Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[C@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([CH2:32]Cl)[O:26]1>[OH-].[Na+].CN(C)C=O>[OH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[C@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([CH2:32][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:26]1
Reactant: Fc1ccccc1S
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Yield: 85.4 %

Procedure:
To a solution of 2-fluorothiophenol (38 mL, 406 mmol) in 2N sodium hydroxide (100 mL) was added 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol (15.0 g, 40.6 mmol) in N,N-dimethylformamide (120 mL). The mixture was warmed to 100 C for 4 hours, following the progress of the reaction by TLC. The N,N-dimethylformamide was removed under reduced pressure, and the remaining mixture was diluted with water (200 mL), neutralized with acetic acid, extracted with ethyl acetate (3×125 mL), and the combined organic layers were dried over MgSO4. After removing the solvent under reduced pressure the residue was triturated with diethyl ether and filtered, to afford 16 grams of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5 S,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol as a white powder (85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Nc1ccc(CCCO)cc1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a mixture of 3-(4-amino-phenyl)-propionic acid (1.85 g, 11.2 mmol) and tetrahydrofuran′(200 ml), was added lithium aluminum hydride (1.0 g, 26 mmol). After stirring for 3 hours, the mixture was quenched by addition of methanol (5 ml) and concentrated under reduced pressure. The residue was treated with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (200 ml). The organic extract was concentrated under reduced pressure to give 3-(4-amino-phenyl)-propan-1-ol (1.5 g, 89% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[C:17](SC)=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:21])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1>O1CCOCC1.[Ni]>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:21])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CSc1ncnc2c1c(C(=O)c1cncc(N)c1)cn2C
Agent: [Ni]
Solvent: C1COCCO1
Product: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Yield: 15 %

Procedure:
A mixture of (5-amino-pyridin-3-yl)-(7-methyl-4-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 231, 1.5 g, 5 mmol), Raney Ni (10 g) and NH3H2O (150 mL) in dioxane (150 mL) was refluxed for 6 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified via preparative HPLC to give (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone as a brown solid in 15% yield, 0.19 g. 1H NMR (400 MHz DMSO-d6) 3.88 (s, 3H), 5.63 (s, 2H), 7.27-7.28 (m, 1H), 8.15-8.18 (m, 2H), 8.40 (s, 1H), 8.97 (s, 1H), 9.42 (s, 1H).
Reaction SMILES: [Ca:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3]>O>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Ca+2:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Ca+2:1].[Ca+2:1]
Reactant: [Ca]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: [Ca+2]
Reaction time: 0.08 h

Procedure:
A solution of 218 g of disodium Na2HPO4.12 H2O in 1.2 liters of distilled water and a solution of 70 g of Ca(NO3)2.4H2O in 0.5 liters of distilled water were prepared. The calcium solution was quickly poured into the phosphate solution at room temperature with stirring. Precipitation was immediate and substantially complete. The precipitate was adjusted to pH 6.4 by the addition of sodium hydroxide solution in order to avoid the formation of acidic calcium phosphates. The precipitate was aged at room temperature for 5 minutes prior to filtration. The precipitate was then filtered through a Buchner filter (with a total surface about 0.1 m2), and was washed by about 3 liters of distilled water. A gel cake of nanocrystalline calcium phosphate obtained on the filter paper.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[OH:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Yield: 71.4 %

Procedure:
A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol), benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140 mmol) and methyl ethyl ketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from isopropyl ether to give the title compound (14.20 g, 71.4%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][CH2:20][OH:21])[C:4]=1[O:22][CH2:23][O:24][CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=[O:21])[C:4]=1[O:22][CH2:23][O:24][CH3:25]
Reactant: COCOc1c(C)c(C=CC=CCO)c(OCOC)c(OC)c1OC
Solvent: ClCCl
Product: COCOc1c(C)c(C=CC=CC=O)c(OCOC)c(OC)c1OC
Yield: 93 %

Procedure:
The alcohol compound (4.85 g, 13.7 mmol) prepared as above was dissolved in methylene chloride and the mixture was oxidized with active magnesese dioxide (14.6 g) at room temperature for 2 hours. Working up in usual way gave 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-(4-formyl-1,3-butadienyl)benzene (oily substance, 67 2.30 (3H), 3.49 (3H), 3.58 (3H), 3.89 (3H), 3.89 (3H), 5.06 (4H), 6.23 (1H), 7.0-7.4 (3H), 9.65 (1H)). Yield 93%.
Reaction SMILES: CO[C:3](=[O:11])[C@@H:4]([CH2:9][OH:10])[NH:5][C:6](=[O:8])[CH3:7].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC)(C)(C)C>[C:6]([NH:5][C@H:4]([CH2:9][OH:10])[C:3]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:8])[CH3:7]
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H](CO)NC(C)=O
Solvent: COC(C)(C)C
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
N-Acetyl-D-serine methyl ester (1.0 g, 0.0062 mole) was dissolved in benzylamine (6.64 g, 0.062 mole) at 0-5° C. The reaction mixture was heated and stirred at 65° C. for 12 hr. The excess benzylamine was removed by distillation under vacuum at 90° C. to get a thick white solid. To this was added 10 ml of methyl tert-butyl ether and stirred for 2 hr at room temperature. The product was filtered and dried under vacuum to obtain (R)-2-acetamido-N-benzyl-3-hydroxy-propionamide (1.09 g, Yield 75%, HPLC: 92%, Chiral HPLC: 78%).
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:18](Cl)=[O:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]>[Pd]>[C:1]([C:5]([C:8]([O:11][C:12]([CH:18]=[O:19])([C:14]([F:16])([F:17])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=C(Cl)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Pd]
Product: O=CC(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 75 h
Yield: 53.5 %

Procedure:
A 3-necked round bottom flask equipped with a dropping funnel and reflux condenser was charged with 10% Pd/C (0.35 g) and cooled to 0° C. Triisoprolpylsilane (6.0 g) was added. CF3CF2CF2OCF(CF3)COCl (10.9 g) was added, and the mixture was stirred at 25° C. for 75 hr. During this period, a total of 0.5 g of additional catalyst was added in ca. 0.1 g increments. Vacuum transfer and separation of the lower layer after chilling at -25° C. provided 5.26 g of liquid. 1H NMR (THF-d8 /F11): 9.9 (m). 19F NMR: -79.4 (m), -81.1 (s), -81.4 (t, J=7.2), -129.5 (s), -138.8 (m). 1H-decoupling experiment showed JHCCF ca. 2.5 Hz.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]([OH:15])=O)[CH:8]=[CH:7][CH:6]=2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH2:20][NH2:21].FC(F)(F)OC1C=CC(CN)=CC=1>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28])[CH2:20][NH:21][C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc2c(CC(=O)O)cccc2cn1
Agent: NCc1ccc(OC(F)(F)F)cc1
Product: Cc1cc2c(CC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 222B using (3-methyl-5-isoquinolinyl)acetic acid and 3-fluoro-4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 2.77 (s, 3H), 4.14 (s, 2H), 4.38 (d, J 6.1, 2H), 7.33 (m, 2H), 7.72 (t, J 7.8, 1H), 7.86 (t, J 7.5, 1H), 8.04 (d, J 6.8, 1H), 8.36 (m, 2H), 9.07 (t, J 6.1, 1H), 9.77 (s, 1H); Anal. Calcd for C20H16F4N2O+1.2 HCl+0.3 DMF: C, 56.62; H, 4.20; N, 7.48. Found: C, 56.79; H, 4.40; N, 7.29.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.B.CO.O>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
3-(3-Trifluoromethyl-phenyl)-propionic acid (12.4 g, 57 mmol) was dissolved in THF (160 ml) in an inert atmosphere and cooled to 0° C. followed by slow addition of borane in THF (85 ml, 85 mmol). Stirring was continued at 0° C. for 1 h and at rt for 24 h. The mixture was cooled to 0° C. and methanol (100 ml) and water (100 ml) was carefully added. The organic solvents were removed under reduced pressure. The remaining aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silicagel, DCM/methanol=9/1) to give 10.97 g (94%) of 3-(3-trifluoromethyl-phenyl)-propan-1-ol. LC-MS: tR=0.87 min; [M+H]+=no ionisation.
Reaction SMILES: [F-].[Cs+].[F:3][C:4]1[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7](I)=[C:8]([OH:10])[CH:9]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)CCC.CN(C)C=O>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.[Cu]I>[F:3][C:4]1[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)=[C:8]([OH:10])[CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1cc(F)c(C(F)(F)F)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Oc1cc(F)c(C(F)(F)F)cc1-c1ccnnc1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
Cesium fluoride (570 mg, 3.8 mmol), tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol), and copper(I) iodide (72 mg, 0.38 mmol) were added to a solution of 5-fluoro-2-iodo-4-(trifluoromethyl)phenol (Preparation 885, 579 mg, 1.89 mmol) and 4-(tributylstannyl)pyridazine (770 mg, 2.1 mmol) in N,N-dimethylformamide (4 mL, 50 mmol). The sides of the flask were washed down with N,N-dimethylformamide (3 mL, 40 mmol). The flask was capped with a septum then evacuated and back-filled with argon (5 cycles). The reaction mixture was heated at 45° C. After 90 min, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and water, and filtered through diatomaceous earth. The solids were washed with additional ethyl acetate. The layers were separated, and the organic layer was washed successively with water, aqueous lithium chloride, and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (24 g SiO2, methylene chloride to 9:1 methylene chloride-methanol) to afford the product as a tan solid (305 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichoride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH:3]=[CH:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2occc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCO2
Yield: 82.9 %

Procedure:
Benzofuran-4-carboxylic acid (10.0 g, 61.7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3-dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5° C.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])(=[O:20])=[O:19]
Reactant: Cc1ncsc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncsc1CCOS(C)(=O)=O

Procedure:
The 4-methyl-5-thiazole ethanol (Aldrich, 0.18 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])[C:13]=1[NH2:29]>>[F:19][C:15]1[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:13]([NH:29][S:7]([C:4]2([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]2)(=[O:9])=[O:8])[C:12]([F:11])=[CH:17][C:16]=1[F:18]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Product: C=CCC1(S(=O)(=O)Nc2c(F)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride was reacted with 3,5,6-trifluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine to obtain the title product. 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H), 6.78 (m, 1H), 6.49 (m, 1H), 5.96 (s, 1H), 5.86 (m, 1H), 5.18 (d, 2H), 2.76 (d, 2H), 1.23 (m, 2H), 0.872 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: BrCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A mixture of 4-iodophenol (15.0 g, 68.2 mmol) and 1,2-dibromoethane (50 ml, 580 mmol) and potassium carbonate (14.0 g, 0.1 mol) was stirred and refluxed for 22 h. After cooling to r.t., the mixture was filtered, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 40: 1 to 20:1) to afford the title compound (18.7 g, 84%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O>O.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(N)c1
Yield: 57.6 %

Procedure:
4-Bromo-3-nitroanisole (10 g, 43 mmol) and iron powder (21.72 g, 385 mmol) were stirred in a mixture of water (10 mL) and acetic acid (100 mL) for 1.5 h. The solvent was removed in vacuo, the brown residue was taken up in water (200 mL) and treated with 10% aq K2CO3 until pH 10. The mixture was extracted with EtOAc (4×150 mL) and the combined organic extracts were dried (MgSO4) and evaporated to give the desired aniline (5.0 g, 57%) as a brown oil; δH (CDCl3, 400 MHz) 3.72 (3H, s), 4.05 (2H, br), 6.22 (1H, dd), 6.32 (1H, d), 7.26 (1H, d); MS m/z (TS+) 202, 204 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.Cl>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Br)c(N)c1
Reaction time: 24 h

Procedure:
A solution of 1-bromo-4-methoxy-2-nitrobenzene (1.0 eq.), iron powder (3.0 eq.), and concentrated HCl (1.04 eq.) were mixed together in ethanol (0.64 M) and heated to reflux. The reaction was stirred for 24 hours, and the solvent was evaporated. The resulting residue was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-15% ethyl acetate in hexane to give the product as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>>[Cl:8][CH2:9][C:10]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:11]
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)CCl
Product: Cc1cc(NC(=O)CCl)no1

Procedure:
A process according to claim 1 wherein, in Step a, 3-amino-5-methylisoxazole is reacted with chloroacetylchloride to form 3-(chloroacetamido)-5-methylisoxazole.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>C1(C)C=CC=CC=1>[CH2:1]([NH:7][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: NCc1ccco1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNCc1ccco1
Yield: 64.3 %

Procedure:
Furfurylamine (15.0 g) and 17.2 g of triethylamine were dissolved in 75 mL of toluene, 20.8 g of ethyl chloroacetate was added thereto and the mixture was heated to reflux for 3 hours. After the reaction solution was cooled, 100 mL of water was added thereto and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 18.2 g of an objective compound as yellow liquid.
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:26]O.S(=O)(=O)(O)O>CCOCC>[C:1]([O:25][CH3:26])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Reaction time: 1 h
Yield: 74 %

Procedure:
10,12-Tricosadiynoic acid (3.0 g, 0.0084 mol), methanol (15 ml) and concentrated sulfuric acid (0.8 ml) were heated to reflux and stirred for 1 hour. The cooled mixture was taken up in ether (40 ml) and washed with 10% NaHCO3 (20 ml) and water (20 ml), and the organic phase was dried (MgSO4). Evaporation of the solvent gave 2.68 g (74%) of the title compound. 1H NMR (60 MHz, CDCl3): δ0.98 (m, 3H, CH3CH2), 1.28 (m, 28H, CH2), 2.25 (m, 6H, CH2), 3.70 (s, 3H, CH3O).
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].[CH2:19]([N:22]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](B(O)O)=[CH:29][CH:28]=1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27]([N:22]([CH2:19][CH2:20][CH3:21])[CH2:23][CH:24]5[CH2:25][CH2:26]5)=[CH:28][CH:29]=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: CCCN(CC1CC1)c1ccc(B(O)O)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCN(CC1CC1)c1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c2ccccc12
Yield: 63.6 %

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), 4-(N-propyl,N-cyclopropylmethylamino)-1-naphthylboronic acid (249 mg, 0.78 mmol), 1.8 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 193 mg (64%) of the title compound as an oil. FDMS: m/e=466. α[D]589 =+50.52 (c=0.95, chloroform).