Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=O)[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1.B.C1COCC1.Cl>C1COCC1>[CH3:23][O:22][C:19]1[C:18]([CH3:24])=[CH:17][N:16]=[C:15]([CH2:14][N:5]2[C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[CH:10][C:9]=3[NH:8][CH2:7][C@@H:6]2[CH3:13])[C:20]=1[CH3:21]
Reactant: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@@H]2C)c1C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(C)cnc(CN2c3nc(N)ncc3NC[C@@H]2C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
(7S)-2-amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7-methyl-7,8-dihydropteridin-6(5H)-one (Example 1)(164 mg, 0.50 mmol) was stirred in THF (3 mL) and borane-THF complex (1M in THF, 2 mL, 2 mmol) was added slowly. The mixture was stirred at room temperature for 1 hour, then heated at reflux for 30 minutes. The mixture was slowly treated with hydrochloric acid (2M, 5 mL). The solution was loaded onto a SCX column and washed with methanol. The product was eluted with methanolic ammonia (7M) and the volatiles were removed under reduced pressure. Further purification was achieved by MPLC eluting with 5-30% methanol/DCM to give the title compound as a cream foam (115 mg, 73%); 1H NMR spectrum (400 MHz, CDCl3) δ1.22 (3H, d), 2.24 (6H, s), 2.94-2.97 (1H, m), 3.13-3.17 (1H, m), 3.20 (1H, s), 3.57-3.62 (1H, m), 3.75 (3H, s), 4.32 (1H, d), 4.36 (2H, s), 5.59 (1H, d), 7.33 (1H, s), 8.17 (1H, s);
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:8])[O:4][CH2:3]1.Cl[O-:11].[Na+]>C(Cl)Cl.O.C(O)(C)C.[Ru](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:11])(=[O:8])[O:4][CH2:3]1
Reactant: CC1(C)COS(=O)OC1
Reactant: [O-]Cl
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CC1(C)COS(=O)(=O)OC1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
10.0 g (0.064 mol) of 5,5-dimethyl-1,3,2-dioxathiane-2-oxide was introduced at 20° C. in 100 ml of methylene chloride and 50 ml of water in a 250 ml three-necked flask. 0.02 g of 90 percent ruthenium trichloride was added as a catalyst. 152.45 g (0.0727 mol) of sodium hypochlorite in water was added with stirring for 20 minutes, and the temperature increased to 30° C. The reaction mixture was stirred for five more hours and mixed with 10 drops of isopropanol; the yellow color faded and a black precipitate formed. The water phase was extracted twice with methylene chloride (50 ml), and the combined organic phases were extracted with NaHCO3 solution (100 ml), dried with Na2SO4 and concentrated by evaporation. The white crystalline product was dried overnight at room temperature at a pressure of 15 mbars and weighed 10.65 g, which corresponded to a yield of 99 percent, relative to the 5,5-dimethyl-1,3,2-dioxathiane-2-oxide used.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C1C[O:26][CH2:25]C1.C([Li])CCC.CN(C)C=O>CCCCCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:25]=[O:26])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: C1CCOC1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To stirred solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (10.0 g, 0.0309 mol;) in THF (400 mL, 5 mol) at −78° C. was added 2.5 M of n-Butyllithium in hexane (18 mL). The solution was stirred at −78° C. for 30 minutes. N,N-Dimethylformamide (5.3 mL, 0.068 mol) was added and stirring continued at −78° C. for 1 hours. The reaction was slowly quenched using 0.1N HCl cold solution. The product was extracted with DCM. The organic extracts were combined, washed with brine, filtered, and concentrated to dryness to give 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde (10.76 g, 99%) as a yellow solid. The crude was carried on without further purification.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([Cl:25])[CH:14]=2)[CH3:8])(=O)=O.[CH2:26]([NH2:28])[CH3:27]>O>[Cl:25][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:7]([CH3:8])[CH2:6][NH:28][CH2:26][CH3:27])[C:22]1[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=1[S:16]2
Reactant: CCN
Reactant: CC(COS(C)(=O)=O)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Solvent: O
Product: CCNCC(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reaction time: 17 h

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (55.1 g) and triethylamine (10.4 cc) in anhydrous pyridine (350 cc) is saturated by bubbling hydrogen sulphide in for 5 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C., and the mixture is then outgassed by bubbling nitrogen through for 90 minutes. The reaction mixture is then diluted with ethyl acetate (1000 cc) and washed with distilled water (5×1000 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column of 0.02-0.6 mm silica gel (height: 31 cm; diameter: 7.5 cm), eluting with an 80:20 (by volume) mixture (30 liters) of cyclohexane and ethyl acetate and collecting 1000 cc-fractions. Fractions 22 to 38 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) to give an oil containing the expected product. The oil obtained is purified by chromatography on a column of 0.04-0.06 mm silica gel with a slight excess pressure of nitrogen (40 kPa) (height: 30 cm; diameter: 4.5 cm), eluting with pure ethyl acetate (1.5 liters) and collecting 100-cc fractions. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (1.7 g). An autoclave is charged with (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propyl methanesulphonate (36 g) and ethylamine (200 cc). The mixture is brought to 100° C. for 17 hours. After cooling, the reaction mixture is poured into water (1 liter). The solution is extracted with ethyl acetate (500 cc) and the organic phase is washed with distilled water (2×500 cc). After settling has taken place, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. to give a brown gum, which is purified by chromatography on a column (height: 50 cm; diameter: 6 cm) of silica (0.06-0.3 mm), eluting with pure ethyl acetate (8 liters) and then with a mixture of ethyl acetate and methanol (97:3 by volume mixture of ethyl acetate and triethylamine) (2 liters) and finally with a mixture (10:90 by volume) (2 liters) of diethylamine and methanol and collecting 500-cc fractions. The fractions 32 to 37 are combined and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[ (2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (20 g) in the form of a brown product of meringue-like consistency.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=3.C1COCC1.CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][Si:30]([C:33]#[C:34][C:4]1[C:5]2[N:6]([CH3:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:2][CH:3]=1)([CH3:32])[CH3:31]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c2ccc(I)cc2c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1c2ccccc2c2cccc(C#C[Si](C)(C)C)c21
Yield: 135.6 %

Procedure:
Firstly, a mixture of PdCl2(PPh3)2 (13 mg, 0.018 mmol), CuI (3.5 mg, 0.018 mmol) and 3,6-diiodo-9-methylcarbazole (200 mg, 0.46 mmol) was added with dist. THF (3 mL), dist. Et3N (1.5 mL) and trimethylsilylacetylene (653 μL, 4.6 mmol). The resultant mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with ether. After that, an organic layer was washed with dist. H2O and sat. NaCl, and was dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. Subsequently, the obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1) to obtain 3,6-bis[(trimethylsilylethynyl)-9-methylcarbazole (173 mg, 100% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[S:22])(OC1C=CC=CC=1C(O)=O)=O)([OH:3])=[O:2].[CH3:23][C:24]1[C:29]([OH:30])=[C:28]([CH2:31]S)[C:27]([CH:33]=[CH2:34])=[CH:26][N:25]=1>C(O)C>[CH3:23][C:24]1[C:29]([OH:30])=[C:28]([CH2:31][S:22][S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1]([OH:3])=[O:2])[C:27]([CH:33]=[CH2:34])=[CH:26][N:25]=1
Reactant: O=C(O)c1ccccc1OS(=O)(=S)c1ccccc1C(=O)O
Reactant: C=Cc1cnc(C)c(O)c1CS
Solvent: CCO
Product: C=Cc1cnc(C)c(O)c1CSSc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.02 moles of o-carboxyphenyl o-carboxybenzenethiosulfonate in 200 ml. of 95% ethanol is added 0.02 moles of fine powdered 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. The reaction mixture is stirred overnight at room temperature and the resulting precipitate filtered to yield o-carboxyphenyl 2-methyl-3-hydroxy-5-vinylpyridin-4-ylmethyl disulfide.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:40][N:41]([CH3:47])[CH:42]1[CH2:46][CH2:45][NH:44][CH2:43]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:44]1[CH2:45][CH2:46][CH:42]([N:41]([CH3:47])[CH3:40])[CH2:43]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CN(C)C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N(C)C)C3)ccc2[nH]1
Yield: 68 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (commercially available), 3-(dimethylamino)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (68%).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:14]1([C:10]2[CH:9]=[C:8]([OH:20])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][C:11]=2[OH:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)C=C1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1cc(-c2ccccc2)c(O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To dry THF was dissolved 0.5 g/1.9 mmol of 2,5-diphenylbenzoquinone in argon atmosphere, and 85 mg/2.24 mmol of lithium aluminum hydride was added to the solution. After stirring at room temperature for 30 minutes, the reaction solution was added to ice containing 1N hydrochloric acid, and the mixture was allowed to stand for 30 minutes. The aqueous layer was extracted with ethyl acetate once, and the extract was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica, gel column chromatography using hexane-methylene chloride for the eluting solution to obtain 0.28 g of the desired 2,5-diphenyl-1,4-dihydroxybenzene. 1H-NNR (CDCl3 +DMSO-d6): δ 4.52 (2H, br), 6.91 (2H, s), 7.33 (6H, m), 7.61 (4H, m).
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC(=O)C)(=O)C>>[CH:10](=[C:8]1[C:9]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: c1cnc2c(c1)CCC2
Solvent: CC(=O)OC(C)=O
Product: C(=C1CCc2cccnc21)c1ccccc1
Yield: 75 %

Procedure:
15 g (0.125 mol) of 6,7-dihydro-5H-[1]pyrindine, 20.1 g (0.19 mol) of freshly destilled benzaldehyde and 24.5 g (0.24 mol) of acetic acid anhydride were heated under reflux for 24 h. The reaction mixture was evaporated, the residual oil dissolved in methylene chloride, the solution extracted with 1N NaOH solution, and the organic phase dried and evaporated. The residue was destilled under reduced pressure to give 19.3 g (75%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH:8]=2)[S:5][CH:6]=1.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]=2)[S:5][CH:6]=1
Reactant: Cc1csc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1csc(C2=CCNCC2)c1

Procedure:
To a crude product synthesized by using tert-butyl 4-(4-methylthiophen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10.0 mg, 0.358 mmol) in a similar manner to Reference Synthesis Example 26, saturated sodium bicarbonate aqueous solution was added and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].N1C=CC=CC=1.Cl[C:40]([O:42][CH2:43][Cl:44])=[O:41]>ClCCl>[C:40](=[O:41])([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)[O:42][CH2:43][Cl:44]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)OCCl)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tolvaptan (5.0 g) and pyridine (1.1 ml) were suspended in dichloromethane (50 ml). Chloromethyl chloroformate (1.1 ml) was added thereto under cooling with ice, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=70:30→50:50). The purified product was concentrated under reduced pressure to obtain 6.1 g of chloromethyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} carbonate as white amorphous solid.
Reaction SMILES: C(=O)=O.COC([CH:8]1[C:17]2[N:16]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)=O.Cl>CO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:17]=2[N:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CCCc2ccc(C(C)(C)C)nc21
Agent: Cl
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)c1ccc2c(n1)CCCC2

Procedure:
was treated with phenyl lithium (0.1 m.) by the general method described in Example 1 to obtain 2-t-butyl[8-Lithio]-5,6,7,8-tetrahydroquinoline which was treated in situ with CO2 and the product converted to methyl-2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxylate by refluxing in methanol saturated with dry HCl gas as described in our copending U.S. Ser. No. 460265.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 146 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:29])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([NH:29][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:39])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC(C)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.2 %

Procedure:
To a solution of 1.4 g (3.44 mmol) of 3-nitro-5-(octadecyloxy)benzenamine and 0.75 ml (5.4 mmol) of triethylamine in 85 ml of THF stirred in an ice bath was added 0.25 ml (3.44 mmol) of acetyl chloride. The ice bath was removed after 15 minutes and the reaction mixture was stirred at room temperature for 17 hours. Triethylamine (0.3 ml) and acetyl chloride (0.15 ml) were added and stirring was continued for 5 hours. The solvent was removed at reduced pressure and the residue was crystallized from ethyl acetate-hexane to give 1.3 g (84% yield, mp 103°-107°) of 3-(acetylamino)-5-(octadecyloxy)nitrobenzene. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:51])[O:38][C@H:39]([CH2:41][CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH3:40].O>O1CCCC1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([B:27]2[O:31][C:30]([CH3:32])([CH3:33])[C:29]([CH3:34])([CH3:35])[O:28]2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:51])[O:38][C@H:39]([CH2:41][CH2:42][OH:43])[CH3:40]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)O[C@@H](C)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)O[C@@H](C)CCO
Yield: 146.6 %

Procedure:
To (S)-4-(tert-butyldimethylsilyloxy)butan-2-ol (1.649 mmol, 337 mg) in dichloromethane (4 ml) were added mol sieves (4A), 2-(4-isocyanato-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.374 mmol, 378 mg) and 4-dimethylaminopyridine (0.275 mmol, 33.6 mg) were added and the mixture was stirred at 40° C. (oil bath temperature) for 18 hours. The mol sieves were removed by filtration and the filtrate washed with water, dried (sodium sulfate) and concentrated in vacuo to give a crude product which was purified by column chromatography (silica gel, heptanes with gradient 10% to 50% of ethyl acetate) to afford (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (443 mg). Tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.22 mmol, 1.22 ml) was added to (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (240 mg) in tetrahydrofuran (1 ml) at room temperature. After 20 hours water was added to the reaction mixture, extracted with dichloromethane, the organic extract dried (sodium sulfate) and concentration in vacuo to yield (S)-4-hydroxybutan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (268 mg) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N:13]1([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-4-fluoronitrobenzene (3.3 g, 19.9 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (3.5 mL, 20 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
4-Fluorobenzoic acid methyl ester (34 mmol), 1-methyl-piperazine (75 mmol) and potassium carbonate (34 mmol) are suspended in acetonitrile (30 ml) and stirred under reflux for three days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale yellow powder with mp. 117-119° C., Rf=0.20 (CH2Cl2/MeOH=95:5) is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[C:23]([C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][CH:26]=1)[O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH:11]=[CH:10][CH:9]=1)#[N:24]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(C)C(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C(Cc1cccc(Oc2cccc(C#N)c2)c1)NC(=O)OC(C)(C)C
Yield: 135.7 %

Procedure:
The tert-butyl [2-(dimethylamino)-1-(3-hydroxybenzyl)-2-oxoethyl]carbamate (0.025 g, 0.081 mmol) from Example 169, step 4, was combined with (3-cyanophenyl)boronic acid (Aldich, Cat. #513016) (0.024 g, 0.16 mmol) and triethylamine (0.022 mL, 0.16 mmol), and copper(II)diacetate (0.015 g, 0.081 mmol) in methylene chloride (1.0 mL) at r.t. The reaction was vigorously stirred exposed to the atmosphere. After stirring for 48 h. this was taken up in ethyl acetate, washed with 1N HCl, brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude tert-butyl 3-(3-(3-cyanophenoxy)phenyl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.045 g) as a semisolid residue. Analytical LCMS (M+H-Boc)+: m/z=310.0.