Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.C[C@H](N)C1C=CC=CC=1.CCCCCCC>COC(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@H:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Product: O=C(O)C1=Cc2cc(Cl)ccc2O[C@@H]1C(F)(F)F
Reaction time: 24 h
Yield: 45.8 %

Procedure:
To a solution of 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 1, Step 2)(12.00 g, 43.07 mmol) and (S)(−)-α-methylbenzylamine (2.61 g, 21.54 mmol) in methyl-tert-butyl ether (30 mL) was slowly added n-heptane (200 mL) until the mixture became cloudy. The mixture was heated (steam bath) to boiling and set aside for 24 h during which time crystals formed. Filtration of the suspension yielded a crystalline product (5.5 g) which was recrystallized from methyl-tert-butyl ether (30 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.1 g). This solid was dissolved in EtOAc (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2×50 mL), dried over MgSO4 and concentrated in vacuo yielding a white solid. Recrystallization of this solid from methyl-t-butyl ether/n-heptane yielded the title compound as the highly enriched isomer, a white solid (2.7 g, 45%): mp 126.7-128.9 ° C. 1H NMR (CDCl3/300 MHz) 7.78 (s, 1H), 7.3-7.1 (m, 3H), 6.94 (d, 1H, J=8.7 Hz), 5.66 (q, 1H, J=6.9 Hz). Anal. Calc'd for C11H6O3F3Cl: C, 47.42; H, 2.17; N, 0.0. Found: C, 47.53; H, 2.14; N, 0.0. This compound was determined to have an optical purity of greater than 90% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:14]2[O:13][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1NCc2c(Cl)ccc(-c3cc4ccccc4o3)c21
Yield: 18.5 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (80.0 mg, 0.273 mmol) was dissolved in acetonitrile (4.0 mL), and the solution was treated with 2-benzofuraneboronic acid (133 mg, 0.819 mmol), palladium acetate (7.4 mg, 0.033 mmol), tri(o-tolyl)phosphine (20 mg, 0.066 mmol) and triethylamine (0.381 mL, 2.73 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=15/1) to obtain Compound 170 (14.3 mg, yield 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12](OC(OCC)OCC)C.O1CCOCC1.C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]cnc2cc(Cl)ccc12
Temperature: 110 °C

Procedure:
To a solution of 2-amino-4-chlorobenzamide (58 g, 0.34 mol) in hot (60° C.) N-methylpyrrolidone (170 mL), triethylorthoformate (151 g, 1.02 mol, 3 equiv) and a 1,4-dioxane 5N HCl solution (ca. 15 mL) were added. The resulting solution was heated at 110° C. for 18 h. Then, the mixture was cooled to room temperature, was poured over cold water and was brought to pH 7 with saturated NaHCO3 solution. The formed precipitate was filtered, washed with water and dried to give the desired product as a slightly beige solid (58 g, 94%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:21]([OH:23])=[O:22])=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[N:9][CH:8]=[N:7]2)[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:24][O:22][C:21]([C:4]1[C:3]([CH2:1][CH3:2])=[C:11]2[N:6]([CH:5]=1)[N:7]=[CH:8][N:9]=[C:10]2[NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:23]
Reactant: CCc1c(C(=O)O)cn2ncnc(Nc3ccc(OC)nc3)c12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1c(C(=O)OC)cn2ncnc(Nc3ccc(OC)nc3)c12

Procedure:
To a solution of Example 84 (3 mg, 0.01 mmol) in methanol (0.3 mL) and toluene (0.7 mL) was added trimethylsilyl diazomethane (100 μL of 2.0 M solution in THF). After 30 min. acetic acid and methanol were added and the reaction mixture was concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 20% ethyl acetate in hexanes to provide 3 mg of white solid. MS: [M+H]+=328.1; 1H NMR (CDCl3): δ 8.30 (s, 1H), 7.94-7.90 (m, 3H), 7.01 (s, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.32 (q, J=7.6 Hz, 2H), 1.56 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br.Cl[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1.Cl.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)C>[F:33][C:19]([F:18])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]=[C:13]([NH2:16])[S:14][CH:15]=4)=[CH:7][CH:6]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Nc1nc(-c2ccc(CCCl)cc2)cs1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccc(CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)cs1

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 0.81 g (2.55 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-aminothiazole hydrobromide, 0.68 g (2.55 mmol) of N-(3-trifluoromethylphenyl)piperazine hydrochloride, 1.06 ml (7.64 mmol) of triethylamine, 0.27 g (2.55 mmol) of sodium carbonate, 2 mg of sodium iodide, and 10 ml of ethanol. The reaction was heated at reflux for 8 days, cooled, and the precipitate filtered, and the reaction mixture taken up in ethyl acetate/water. The layers were separated, the ethyl acetate washed with brine, dried, and evaporated to give a white solid, which was triturated with ethyl acetate. The solid was taken up in ethyl acetate/methanol, ether saturated with HCl added, the precipitate filtered, washed with ether, and dried to give a white solid, 0.255 g (18%), m.p. 274°-277° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.N1C=CC=CC=1>O>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3,5-dichlorobenzenesulfonyl chloride (0.256 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 2 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.355 g), mp 217-219° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][OH:15])[CH:3]=1>O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1cc(Br)ccc1-c1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=Cc1cc(Br)ccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
IBX (7.45 g, 26.6 mmol) was added to (4-bromobiphenyl-2-yl)methanol (3.5 g, 13.30 mmol) in dmso (40 mL) and stirred at 60° C. for 2 hours. The reaction was cooled in an ice bath and diluted with water and diethyl ether. The ether layer was washed with brine, dried over MgSO4, filtered and evaporated to give 4-bromobiphenyl-2-carbaldehyde (3.32 g, 12.71 mmol, 96% yield) as an orange oil. LCMS: rt=1.66 min.; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29-7.39 (m, 3H) 7.43-7.58 (m, 3H) 7.76 (dd, j=8.16, 2.13 Hz, 1H) 8.15 (d, J=2.01 Hz, 1H) 9.91 (s, 1H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:13]([Cl:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([Cl:11])=[O:10])([O-])=O.[N+:16](C1C=C(C(O)=O)C=C(C=1)C(O)=O)([O-:18])=[O:17].S(Cl)(Cl)=O>CN(C)C=O>[N+:16]([C:7]1[C:8]([C:9]([Cl:11])=[O:10])=[CH:12][CH:4]=[CH:5][C:6]=1[C:13]([Cl:15])=[O:14])([O-:18])=[O:17]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A mixture of 100 g of 5-nitroisophthaloyl dichloride (prepared by taking a mixture of 60.0 g of 5-nitroisophthalic acid, 300 ml of thionyl chloride and one ml of dimethylformamide, stirring at room temperature for 30 minutes followed by refluxing for one hour; allowing the solution to stand 24 hours, followed by evaporation to a small volume in vacuo re-evaporating with toluene and then diluting the resulting liquid with 250 ml of hexane, followed by stirring and cooling until the resulting oil is solidified; and grinding the product to a powder, and recrystallizing twice from carbon tetrachloride to afford 47.4 g of nitroisophthaloyl chloride) 100 g of 2-methoxyethanol (dried over molecular sieves) and 400 ml of acetonitrile (dried over molecular sieves) is heated to boiling on a steam bath. Heating is continued for 15 minutes, then the mixture is cooled to room temperature and is poured into 2 liters of cold water with vigorous stirring. The precipitate formed (129 g) is collected by filtration, air dried and set aside. The above filtrate is extracted with benzene. The benzene extract is washed with water, dilute sodium dicarbonate and water and is dried over anhydrous sodium sulfate. The solvent is evaporated to give a mixture of crystals and oily liquid. This material is combined with the precipitate set aside above and dissolved in 580 ml of hot ethyl alcohol. The resultant solution is neutralized with 5.0 ml of 5N sodium hydroxide and is slowly diluted with 450 ml of water. The solution is allowed to crystallize at room temperature then is placed in a chill room for 16 hours. The product is collected by filtration, then is recrystallized and filtered as above from 450 ml of ethyl alcohol and 350 ml of water to give 92.1 g of 5-nitroisophthalic acid bis(2-methoxyethyl)ester as colorless needles.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl.[Ag]=O>[CH3:14][S:15]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCOCCOCCO
Agent: O=[Ag]
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
250 mL of dichloromethane was added to 25 g of tetraethylene glycol and 32.8 g of silver oxide, and then a solution of 17.7 g of methanesulfonyl chloride in 50 ml of dichloromethane was added dropwise. After stirring the reaction solution at room temperature for 2 days, the solution was filtered with a celite, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 24 g of the objective compound.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(N1[CH2:29][CH2:28][CH2:27]C1=O)C.C1(CBr)CC1.C(N(CC)C(C)C)(C)C.Cl>O>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:27]4[CH2:28][CH2:29]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CCN1CCCC1=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: BrCC1CC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 54.5 °C
Yield: 100.1 %

Procedure:
A mixture of noroxymorphone (60 Kg, 0.209 Kmol), N-ethyl-2-pyrrolidinone (180 kg), cyclopropymethyl bromide (36.6 kg) and N,N-diisopropylethylamine (35.1 kg) was heated to 52-57° C. for 20 hours and 10 minutes. The mixture was then diluted with a solution prepared by mixing hydrochloric acid 37% (29 kg) and water (79 kg). Low boiling compounds were removed by distillation under vacuum keeping the temperature below 70° C. After cooling to 25-30° C. the mixture was further diluted with water (1910 kg). Ammonium hydroxide 4% (199 kg) was then added over three hours till pH=9-10 to precipitate the product. The solid was filtered, washed with water (2×120 kg) and dried under vacuum at 60° C. obtaining 68.5 kg of naltrexone (molar yield 93.2%). HPLC analysis (% by area): naltrexone 99.1%, noroxymorphone 0.11%, 3-cyclopropylmethylnaltrexone 0.41%
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][OH:5])[C@@H:2]1[CH2:6][OH:7].C(OCC)(=O)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:7][CH2:6][C@H:2]1[C@@H:3]([CH2:4][O:5][S:15]([CH3:14])(=[O:17])=[O:16])[O:1]1)(=[O:17])=[O:16]
Reactant: OC[C@@H]1O[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC[C@@H]1O[C@@H]1COS(C)(=O)=O
Reaction time: 4 h

Procedure:
To a mixture of 2.3 g of cis-oxirane-2,3-dimethanol and 200 ml of ethyl acetate was added 9.3 ml of triethylamine and then 4.3 ml of methanesulfonyl chloride under ice-cooling, followed by stirring at the same temperature for 4 hours. The reaction mixture was filtered through silica gel and washed with ethyl acetate. Thereafter, the filtrate was evaporated, to give 5.4 g of the title compound.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH3:30])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl- thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.ClC1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>>[CH2:6]([NH:7][C:2]1[NH:26][C:3]2[C:2]([N:1]=1)=[N:7][CH:6]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[CH:35]=[CH:34][N:33]=[CH:32][N:31]=4)[CH2:13][C:12]=3[CH:25]=1)[CH:4]=2)[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Reactant: Clc1ccncn1
Product: CCNc1nc2ncc(-c3ccc4c(c3)CN(c3ccncn3)CCO4)cc2[nH]1

Procedure:
Prepared as an acetate salt according to the method of example 11 by using tert-butyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Example 26) in step 1 and 4-chloropyrimidine in step 4. 1H NMR (400 MHz, DMSO-D6-d6) δ 8.13-8.06 (m, 1H), 7.61 (d, 1H), 7.45-7.41 (m, 2H), 7.37-7.30 (m, 2H), 7.19-7.12 (m, 2H), 6.98 (d, 1H), 6.68-6.62 (m, 1H), 5.05 (s, 2H), 4.43 (d, 2H), 4.20 (d, 2H), 3.35-3.28 (m, 2H), 2.46 (s, 3H), 1.89 (s, 4H), 1.18 (t, 3H); MS (EI) for C21H21N7O: 388 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[CH:7]2.B(Br)(Br)Br>>[Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[CH:7]2
Reactant: COc1ccc(-c2cc(C#N)c3c(Br)c(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: N#Cc1cc(-c2ccc(O)cc2)cc2ccc(O)c(Br)c12

Procedure:
The title compound was prepared by reacting 8-bromo-7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.13 g, 0.37 mmol) with boron tribromide (1.1. mL of 1N solution, 1.1 mmol) according to method D to yield 0.050 g (40%) of an off white solid: mp 204–208° C.(d);1H NMR (DMSO-d6): δ 6.90 (2H, d, J=8.30 Hz), 7.41 (1H, d, J=8.79 Hz), 7.72 (2H, d, J=8.79 Hz), 8.02 (1H, d, J=9.23 Hz), 8.37 (1H, d, J=1.95 Hz), 8.47 (1H, d, J=2.44 Hz), 9.72 (1H, s), 11.16 (1H, s); MS (ESI) m/z 338/340 (M−H).Anal. for C17H10BrNO2
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([O:22][C:23]([N:25]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[NH2:26])=[O:24])([CH3:21])[CH3:20]>>[C:19]([O:22][C:23]([N:25]([CH2:27][CH:28]1[CH2:29][CH2:30]1)[NH:26][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])=[O:24])([CH3:21])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(N)CC1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(C)OC(=O)N(CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 1-(cyclopropylmethyl)-hydrazinecarboxylic acid 1,1-dimethylethyl ester (CAN 1314973-05-1) as starting materials; LC-MS (UV peak area/ESI) 100%, 402.2375 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([S:8]([OH:11])(=[O:10])=[O:9])[CH:7]=1.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15].Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]([S:8]([O:11][Si:14]([CH3:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(O)c1cc(F)ccc1O
Reactant: C[Si](C)(C)Cl
Agent: Cl
Product: C[Si](C)(C)Oc1ccc(F)cc1S(=O)(=O)O[Si](C)(C)C

Procedure:
302 g (1.57 mol) of 5-fluoro-2-hydroxybenzenesulfonic acid are admixed, under an inert gas atmosphere at room temperature with stirring, with 794 ml (683 g, 6.28 mol) of chlorotrimethylsilane, and the mixture is heated to boiling. After the vigorous release of HCl has died down, a further 794 ml of chlorotrimethylsilane are added and the turbid solution is heated under reflux for 96 hours. After cooling, the precipitate is filtered off under inert gas, the excess chlorotrimethylsilane is removed at 40-50° C. under slightly reduced pressure (about 4000 Pa) and the product is obtained by fractional distillation in vacuo.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)(=O)C>C1(C)C=CC=CC=1>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[O:25][C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:3][CH2:4]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCN(C2CCCCC2)CC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCN(C2CCCCC2)CC1

Procedure:
Refluxing 4-amino-1-cyclohexylpiperidine and 9-acetoxyxanthene in dry toluene for 24 hours, then working up as in Example 1 gives N-(N-cyclohexyl-4-piperidinyl)-9-xanthenylamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].C[CH2:12][OH:13]>[C-]#N.[C-]#N.[Zn+2]>[OH:7][C:6]1[CH:5]=[C:4]([OH:10])[C:3]([Cl:2])=[CH:9][C:8]=1[CH:12]=[O:13]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CCO
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: O=Cc1cc(Cl)c(O)cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
At 0° C., a stream of hydrogen chloride was blown into a suspension of 4-chlororesorcinol (10.9 g, 75.43 mmol), Zn(CN)2 (13.5 g, 115 mmol), and KCL (0.25 g, 3.36 mmol) in EtOH (35 mL). The solution was stirred at 0° C. until the absorption of HCl gas stopped. The stirring was continued for another 2 hours at 10° C., during which more precipitate formed. After the precipitate was allowed to settle, the ethereal solution was decanted. The solid was treated with ice water (about 100 mL) and then heated to 100° C. for 0.5 hours. Upon cooling to room temperature, the product was formed as a solid at the bottom of the flask. Filtration and drying under a high vacuum afforded the desired product as a white solid (1.5 g, 11.5%).
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.Cl.[CH3:14][C:15]([CH3:17])=[O:16]>>[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.6 %

Procedure:
Water (20 ml) and 10% NaOH aqueous solution (4 ml) were added under stirring to the solution of 4-methylbenzaldehyde (10.2 g, 10 mmol) in acetone (10 ml). The reaction mixture was stirred for 14 hr at room temperature, then the pH value was adjusted to pH=7.0 with 10% hydrochloric acid, extracted with methylene chloride. The combined methylene chloride extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 0.73 g of a yellow viscous oil, yield: 45.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH.