Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2].C(N(CC)CC)C.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C(Cl)Cl>[P:1]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2]
Reactant: CCCSP(=S)(Cl)SCC
Reactant: O=Cc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCSP(=S)(Oc1ccccc1C=O)SCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-ethyl S-propyl chlorotrithiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 2-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-ethyl S-propyl O-(2-formylphenyl)trithiophosphate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C@@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-1-pentanol (CAN 7533-40-6) as starting materials and isolated (19.4 mg, 59%) as white solid; MS (ESI, m/z): 327.1 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]=1[SH:23]>CC(C)=O>[BrH:1].[Cl:16][C:11]1[CH:10]=[C:9]([C:5]2([C:3](=[O:4])[CH2:2][S:23][C:18]3[NH:19][CH2:20][CH2:21][CH2:22][N:17]=3)[CH2:8][CH2:7][CH2:6]2)[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: SC1=NCCCN1
Reactant: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CC(C)=O
Product: Br
Product: O=C(CSC1=NCCCN1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (3.2 g) in acetone (25 ml) was added to a solution of 3,4,5,6-tetrahydropyrimidine-2-thiol (1.2 g) in acetone (150 mL), then the mixture was heated under reflux for 0.5 hour, and allowed to cool to ambient temperature. The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanone hydrobromide as a white solid (3.9 g), m.p. 203-204° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1[nH]c(=O)ccc1C#N
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1C#N

Procedure:
A mixture of 2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (44 g) and POCl3 (250 ml) was refluxed for 3 h. The reaction mixture was dried down in vacuum and ice followed by conc. aqueous ammonia (300 ml) was added. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum affording the title compound (23.5 g, BP (18 mbar) 119-120° C.).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][Al:9](C)C>CCCCCC>[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][Al+2:9]
Reactant: C[Al](C)C
Reactant: Oc1ccccc1
Solvent: CCCCCC
Product: C[Al+2]
Product: [O-]c1ccccc1
Reaction time: 8 h

Procedure:
Under an argon atomosphere, 5 g of phenol was dissolved in 25 ml of hexane. This was added dropwise to 26.5 ml of a hexane solution containing 1.0 M trimethylaluminum at −20° C. over 1 hour. This was brought to room temperature and allowed to stand overnight. The precipitate was filtered and washed with hexane. Recrystallization from ether gave 4.36 g of methylaluminum diphenoxide.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.O>CN(C=O)C>[C:12]1([CH3:11])[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3](=[O:5])[CH3:4])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CSc1ccc(C)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Chloroacetone (11.6 g, 125 mmol) and NaHCO3 (12.6 g, 150 mmol) were added to a solution of 4-methylthiophenol (10 g, 80.5 mmol) in dry DMF (50 mL). The mixture was stirred at 50-60° C. for 1 h. The cooled reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried with K2CO3, evaporated to dryness and the residue was distilled (b.p. 145-148° C./12 mm) to give 11.7 g of 1-(p-tolyl sulfanyl)propan-2-one (81%).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Upon boiling a solution of 7.8 g 1-naphthaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(naphth-1-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 162° - 163° C (ethanol) is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O-].[Na+].C([O:11][C:12](=O)[CH2:13][C:14]([O:16]CC)=O)C.CI>CO>[OH:11][C:12]1[N:5]=[C:3]([S:4][CH3:6])[N:2]([CH3:1])[C:14](=[O:16])[CH:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNC(N)=S
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(O)cc(=O)n1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A mixture of 45 g (0.5 mol) of N-methylthiourea, 54 g (1 mol) of sodium methylate, 200 ml of methanol and 80 g (0.5 mol) of malonic acid diethyl ester was boiled for 3 hours under reflux. 71 g (0.5 mol) of methyl iodide were then added dropwise at about 50° C. and the mixture was stirred for a further 0.5 hour at 50° C. The salt which crystallized out was filtered off and was then dissolved in 400 ml of water. The solution was neutralized by adding glacial acetic acid, the precipitate was then filtered off, and 80 g (93% of theory) of 1,6-dihydro-4-hydroxy-1-methyl-2-methylthio-6-oxo-pyrimidine were thus obtained in the form of a colorless powder of melting point 198° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][C:6]([C:8]1[N:9]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7]>CO>[ClH:4].[CH3:1][N:2]([CH2:5][C:6]([C:8]1[N:9]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7])[CH3:3]
Reactant: O=C(CCl)c1cccn1C(c1ccccc1)c1ccccc1F
Reactant: CNC
Solvent: CO
Product: CN(C)CC(=O)c1cccn1C(c1ccccc1)c1ccccc1F
Product: Cl
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of methanol saturated with dimethylamine was added 1-[(2-fluorophenyl)phenylmethyl]pyrrol-2-yl chloromethyl ketone (20.39 g in 500 ml of MeOH). This was heated at an oil bath temperature of 85° C. and stirred for 2 hours.
Reaction SMILES: C([O:5][C:6]([C@:8]1([NH:27]C(OC(C)(C)C)=O)[CH2:13][C@@H:12]([S:14][C:15]2[CH:19]=[N:18][NH:17][N:16]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:20]([O:22]C(C)(C)C)=[O:21])=[O:7])(C)(C)C.[Cl:35]CCl>[Br-].[Br-].[Zn+2]>[ClH:35].[NH2:27][C@@:8]1([C:6]([OH:7])=[O:5])[CH2:13][C@@H:12]([S:14][C:15]2[CH:19]=[N:18][NH:17][N:16]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:20]([OH:22])=[O:21]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Sc2cn[nH]n2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: [Br-]
Agent: [Zn+2]
Product: Cl
Product: N[C@@]1(C(=O)O)C[C@@H](Sc2cn[nH]n2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 50 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Add zinc dibromide (0.88 g, 3.91 mmol) to a stirring solution of ditert-butyl(1R,2S,4R,5R,6R)-2-tert-butoxycarbonylamino-4-(2H-[1,2,3]triazol-4-ylsulfanyl)-bicyclo[3.1.0]hexane-2,6-dicarboxylate (194 mg, 0.39 mmol) in dichloromethane (30 mL). Stir overnight at 50° C. Add more zinc dibromide (0.44 g, 1.95 mmol) and continue to stir at 50° C. until starting material is completely consumed. Evaporate solvent and stir residue in 2M aqueous hydrochloric acid (5 mL) at 50° C. until only desired product is present. Cool reaction mixture and purify the residue by cation-exchange chromatography (DOWEX® 50WX8-100). Allow the compound to flow through the column at a drip rate of about 1 drop every 1-2 seconds. After the initial loading volume has dropped to the resin surface, rinse with water (5 to 10 mL) and repeat 3 times. Monitor the pH of the effluent and continue rinsing with water until application complete (pH cycle observed: effluent from the column initially at pH=7 then drop to pH=1 and return back to pH=7). Wash the column with at least one column volume each of water, water:tetrahydrofuran (1:1) then water. Displace the product from the resin with 10% pyridine:water. Continue to elute with 10% pyridine:water until no additional product is detected. Concentrate the fractions containing the product to obtain a colorless solid. Dry the solid. Dissolve in 2M hydrochloric acid and evaporate to provide the title compound as a white solid (94 mg, 75%). MS (m/z): 285 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[O:9])[CH2:7]Br.C1N2CN3CN(C2)C[N:16]1C3.C(Cl)(Cl)(Cl)[Cl:26]>>[ClH:26].[NH2:16][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)=[O:9]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: Cl
Product: NCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Add 3-(trifluoromethyl)phenacyl bromide (10 g, 37.4 mmol) to a solution of hexamethylenetetramine (HMTA) (5.80 g, 41.3 mmol) in carbon tetrachloride (100 mL). Stir at room temperature overnight. Filter the precipitate and suspend the filter cake in ethanol (200 mL). Dilute the mixture with concentrated hydrochloric acid (28 mL), and stir the mixture at room temperature overnight. Filter the precipitate, and concentrate the filtrate in vacuo to provide an off-white solid. Recrystallize the solids from hot 1% concentrated hydrochloric acid in 2-propanol taking care not to cool below room temperature to provide 2-amino-1-(3-(trifluoromethyl)phenyl)ethanone hydrochloride (7.67 g, 86%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br>C(#N)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[N:15]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Yield: 88.1 %

Procedure:
1-N-Boc-1,2-cis-cyclohexyldiamine 5 (CAS 184954-75-4) (1.65 g, 7.7 mmol) was dissolved in 100 mL acetonitrile. Potassium carbonate (5.3 g, 39 mmol) and 1,4-dibromobutane (2.8 g, 13 mmol) were added and the reaction mixture was refluxed overnight. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-(2-pyrrolidin-1-yl-cyclohexyl)-carbamic acid tert-butyl ester as a yellow liquid (1.82 g, 88%), MS: m/e=269.4 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CN(C)[C:16](=[O:18])[CH3:17].[NH4+].[Cl-]>C1CCCCC1.CCOCC>[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N(C)C
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(=O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of 3.00 g (12.7 mmol) of 2,6-dibromopyridine in 20 mL anhydrous. Et2O at −78° C. was added dropwise over 30 min. 8.0 mL (12.8 mmol) of 1.6 M n-BuLi in cyclohexane. After stirring for 3 h at −78° C., 8.2 mL (88 mmol) of N,N-dimethylacetamide was added dropwise and the solution was stirred at −78° C. for 1 h. On warming to RT, Et2O (100 mL) and saturated aqueous NH4Cl (50 mL) were added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting yellow solid was recrystallized from hexanes to provide 1.8 g (71%) of 2-acetyl-6-bromopyridine as colorless crystals. 1H NMR (CDCl3): σ2.81 (s, 3H); 7.67-7.77 (m, 2H); 8.22 (dd, J=6.8, 1.6 Hz, 1H). Mass Spec.: m/e 200.
Reaction SMILES: S1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([CH2:17][N:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1.O[O:32][S:33]([O-:35])=O.[K+]>CO.O.C([O-])([O-])=O.[Na+].[Na+]>[O:32]=[S:33]1(=[O:35])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([CH2:17][N:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: c1cncc(N(Cc2cccnc2N2CCSc3ccccc32)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCN(c2ncccc2CN(c2cccnc2)c2cccnc2)c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of: N-{[2-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)pyridine-3-yl]methyl}-N-pyridin-3-ylpyridin-3-amine (52 mg, 0.126 mmol) in methanol (1.5 mL) and water (1 mL) was added Oxone™ (97 mg, 0.157 mmol). The reaction progress was monitored by LC/MS and after 2 hours the reaction was diluted with water and Na2CO3 solution and the product was extracted into ethyl acetate, the solution dried, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-100% acetone/hexane gradient to give the title compound as a coloress glass. 1H-NMR (500 MHz, CDCl3): δ 8.51 (1H, d, J=3.6 Hz), 8.29 (2H, s), 8.26 (2H, d, J=3.9 Hz), 7.88 (2H, t, J=9.0 Hz), 7.26-7.31 (4H, m), 7.18-7.21 (2H, m), 7.00 (1H, t, J=7.3 Hz), 6.22 (1H, d, J=8.3 Hz), 4.76 (2H, s), 4.38 (2H, br s), 3.57 (2H, t, J=5.8 Hz). m/e (m+1): 444.2.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[Se:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li][CH2:22]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:22][C:18]1[Se:17][C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)=[CH:20][CH:19]=1
Reactant: [Li]CCCC
Reactant: CCCC1CCC(C2CCC(c3ccc[se]3)CC2)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCCC1CCC(C2CCC(c3ccc(C)[se]3)CC2)CC1
Temperature: -60 °C
Reaction time: 8.5 h

Procedure:
2.0 g (5.9 mmol) of 2-(4′-propylbicyclohexyl-4-yl)selenophene are initially introduced in 20 ml of diethyl ether, and 5.0 ml (8.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −60° C. 1.5 ml (24.1 mmol) of methyl iodide are added, and the batch is stirred for 8.5 h with slow thawing to RT. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane n-heptane:EtOAc=95:5). The further purification is carried out by recrystallisation from IPA/n-heptane (10:1) and from acetone. 2-Methyl-5-(4′-propylbicyclohexyl-4-yl)selenophene is obtained as a colourless solid (m.p. 26° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[C:22](=O)(O)[O-].[Na+]>CO>[CH3:22][O:11][C:10](=[O:12])[CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#C[C@H](CC(=O)O)c1ccc(O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC#C[C@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 265 %

Procedure:
To a solution of (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (25 g) obtained in Step 2 in methanol (125 mL) was added concentrated sulfuric acid (1.25 mL), followed by stirring the mixture at 80° C. for 2.5 hours. After cooling down to room temperature, water (100 mL) and sodium bicarbonate (4.14 g) were added to the reaction mixture, followed by concentration of the mixture. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was distilled azeotropically with toluene to give (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (28.5 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:20]=[CH:19][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ccccc5c4)cc3CC[C@@H]12
Yield: 54.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-naphthylboronic acid (168 mg, 0.98 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80° for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatagraphy (ethyl acetate eluent) to give 126 mg (55%) of the title compound as a white solid. mp 221°-223°. FDMS: m/e=355. α[D]589 =+73.58 (C=1.06, chloroform).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18]/[C:19](=[CH:23]/[CH:24]([CH3:36])[CH2:25][P:26]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])/[C:20]([OH:22])=[O:21])=[O:17].[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH:16]([NH:18][CH:19](/[CH:23]=[C:24](\[CH3:36])/[CH2:25][P:26]([O:28][CH:29]([CH3:30])[CH3:31])([O:32][CH:33]([CH3:35])[CH3:34])=[O:27])[C:20]([O:22][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:21])=[O:17]
Reactant: CC(/C=C(/NC=O)C(=O)O)CP(=O)(OC(C)C)OC(C)C
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C(=C\C(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
11.5 g (56.4 mmols) of dicyclohexylcarbodiimid are added to a solution of 18.1 g (56.4 mmols) of E-2-formylamino-4-methyl-5-diisopropylphosphono-pentenoic acid, 6.1 g (56.4 mmols) of benzyl alcohol and 0.7 g of 4-(N,N-dimethylamino)pyridine in 140 ml of dichloromethane. The reaction mixture is stirred 2 hours in an ice bath and 10 hours at room temperature. The reaction solution is filtrated clear, washed with diluted hydrochloric acid and twice with water, dried over magnesium sulfate and chromatographed over silica gel with first ethyl acetate and then ethyl acetate/isopropanol as eluent. Benzyl E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate is obtained as an orange-colored oil which can be crystallized from diethyl ether/hexane; m.p. 50°-58°.