Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[Cu][C:16]#[N:17]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:7]1[C:2]([C:16]#[N:17])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Bromo-3-nitro-5-trifluoromethyl-pyridine (10.00 g, 36.87 mmol) was dissolved in toluene (250 ml) with stirring to give a pale yellow solution. Tetrabutylammonium bromide (11.90 g, 36.9 mmol) was added followed by copper(I) cyanide (9.92 g, 111 mmol) and the mixture was heated at reflux for 10 h. After cooling to RT, the reaction mixture was partitioned between water (750 ml) and EtOAc (750 ml). The organic fractions were combined, washed with water (2×250 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title product. 1H-NMR: [400 MHz, DMSO-d6 δH 9.55 (1H, m, ArH), 9.24 (1H, m, ArH)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1C.C(N(C(C)C)CC)(C)C.C1CN([P+]([Br:36])(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:44][CH:45]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:36][C:3]1[CH:4]=[C:5]([C:7]([NH:44][CH:45]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:9])[S:6][C:2]=1[Cl:1]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C(=O)O)sc1Cl
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)c(Cl)s1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 5-chloro-4-methyl-2-thiophenecarboxylic acid (242 mg, 1.0 mmol) and diisopropylethyl amine (2.5 mL, 14.60 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (2.5 g, 5.30 mmol) in one portion. After 30 min, 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (250 mg, 1.0 mmol) was added at one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 10-40% EtOAc in Hexane) affording the title compound (460 mg, 97%) as a white solid: LC-MS (ES) m/z=474 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[CH3:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:20][C:21]1[CH:22]=[C:23]([S:27][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Sc2ccc3c(c2)CCCC3=O)c1
Yield: 110 %

Procedure:
The suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.8 g, 6.1 mmol), 3-methylbenzene-1-thiol (0.76 g, 6.1 mmol), Pd2(dba)3 (142 mg, 0.153 mmol), Xantphos (177 mg, 0.306 mmol) and DIEA (1.58 g, 12.2 mmol) in 1,4-dioxane (60 mL) was stirred at reflux overnight under N2. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=5:1) gave 1.8 g (100%) of the title compound as an orange oil. [M+H] Calc'd for C17H16OS, 269. Found, 269.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28]C)[N:22]=2)=[CH:13]\[C@@H:14]2[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:21]2[NH:22][C:23](=[O:28])[C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:20])[N:18]2[CH3:19])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2C)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)CC[C@@H]1/C=C(\c1ccc(C(C)(C)C)cc1)c1ccc(Cl)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
48% hydrobromic acid (3 mL) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]-1-methylpyrrolidin-2-one (152 mg) in 1,4-dioxane (6 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (chloroform:methanol=100:0→98:2) to give a colorless powder (151 mg). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (99 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O>[N:1]([C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[N+:19]=[N-:20]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
73 mmol of 5-aminoisophtalic acid were placed in a beaker together with 100 mL of water. 18 mL of HCl (37%) were added dropwise. The mixture was cooled in an ice bath at 0-5° C. 75.3 mmol of NaNO2 were dissolved in 25 mL of distilled water and added dropwise to the mixture, stirring it for 30 minutes. Then, 73 mmol of NaN3 were dissolved in 25 mL of distilled water and added dropwise to the mixture. A solid was formed and gas evolution was observed, making it difficult to keep the stirring. The mixture was stirred until the evolution of gas was no longer detected. The product was then filtered off, washed with distilled water, and dried at room temperature. Yield: 85%. M.p.: 250° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[C:25]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH:37]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][C:24]2[C:25]3[C:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[CH:37]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCOc1cc2ccccc2c2ccccc12
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(9-phenanthrenyloxy)ethyl methanesulfonate (1.26 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and the solids were filtered off, dissolved in dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloro-methane-diethyl ether provided 0.8 g of alpha-oxo-4-[[2-(9-phenanthrenyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a yellow solid, mp 147°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150 mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling, and the mixture was stirred overnight at 70° C. under argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].O.[OH-].[Li+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.482 g, 9.25 mmol) with 1,4-difluoro-2-nitro-benzene (1.47 g, 9.25 mmol) and lithium hydroxide monohydrate (0.78 g, 18.50 mmol) in DMSO (20 ml) to 70° C. for 38 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and collection by filtration to obtain 2.236 g (7.47 mmol, 81% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 300(M+1).
Reaction SMILES: ClCC([NH:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=O.NC(N)=S.C(O)(=O)C.[OH-].[Na+]>C(O)C.O>[CH3:16][C:6]([NH2:5])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CC(C)(C)NC(=O)CCl)cc1
Agent: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1ccc(CC(C)(C)N)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
6.24 g (26.0 mmol) of 2-chloro-N-(2-methyl-1-p-tolylpropan-2-yl)acetamide and 1.98 g (26.0 mmol) of thiourea were dissolved in 50 mL of ethanol, and 10.2 mL of acetic acid was added dropwise at room temperature. After 3 hours of stirring at 85° C., the resulting white suspension was allowed to cool and diluted with 300 mL of water. The reaction solution was basified with 20 wt % aqueous sodium hydroxide and extracted with hexane, and the extract was washed with saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure to give 4.04 g of the desired product as a yellow green liquid.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23].C>O.ClCCl.C(N(CC)CC)C>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=P(O)(O)CCCNO
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (820 mg), bis(trimethylsilyl)acetamide (5.0 g), triethylamine (1.01 g) and dichloromethane (40 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was cooled to 0°-5° C. and mesyl chloride (1.15 g) was added dropwise with stirring. The reaction mixture was stirred for 1.25 hours and then concentrated under reduced pressure to give a residue, which was dissolved in water (50 ml). The solution was subjected to a column chromatography using activated charcoal. After the column was washed with water, the object compound was eluted with 70% aqueous acetone. The eluate was collected and evaporated to dryness to give powdery 3-(N-hydroxy-N-mesylamino)-propylphosphonic acid (320 mg). This powder was dissolved in ethanol (20 ml). To the solution was added conc. aqueous ammonia (0.4 ml) to give precipitates, which were separated by filtration and dried to give crystalline monoammonium salt of 3-(N-hydroxy-N-mesylamino)-propylphosphonic acid (220 mg). Mp 103°-105° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH2:11]([N:18]1[CH2:24][CH2:23][C:22]([Cl:25])=[C:21]([CH:26]=[O:27])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([N:18]1[CH2:24][CH2:23][C:22]([Cl:25])=[C:21]([CH:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:27])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Brc1ccccc1
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC(C1=C(Cl)CCN(Cc2ccccc2)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 323 %

Procedure:
136.6 g brombenzol in 300 mL diethylether was added to 21.2 g magnesium in 100 mL diethylether. The Grignard reaction is initiated with a small amount of iodine, kept at reflux by adding the bromebenzole and stirred additional 15 min for completion. Then, 21.2 g 1-benzyl-5-chloro-2,3,6,7-tetrahydro-1H-azepine-4-carbaldehyde in 300 mL diethylether was added. The mixture was stirred 2 h at 50° C. and quenched with 200 ml 6 M HCl solution at 0° C. The reaction was filtered and the filtrate was washed with diethylether and water. The filtrate was dissolved in sodium carbonate solution and chloroform. The layers were separated and the organic layer was washed with water and evaporated to give 89.9 g of the desired product. Fp:124° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].O>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:18])([F:17])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:8]
Reactant: O=Cc1cccnc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1cccnc1)C(F)(F)F
Yield: 90.8 %

Procedure:
3-Pyridinecarboxaldehyde (200 μL, 2.12 mmol) and potassium carbonate (58.6 mg, 0.424 mmol) were suspended in N,N-dimethylformamide (4.0 mL). To this, (trifluoromethyl)trimethylsilane (940 μL, 3.63 mmol) was added dropwise under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1.5. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was dissolved in tetrahydrofuran (4.0 mL). To this, a 1 mol/L aqueous hydrogen chloride solution (5.0 mL) was added at room temperature and the mixture was stirred at the same temperature for 10 minutes. Then, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give 3-(2,2,2-trifluoro-1-hydroxyethyl) pyridine (Compound CB) (341 mg, yield: 91%).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].[NH2:14][C:15]1[CH2:16][C:17]([C:33](OCC)=[O:34])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][C:20]=2[N:21]=1>C1(C)C=CC=CC=1.ClCCCl>[NH2:14][C:15]1[CH2:16][C:17]([C:33]([N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][O:6][CH3:5])=[O:34])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[CH:22][C:20]=2[N:21]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Reactant: COCCNCCOC
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 75 °C

Procedure:
Trimethylaluminum (0.34 mL of a 2.0 M solution in toluene) was added to bis(2-methoxyethyl)amine (92 mg, 0.69 mmol) in DCE (3 mL). After 10 minutes solid (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (80 mg, 0.23 mmol) was added and the vessel was sealed and heated to 75° C. for 16-20 hours. Upon cooling the reaction was quenched with saturated Rochelle's salt (2 mL) and after 20 minutes the mixture was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (2×20 mL). The combined organics were dried and concentrated. The crude material was purified via preparative TLC (2, 0.5 mm plates, eluting with 5-10% MeOH/CH2Cl2 with 4-6 drops of NH4OH). 1H NMR (CDCl3) δ 2.81 (s, 2H), 3.36 (s, 6H), 3.55-3.74 (m, 8H), 6.98 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.39 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]([C:20]([O:22][CH3:23])=[O:21])[CH2:12]2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([CH:13]1[C:14](=[O:19])[NH:15][C:16]2[N:17]=[CH:18][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10][C:11]=2[CH2:12]1)=[O:21]
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reaction time: 2 h
Yield: 107.8 %

Procedure:
To a solution of methyl 6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (115 mg, 0.346 mmol; which may be prepared as described in Step 3) in DCM (693 μL) at 0° C. under Argon was added TFA (693 μL). The reaction was allowed to come back to room temperature under stirring for 2 h and then concentrated under vacuo to give the title compound (103 mg, quantitative) as a brown solid. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(CCCCO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the 4-(3-aminophenyl)butan-1-ol [Hua Hsueh Hsueh Pao 1964, 30, 166-75. CAN 61:47615] (3.66 g) in dry DMF (30 ml) was treated with imidazole (1.66 g) and tert-butyldimethylsilyl chloride (3.5 g). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue partitioned between sat. NH4Cl(aq) and ethyl acetate. The aqueous phase was extracted with EtOAc and the combined organic phase washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, Petroleum ether-EtOAc 9:1) to give the title compound. LCMS RT=3.89 min.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[CH:7]=1)(=[O:5])=[O:4].N([O-])=[O:14].[Na+].NC(N)=O>O.OS(O)(=O)=O>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: O=N[O-]
Reactant: CNS(=O)(=O)c1cccc(N)c1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CNS(=O)(=O)c1cccc(O)c1
Reaction time: 0.17 h

Procedure:
N-Methyl-3-aminobenzene sulfonamide (488 mg, 2.62 mmole) was dissolved in a mixture of 10 mL of H2O and 2 mL of conc. H2SO4, and was cooled to −5°. A solution of NaNO2 (207 mg, 3 mmole) in 2 mL of H2O was added dropwise at such a rate that the temperature doesn't exceed 0°. The reaction was stirred for 10 minutes, urea (100 mg) was added, and the reaction was stirred an additional 10 minutes. The cold solution of diazo compound was slowly added with stirring to a 0° solution of Cu(NO3)2 dihydrate (10.3 g, 43 mmole) and Cu2O (363 mg) in 100 mL of H2O. Stirring was continued for 30 minutes as the temperature was allowed to warm to 23°. The heterogeneous reaction was extracted with Et2O, and the extracts were extracted with 0.2N NaOH. The basic extracts were washed with Et2O, acidified, and extracted with CH2Cl2. The extracts were dried, and the solvent removed. The residue was chromatographed on a silica gel column, and elution with 50% EtOAc in hexane gave the titled product, 175 mg (36%). MS (ESI) 188 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].C1COCC1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH2:17]([N:24]1[CH2:28][CH2:27][C@H:26]([O:29][C:8](=[O:10])[CH3:9])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CCN(Cc2ccccc2)C1
Yield: 90 %

Procedure:
Triethylamine (1.3 mL, 9.30 mmols) and acetyl chloride (0.6 mL, 8.46) were added to THF (20 mL) solution of (3S)-1-benzyl-3-hydroxypyrrolidine (1.5 g, 8.46 mmols) by the order stated, under cooling with ice, and stirred at the same temperature for an hour. Ethyl acetate was added to the reaction liquid which then was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentrating the reaction liquid under reduced pressure, the residue was purified on silica gel column chromatography (KP—NH, ethyl acetate:hexane=1:20) to provide the title compound (1.68 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:18]([O-])=O.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:18]
Reactant: COc1ccc(CSc2ccc([N+](=O)[O-])c(F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CSc2ccc(N)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred ice-cold mixture of 2-fluoro-4-(4′-methoxy-benzylmercapto)nitrobenzene and NiCl2.6H2O (6.08 g, 25.6 mmol) in CH3OH was added NaBH4 (1.93 g, 51.1 mmol) in portions. The reaction mixture was stirred for 1 h at 0° C., then poured into cold water. The whole was extracted with CH2Cl2 (3×100 ml) and the combined organic layers were dried (Na2SO4), filtered, and evaporated to give 2-fluoro-4-(4′-methoxybenzylmercapto)aniline. MS (Cl) m/e 264 (M+H)+.
Reaction SMILES: [CH2:1]([P:14](=[O:25])([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[P:2](=[O:13])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7].C=O.[CH2:28](NCC)C>CO>[C:1]([P:2](=[O:13])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7])([P:14](=[O:25])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH2:28]
Reactant: CCCCOP(=O)(CP(=O)(OCCCC)OCCCC)OCCCC
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCC)OCCCC)P(=O)(OCCCC)OCCCC
Yield: 65.8 %

Procedure:
6.95 g (17.4 mmol) of tetra-n-butyl methylenebisphosphonate, 2.61 g (86.8 mmol) of paraformaldehyde and 1.27 g (17.4 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 46 hours. After the methanol is eliminated as described above in Example I, 4.72 g of tetra-n-butyl ethenylidenebisphosphonate is produced as a clear liquid.