Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[F:27][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:26])[N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=1)[C:4]([C@@H:2]([NH:1][C:29]1[C:30]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=1)[CH3:3])=[N:5]2
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: FC(F)(F)c1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cc(C(F)(F)F)c12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (76 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.4 mL) at 23° C. was added 4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (49 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 50 mg of the title compound (44% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[OH:33][CH2:32][C:31]([CH3:36])([CH3:35])[C:30]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:29]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)C(C)(C)CO)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 4 h
Yield: 13 %

Procedure:
A solution of 11.6 g of cholesterol and 3.6 g of hydroxypivalic acid in 80 ml of toluene is treated with 1 g of p-toluenesulphonic acid and boiled for 4 hours. The reaction mixture is treated with water and extracted with ether. The organic phase is dried and concentrated and the residue is purified over silica gel with petroleum ether/ether (4:1). There are obtained 1.9 g of cholest-5-en-3β-yl 3-hydroxy-2,2-dimethyl-propionate, m.p. 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].O.[NH2:22]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:22]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: NN
Reactant: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CO
Solvent: O
Product: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]carbamate (i.e. the product of Step A) (4.14 g, 13.9 mmol) in methanol (80 mL) was added hydrazine hydrate (0.771 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the solid collected was dried under reduced pressure to provide the title compound, a compound of the present invention, as a solid (3.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]3[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.[Br:21]Br>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Br:21][C:12]1[N:7]2[C:8]([S:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=32)=[N:10][C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: COc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)sc1nc(-c3ccccc3)c(Br)n12
Yield: 78 %

Procedure:
While stirring vigorously a mixture of a solution of 2.0 g of 7-methoxy-2-phenylimidazo[2,1-b]benzothiazole in 50 ml of chloroform and 30 ml of a saturated aqueous sodium hydrogencarbonate solution, a solution of 1.2 g of bromine in 5 ml of chloroform was gradually added dropwise to the mixture at room temperature. Thereafter, the chloroform layer was recovered, dried by anhydrous magnesium sulfate, and concentrated under reduced pressure to form a solid material. The solid product was recrystallized from a mixture of toluene and n-hexane to provide 2.0 g of 3-bromo-7-methoxy-2-phenylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[I:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cccc(I)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(I)c4)cc23)CC1
Yield: 78.7 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.0 mg (0.131 mMol) 3-iodobenzoic acid, 15.9 mg (80%) of the title compound were recovered.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH3:19][N:20]([CH3:24])[C:21]([N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:22]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)CCNc1nccs1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)N(C)C)c1nccs1

Procedure:
Following the procedure of Example 1C using 18.2 g. (0.1065 moles) of N,N-dimethyl-N'-(2-thiazolyl)-1,2-ethane diamine, 12.1 g. (0.120 moles) of triethylamine, 12.5 g. (0.116 moles) of dimethylcarbamoyl chloride and 135 ml. of dry benzene, there is obtained 20.1 g. of N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-thiazolyl) urea as an oil which is distilled at 108°-110° C., at 0.02 mm. of Hg.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[CH3:25][N:26]([CH3:28])O.[OH-].[Na+]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:26]([CH3:28])[CH3:25])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CN(C)O
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 15, 8-methylthio-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of N,N-dimethylhydroxylamine and sodium hydroxide in dimethylformamide to give 8-methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.Br[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:41]1(=[O:50])[N:40]([CH2:39][CH2:38][CH2:37][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([NH:20][C:21]([NH:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]2=[O:19])[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]12
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c3ncccc23)c1
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (200 mg, 0.43 mmol) and N-(3-bromopropyl)phthalimide (133 mg, 0.50 mmol) in DMF (10 ml) was added potassium carbonate (114 mg, 0.83 mmol), and the mixture was stirred at 50°-60° C. for one hour. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from hexane to give the title compound (229 mg, 0.35 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>CN(C)C=O>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH2:27][N:11]([CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:29][CH:30]=1)#[N:33]
Reactant: O=S(=O)(NC1CC2CCC1C2O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN(C2CC3CCC2C3O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 49.4 %

Procedure:
A solution of 2-(4-chlorophenylsulfonamido)bicyclo[2.2.1]heptan-7-ol (604 mg, 2.0 mmol), cesium carbonate (1.30 g, 4.0 mmol), and 4-(bromomethyl)benzonitrile (471 mg, 2.4 mmol) was stirred in 10 mL dimethylformamide for 1 h. The crude reaction product was treated with additional cesium carbonate (261 mg, 0.8 mmol) and 4-(bromomethyl)benzonitrile (94 mg, 0.5 mmol) to complete the reaction. The reaction was partitioned between 50 mL ethyl acetate and 50 mL 0.1 M HCl, concentrated and purified by flash chromatography on 120 g silica gel with 30 to 50% ethyl acetate in hexane to yield N-(4-cyanobenzyl)-N-(7-hydroxybicyclo[2.2.1]heptan-2-yl)-4-chlorobenzenesulfonamide (412 mg, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 7.70-7.77 (2H, m), 7.59 (2H, d, J=8.56 Hz), 7.44-7.50 (4H, m), 4.81 (2H, dd, J=39.53, 17.88 Hz), 4.06 (1H, t, J=7.81 Hz), 3.84 (1H, br. s.), 1.91 (1H, br. s.), 1.75-1.82 (2 Hon), 1.43-1.66 (3H, m), 1.07-1.17 (2H, m). LC/MS R.T.=1.97 min; [M+H]+=417.15.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]2[C:18]3[S:19][CH:20]=[C:21]([CH3:22])[C:17]=3[C:16]3=[N:23][CH:24]=[N:25][N:15]3[C:14]2=[O:26])=[CH:10][CH:9]=1.[C:29](=O)([O-])[O-:30].[K+].[K+]>CN(C)C=O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:18]3[S:19][C:20]([CH:29]=[O:30])=[C:21]([CH3:22])[C:17]=3[C:16]3=[N:23][CH:24]=[N:25][N:15]3[C:14]2=[O:26])=[CH:27][CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3c(C)csc32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(=O)n3ncnc3c3c(C)c(C=O)sc32)cc1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
Phosphorus oxychloride (1.47 ml, 15.8 mmol) was added to N,N-dimethylformamide (13 ml) and the mixture was stirred for 20 minutes. 6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (1.29 g, 3.94 mmol) was added as a solid and the mixture was heated at 90° C. for 45 minutes. The mixture was cooled to room temperature and poured into a mixture of ice (30 mL) and potassium carbonate (5 g). After the ice had melted the pH was 8-9. The mixture was extracted with dichloromethane (3×30 mL) and the combined extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under vacuum. The residue was purified by flash LC (20-100% ethyl acetate in hexanes) to afford the aldehyde (0.87 g, 62%) as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 3.01 (s, 3H), 3.78 (s, 3H), 5.38 (s, 2H), 6.86-6.88 (m, 2H), 7.44-7.46 (m, 2H), 8.33 (s, 1H), 10.12 (s, 1H). LCMS (MH+, 355.0).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][OH:16]>>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: OCc1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1ccncc1OCc1ccc(Cl)cc1Cl
Yield: 68.2 %

Procedure:
In accordance with the same procedures as in Steps 3 and 4 of Preparation 1, except for using 3-bromo-4-nitropyridin-N-oxide prepared in Step 2 of Preparation 1 and 2,4-dichlorobenzyl alcohol, the titled compound was obtained (Yield: 68.2%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N1CCCCC1>C(OCC)(=O)C.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>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCCC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C#CCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
A solution of 4-pentynoic acid (2.15 g, 22 mmol), 4-bromobenzonitrile (3.64 g, 20 mmol), and piperidine (40 mL) was degassed by bubbling nitrogen through the solution for 5 min. prior to the addition of tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.2 mmol). The reaction vial was sealed and warmed to 80° C. for 1.5 hours. After cooling to 23° C., the reaction mixture was diluted with ethyl acetate (200 mL), filtered, and concentrated in vacuo. The residue was diluted with ethyl acetate (300 mL), washed with 5% HCl (2×100 mL), washed with water (1×100 mL), and extracted with 3% sodium carbonate (2×200 mL). The basic aqueous layer was treated with decolorizing carbon, filtered, and acidified to pH=2. The resultant solid was filtered, washed with water, dried, and purified by flash chromatography (gradient ethyl acetate:methylene chloride:acetic acid 1:9:0.005) and fractional recrystallization (methylene chloride-ether) to afford 5-(p-cyanophenyl)-4-pentynoic acid as a white solid: m.p. 149°-152° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]=[O:13])=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=CCCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCCO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
3-(4-Nitro-2-(trifluoromethyl)phenyl)propionaldehyde (1700 mg, 6.9 mmol) was dissolved in methanol (10 mL), and sodium borohydride (100 mg, 2.64 mmol) was added thereto. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then purified by silica-gel column chromatography (n-hexane:ethyl acetate=3:1) to give 3-(4-nitro-2-(trifluoromethyl)phenyl)propan-1-ol (859 mg, 50%) as a light-yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:30]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=1)[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[CH:24][CH:23]=[C:22]([OH:29])[CH:21]=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:41][CH:42](Br)[CH3:43]>CN(C)C=O>[Br:41][CH2:42][CH2:43][O:29][C:22]1[CH:21]=[C:20]2[C:25]([C:26](=[O:28])[CH:27]=[C:18]([C:17]3[CH:16]=[C:15]([O:14][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:32]=[C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:30]=3)[O:19]2)=[CH:24][CH:23]=1
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(O)ccc12
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCCBr)ccc12
Reaction time: 0.5 h

Procedure:
Potassium carbonate (2.76 g, 20 mmol) was added to a stirred solution of 3′,5′-dibenzyloxy-7-hydroxy-flavone, 22 (2.25 g, 5 mmol) in dry dimethyl formamide (120 mL). After the mixture was stirred for 30 min, dibromo ethane (5 mL, 58 mmol) was added and the resultant was stirred at room temperature for 12 h. Reaction mixture was filtered through celite, concentrated under reduced pressure and extracted with chloroform. The extract was washed with water, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 56.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1.O>CS(C)=O>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: OC1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 95 %

Procedure:
Potassium carbonate (4.85 g, 35.06 mmol) was added to a stirring solution of 4-fluoro-2-methoxy-1-nitrobenzene (5.0 g, 29.22 mmol) and piperidin-4-ol (2.96 g, 29.22 mmol) in DMSO (20 mL) and the reaction mixture was heated at 90° C. for 1 h. The reaction mixture was allowed to cool to RT and water (200 mL) was added. The resultant precipitates were collected by vacuum filtration and washed with water and Et2O to give the title product as a yellow solid (7.0 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(OS(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=O)=O)=CC=1>CN(C=O)C>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:3][CH:4]=1
Reactant: Cc1ccc(OS(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)cc1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCO)cc1
Temperature: 60 °C
Reaction time: 19 h

Procedure:
A 100 ml round bottom flask was charged with 4-hydroxyphenethyl alcohol (1.14 g, 8.2 mmol), cesium carbonate (4.02 g, 12.4 mmol), and tert-butyl 2-(2-{[(4-methylphenoxy)sulfonyl]oxy}ethoxy)-ethylcarbamate (2.96 g, 8.2 mmol) (prepared using standard chemistry). This reaction mixture was slurried with 10 ml of DMF and heated to 60° C. by use of an oil bath. The reaction proceeded for 19 hours at which point was it was cooled and the DMF removed under reduced pressure. Upon adding dichloromethane the reaction mixture was filtered through a plug of celite and then the solvent removed. The resultant solid was dried under high vacuum. A near quantitative yield of product was isolated: 1H NMR (CDCl3) δ 7.11 (d, 2H, Ar), 6.98 (d, 2H, Ar), 4.97 (bs, exchangeable, NH), 4.07 (dd, CH2—O), 3.79 (t, CH2—OH), 3.78 (dd, CH2—O), 3.57 (t, CH2—O), 3.30 (bm, CH2—NH), 2.78 (t, CH2—Ar), 1.82 (bs, exchangeable, OH) 1.41 (s, 9H, CH3). Mass spectrum, m/e Calcd for C17H28NO5+: 326.20 (100%), 327.20 (19.5%). Found: 326.56, 327.57.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29]>C(#N)C>[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c(F)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,4-difluorobenzylamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a graded solvent mixture of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=387.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([NH2:20])=O)[CH:3]=1.C(O)(=O)C>P(Cl)(Cl)(Cl)=O>[C:18]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=1)#[N:20]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(N)=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCCOc1ccccc1-c1nc(O)cc(C#N)n1

Procedure:
A stirred solution of 6-hydroxy-2-(2-propoxyphenyl)-pyrimidine-4-carboxamide (0.50 g) in phosphoryl chloride (16 ml) was heated under reflux for 4 hours and then the reaction mixture was evaporated under reduced pressure to remove excess phosphoryl chloride. Water was added to the residue, which was extracted with chloroform (3×20 ml). The combined extracts were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure to yield an oil which was heated on a steam bath with glacial acetic acid (15 ml) for 4 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a crude product which was combined with further product similarly prepared from 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide (0.82 g) and phosphoryl chloride (25 ml). The combined products were eluted from silica with ether:chloroform (9:1) and fractions containing product were combined and evaporated under reduced pressure to yield the title compound, 0.31 g, m.p. 135°-6° C., (from isopropanol/ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=O)[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>O.NN>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21

Procedure:
4.68 g (18 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid and 50 ml of hydrazine hydrate are introduced into a round-bottomed flask and the mixture is heated to reflux until dissolution has taken place. At 100° C., 8 g of potassium hydroxide are added in small portions and the mixture is heated to reflux for four hours. The reaction medium is evaporated to dryness, the residue is taken up with water, the mixture is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether, and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (95:5). After evaporation of the solvents, 3.8 g (86%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid, melting point 149°-150° C., are collected.