 2-hydroxyethyl 2-methylpropionate. After the dropwise addition, the flask was immersed in an oil bath of 50° C. and the flask contents were stirred for 1 hour. The flask was cooled to room temperature and 50 ml of water was added, followed by stirring for several minutes. All the flask contents were transferred into a separating funnel and the aqueous layer was separated to remove. The organic layer taken out was returned to the separating funnel. Thereto was added a 5% aqueous sodium carbonate solution, followed by mixing. The lower layer (organic layer) was taken out and dried over anhydrous magnesium sulfate. From the dried solution was removed dichloromethane by distillation by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from a mixed solvent consisting of 200 ml of methanol and 100 ml of water to obtain 2-(3,5-dinitrobenzoyloxy)ethyl isobutyrate (compound 3). Yield: 100 g (86%) Melting point: 55-58° C.
Reaction SMILES: C(OC(C)C#N)CCC.C(O)C.[OH-].[NH4+].[OH-].[NH4+].[CH2:17]([O:21][CH:22](OCCCC)[CH2:23][CH2:24][NH2:25])[CH2:18][CH2:19][CH3:20]>[Ni]>[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(CCN)OCCCC
Agent: [Ni]
Agent: CCCCOC(C)C#N
Agent: [NH4+]
Solvent: CCO
Product: CCCCOCCCN
Temperature: 60 °C
Reaction time: 20 h
Yield: 79.5 %

Procedure:
The previously prepared butoxypropionitrile (224.8 grams) was combined with Raney nickel (20 grams of 50/50 mixture with water) in a 1-liter stainless steel autoclave along with a premixed ethanol/ammonium hydroxide solution (37.5 grams of ammonium hydroxide and 212.5 grams of ethanol). The addition of the ammonium hydroxide limits the reaction that leads to the formation of by-product dibutoxypropylamine. After purging with nitrogen, the reactor was pressurized with 500 psi of hydrogen and heated to 60° C. After 20 hours at this temperature, the reactor was cooled to room temperature and the product discharged. The product was filtered to remove the Raney nickel and then distilled using a simple Vigreux column to extract the butoxypropylamine. The distillation produced a yield of about 79.5% of product and 18.3% of the secondary amine.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH2:27][C@H:28]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:29]([O:31][CH3:32])=[O:30])(=[O:25])=[O:24])=[CH:19][CH:18]=1>CC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:27][C@H:28]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:29]([O:31][CH3:32])=[O:30])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
420 mg (1.3 mmol) of cesium carbonate and then 0.2 ml (1.3 mmol) of 1-bromomethyl-4-fluorobenzene are added to a solution of 400 mg (1.2 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate in 10 ml of acetone. After stirring at ambient temperature for 18 h, the reaction medium is filtered and then the filtrate is concentrated under vacuum. The crude product is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 460 mg (87%) of methyl(S)-3-[4-(4-fluorobenzyloxy)benzenesulfonylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.ClCCl.ClC(Cl)(Cl)C([N:44]=C=O)=O>C(Cl)(Cl)Cl.CO>[NH2:44][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (3.0 g, 8.79 mmol) in chloroform (60 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 3.2 g, 10.5 mmol). After 2 h, the solution was transferred to a separatory funnel and washed with 10% Na2CO3 (100 mL). The aqueous layer was back-extracted with chloroform. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to yield a light orange solid. To the solid was added dichloromethane (30 mL). Trichloroacetyl isocyanate (1.05 mL, 8.79 mL) was added dropwise. After 1 h, additional trichloroacetyl isocyanate (0.3 equivalent) was added. After 1 h, the volatiles were removed under reduced pressure and the residue was dissolved in methanol (30 mL). A solution of sodium methoxide in methanol (25%, 5.0 mL) was added and the solution stirred overnight at rt and concentrated under reduced pressure. The residue was partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted with dichlormethane (2×100 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) to afford a clear oil that was triturated with isopropanol (50 mL) to afford white crystals. The crystals were dissolved in methanol, concentrated under reduced pressure, and dried in a vacuum oven at 80° C. to provide 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (1.27 g, 41%) as a white frothy solid, mp 212-214° C. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H), 7.40 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 7.22 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 6.37 (br s, 2H), 4.90 (br s, 2H), 4.88 (s, 1H), 4.70 (br s, 2H), 3.62-3.47 (m, 6H), 1.87-1.74 (m, 2H), 1.28 (m, 2H), 1.14 (t, J=7.0 Hz, 3H); MS (APCI) m/z 357 (M+H)+; Anal. Calcd for C19H24N4O3: C, 64.03; H, 6.79; N, 15.72. Found: C, 63.75; H, 7.06; N, 15.71.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:26]([O-:28])=[O:27])=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:8]=[C:9](F)[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c([N+](=O)[O-])c(OCCCl)c2)CC1
Temperature: 40 °C
Reaction time: 10 h
Yield: 850 %

Procedure:
A mixture of 1-[3-(2-chloroethoxy)-5-fluoro-2-nitrophenylmethanesulfonyl]-naphthalene (0.42 g, 0.1 mmoles) and N-methylpiperazine (0.168 g, 1.1 mmoles) in DMF was stirred under nitrogen at 40° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound (0.45 g, 0.85 mmoles), identified by HNMR and mass spectral analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:17]C(=O)C)([O-:3])=[O:2]>Cl.O>[N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]([F:16])([F:14])[F:15])(=[O:11])=[O:12])[CH:7]=[CH:6][C:5]=1[NH2:17])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Reflux N-(2-nitro-4-trifluoromethylsulfonyl-phenyl)-acetamide (600 mg) for 40 minutes in concentrated HCl (15 mL) and water (5 mL). Cool the mixture to room temperature and collect the precipitate obtain 2-nitro-4-trifluoromethylsulfonyl-phenylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.N([O-])=O.[Na+].[N:24]#[N:25]>O.C(O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])=[N+:24]=[N-:25]
Reactant: COC(=O)C(c1ccc(O)c(N)c1)C1CCCC1
Reactant: N#N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(c1ccc(O)c(N=[N+]=[N-])c1)C1CCCC1

Procedure:
5.0 g (20 mmol) of the crude product from Example XII are dissolved in 20 ml of H2O, 10 ml of ethanol and 20 ml of conc. HCl and the solution is diazotised at 0° C. with 1.8 g (26 mmol) of sodium nitrite in 10 ml of H2O. After evolution of N2 has ended, the mixture is extracted three times with 100 ml of CH2Cl2, the organic phases are concentrated and the residue is chromatographed on silica gel 60 (CH2Cl2 /MeOH=100:2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C@@:14]2([O:53][CH3:54])[C@H:19]([O:20]CC3C=CC=CC=3)[C@@H:18]([O:28]CC3C=CC=CC=3)[C@H:17]([O:36]CC3C=CC=CC=3)[C@@H:16]([CH2:44][O:45]CC3C=CC=CC=3)[O:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C@@:14]2([O:53][CH3:54])[C@H:19]([OH:20])[C@@H:18]([OH:28])[C@H:17]([OH:36])[C@@H:16]([CH2:44][OH:45])[O:15]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 15 h
Yield: 100.1 %

Procedure:
2-((2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)ethyl 4-methylbenzenesulfonate (9) (0.32 g, 0.42 mmol) was dissolved in MeOH (3 mL). Pd/C (60 mg, 10% Pd/C) was added and the reaction flask was flushed with H2 (3×), and then allowed to stir under a balloon of H2. After 15 h, the reaction was filtered through a celite plug, rinsing with MeOH and CH2Cl2 and concentrated to provide an oil (165 mg, 100%). LC/MS: tR=1.36 min, calcd for C16H24O9S: 392.11, found 415.2 (M+Na)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33][C:27]=3[CH:26]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C(OCC)(=O)C>[CH3:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:9][O:8][C:7]2[C:2]([C:25]3[CH:42]=[CH:41][C:28]4[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33][C:27]=4[CH:26]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CC1
Reactant: Cc1ccnc(COc2cccnc2Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc(COc2cccnc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Temperature: 120 °C

Procedure:
To a degassed mixture of 2-bromo-3-{[(4-methyl-2-pyridinyl)methyl]oxy}pyridine (2.83 g), 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (4.54 g) and cesium carbonate (9.9 g) in dioxane:water (4:1, 40 ml) was added PdCl2.dppf (0.828 g). The reaction mixture was heated at 120° C. overnight. The reaction mixture was added to water and extraction was carried out with ethyl acetate. The organic layer was dried over sodium sulphate and the filtrate was concentrated in vacuo. The crude product was purified through silica, eluting with 0-40% ethyl acetate in hexane. Appropriate fractions were concentrated in vacuo to yield the title compound, 3.8 g (84%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[S:12]([NH2:15])(=[O:14])=[O:13].[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Br:37])[C:25]=1[O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH:34]([CH3:36])[CH3:35])[CH:28]=1)[C:20](O)=[O:21].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C1C=CC2N(O)N=NC=2C=1.CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Br:37])[C:25]=1[O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH:34]([CH3:35])[CH3:36])[CH:28]=1)[C:20]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[OH:1])[C:7]=1[S:12]([NH2:15])(=[O:13])=[O:14])=[O:21]
Reactant: NS(=O)(=O)c1cccc2c(O)cccc12
Reactant: CC(C)c1cc(Oc2c(Br)cc(C(=O)O)cc2Br)ccc1O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3ccc4c(O)cccc4c3S(N)(=O)=O)cc2Br)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred mixture of 5-hydroxy-1-naphthalenesulphonamide (0.175 mmol) in dichloromethane (0.2 ml) was added a solution of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (0.035 mmol), DIEA (0.175 mmol) and dichloromethane (0.2 ml), dimethyl formamide was added to the solution if the sulphonamide not dissolved completely in dichloromethane. After 15 minutes PyBOP (0.042 mmol) and HOBt (0.001 mmol) in dichloromethane (0.3 ml) was added. The reaction mixture was heated at 50° C. for 20 hours. After cooling to room temperature, dichloromethane (1 ml) and citric acid solution (5%, 1 ml) was added and stirred vigorously for 30 min. The organic phase was dried, concentrated and the residue was finally subjected to semi-preparative HPLC (Silica column: 250×20 mm, ethyl acetate/n-heptane (both with 0.5% acetic acid). Gradient: first 2 min 15% ethyl acetate, then over 13 min to 100% ethyl acetate, then additional 5 min 100% ethyl acetate) to give 12 mg (54%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:3]=1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC.CC([O-])(C)C.[K+].C1COCC1.[NH4+].[Cl-]>O.ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][CH:20]=[C:9]2[S:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Nc1ccc(Br)cc1CS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(Br)cc12
Reaction time: 16 h
Yield: 72 %

Procedure:
A stirred solution of 4-bromo-2-[(phenylsulfonyl)methyl]aniline (3.26 g, 10.00 mmol, p-toluenesulfonic acid monohydrate (0.20 g), triethyl orthoformate (8.32 mL, 50 mmol) and 1,2-dichloroethane (70 mL) is heated at reflux under nitrogen for 5 hours and then at room temperature for 16 hours. The reddish reaction is concentrated in vacuo to a red oil. The resulting crude intermediate iminoether is stirred in dry THF (50 mL) and treated with 1.0M KOtBu in THF (13 mL, 13 mmol). After 5 min, a tan precipitate is evident. After 1 hour, the reaction is treated with water (30 mL) and NH4Cl (0.60 g), extracted with CH2Cl2 (150 mL), dried (MgSO4), filtered and concentrated in vacuo to a light orange solid. Trituration with ethyl acetate and hexanes affords the title compound as a light orange solid (2.78 g, 72%). Mp: 176-178° C. MS (ES−): 334 (M−H).
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[C:6]([CH3:12])=[N:5]1)(=O)C.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[CH3:12][C:6]1[C:7](=[O:11])[N:8]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[C:9](=[O:10])[NH:4][N:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)n1nc(C)c(=O)[nH]c1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1n[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-acetyl-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione (P1, 196 mg, 1.159 mmol) in 1,4-Dioxane (2 mL) and dry pyridine (0.281 mL, 3.48 mmol) at 5° C. was treated benzoyl chloride (0.155 mL, 1.333 mmol) was added dropwise, then the mixture was stirred at room temperature overnight. The day after 0.1 eq of Benzoyl chloride were added and the mixture stirred at rt for further 4 hours. The reaction mixture was then filtered to remove the piridinium salt and the solvents evaporated under vacuum. The residue was dissolved in EtOH (5 mL), then HCl 37% (126 μL) was added and the reaction was refluxed for 15 minutes. Solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (eluent: DCM to DCM/MeOH 6:4) providing the title compound 6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (180 mg, 0.779 mmol, 67% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][Si:8]([C:11]#[CH:12])([CH3:10])[CH3:9]>ClCCl.[Zn+2].[I-].[I-].C1(P(CC)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2]1[CH2:1][CH:12]=[C:11]([Si:8]([CH3:10])([CH3:9])[CH3:7])[CH2:5][C:4]=1[CH3:6]
Reactant: C=C(C)C(=C)C
Reactant: C#C[Si](C)(C)C
Agent: CCP(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1=C(C)CC([Si](C)(C)C)=CC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
In a four-necked flask, 0.54 g (2.5 mmol) of CoBr2, 2.62 g (8.2 mmol) of ZnI2 and 1.09 g (2.7 mmol) of diphenylphosphinoethane were dissolved in 120 ml of dichloromethane and the mixture was stirred for 0.5 hour at 30° C. Subsequently, 27.5 ml (244 mmol) of 2,3-dimethyl-1,3-butadiene, 21.5 g (219 mol) of trimethylsilylacetylene and 0.69 g (2.7 mmol) of Bu4NBH4 were added thereto, and the mixture was allowed to react for one hour at 30° C. After dichloromethane was evaporated under reduced pressure, 23.3 g of the title compound was obtained at a yield of 59.0% (GC purity 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13]C(OC(C)(C)C)=O)[CH2:9]2)[CH:3]=1.Cl>ClCCl.O1CCOCC1>[NH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:9]1
Reactant: Cc1ccnc(N2CCC(NC(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(N2CCC(N)C2)c1
Yield: 88.9 %

Procedure:
To a solution of 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (0.72 g) in dichloromethane (5 ml) was added a solution of hydrogen chloride in 1,4-dioxane (5 ml), and the resultant mixture was stirred at ambient temperature for 3 hours and evaporated under reduced pressure. To the residue was added 1N aqueous sodium hydroxide (30 ml) and extracted with ethyl acetate-tetrahydrofuran (2:1) three times. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give 3-amino-1-(4-methylpyridin-2-yl)pyrrolidine (409 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17].O>CC(C)=O>[CH3:17][CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:18]
Reactant: CC(C)OCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-isopropoxy-1-propylamine (3.51 g, 0.030 mole) was heated at 140° C. for 5 hrs. After standing at ambient temperature for 18 hrs the mixture was dissolved in acetone (20 ml) and the solution poured into water (120 ml). A solid formed rapidly and was collected by filtration and dried at ambient temperature. The solid (2.80 g, 89%) was recrystallized from toluene-isooctone to yield 2.08 g of a fluffy white solid, m.p. 106°-108° C.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH3:9][C:10]1([CH3:33])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14]([C:22]([CH3:32])=[CH:23][C:24]3[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=3)[CH:13]=[CH:12][C:11]1=2.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[P:1]([O:5][CH2:6][CH3:7])([O:2][CH2:3][CH3:4])([O:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([CH:23]=[C:22]([C:14]2[CH:13]=[CH:12][C:11]3[C:10]([CH3:33])([CH3:9])[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=3[CH:15]=2)[CH3:32])=[CH:25][CH:26]=1)=[O:8]
Reactant: CC(=Cc1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOP([O-])OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)OCc1ccc(C=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3.5 g (25 mmol) of diethyl phosphite in 6 ml of carbon tetrachloride was added dropwise, while cooling with ice, to a mixture of 7 g (20 mmol) of 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]-benzyl alcohol, 12 ml of carbon tetrachloride, 0.16 g of tetrabutylammonium bromide and 6 ml of 50% strength sodium hydroxide solution. The mixture was stirred for 3 days at room temperature, then extracted with 30 ml of methylene chloride, the organic phase was washed with 10 ml of 2% strength hydrochloric acid and twice with 10 ml of water each time, and was dried over Na2SO4 and evaporated down. The residue was recrystallized from pentane and once again from petroleum ether, to give 0.3.g of the title compound of melting point 70°-74° C., which was 98% pure according to HPLC (C18 reverse phase; hexane/ethanol/0.1% strength acetic acid; 100 ml/min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH2:17][CH2:18][OH:19].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:19][CH2:18][CH2:17][CH2:16][C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C)c(CCCO)c(OC)c(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(CCCOS(C)(=O)=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 9 (3.88 g, 15 mmol) and triethylamine (3.0 g, 30 mmol, 4.2 mL) in CH2Cl2 (50 mL) was stirred at room temperature for 10 mins. Methane sulfonyl chloride (1.8 g, 1.20 mL, 15.75 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 mins and the reaction mixture stirred at room temperature for 1 hr. The mixture was then diluted with CH2Cl2 (50 mL) and the organic layer washed with H2O (5×100 mL), 10% aqueous NaHCO3 (100 mL), dried (MgSO4), filtered and the solvent removed in vacuo by rotary evaporation to afford pure 3 as a liquid (4.8 g, 95%).