Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][N:14]([CH3:16])[C:13](=O)[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=2[CH2:10][N:9]1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([CH:8]1[N:9]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])(=[O:24])=[O:23])[CH2:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[CH2:13][N:14]([CH3:16])[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)N(C)CC1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2CN(C)CC1Cc1ccccc1
Temperature: 5 °C
Yield: 13.9 %

Procedure:
To a solution of compound 2h (150 mg, 0.33 mmol) in tetrahydrofuran (10 mL) at 5° C., LAH (76 mg, 2 mmol) was added. The resulting mixture was heated to reflux for 2 h and then cooled to 5° C., quenched with one drop of water. The precipitate formed was removed by filtration. The filtrate was diluted with 1N aqueous NaOH and extracted with EA. The organic layer was washed with brine and dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by prep-HPLC to give compound 2 as a yellow solid (20 mg, 13% yield). 1H-NMR (400 MHz, CDCl3) δ 8.00 (dd, 1H, J=8.0, 2.0 Hz), 7.44 (m, 1H), 7.19-7.00 (m, 8H), 6.87-6.81 (m, 3H), 5.30 (d, J=17.6 Hz, 1H), 4.59-4.55 (m, 2H), 4.29 (m, 1H), 3.72 (s, 3H), 3.45 (d, J=12.4 Hz, 1H), 2.62 (dd, J=13.2, 10.4 Hz, 1H), 2.49-2.39 (m, 3H), 2.24 (s, 3H). MS (ESI+) m/z: 437 [M+H]+
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:27]#[N:28])[C:10]([CH3:26])=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]=3[C@H:13]3[CH2:17][C@H:16](I)[C@@H:15]([OH:19])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:27]#[N:28])[C:10]([CH3:26])=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]=3[C@H:13]3[CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccc2)c([C@@H]2C[C@H](O)[C@@H](I)C2)c2oc(C3CC3)nc2c1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c([C@H]2CC[C@@H](O)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Yield: 0.1 %

Procedure:
2-Cyclopropyl-7-[(1R*,3S*,4S*)-3-hydroxy-4-iodocyclopentyl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-301) (240 mg, 0.50 mol) was dissolved in toluene (4.8 ml), then at room temperature, 2,2′-azobisisobutyronitrile (8 mg, 0.05 mmol) and tri-n-butyltin hydride (180 μl, 0.64 mmol) were added. The solution was heated under reflux under nitrogen atmosphere for 3 hours. Monitoring the reaction by TLC showed the remaining starting material, and the solution was cooled to room temperature and tri-n-butyltin hydride (89 μl, 0.32 mmol) was again added. After further heated under reflux for 1 hour, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was combined with the entitled compound (I-302) separately synthesized according to a different method, and purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=1:1, v/v) to obtain the entitled compound (113 mg, 60%) as a colorless gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=3)[CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccccc3F)c2)nc1
Temperature: 120 °C
Yield: 28.8 %

Procedure:
A mixture of 1-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-1,2,3-triazole (268 mg, 1.1 mmol), methyl 6-chloronicotinate (190 mg, 1.1 mmol) and potassium carbonate (305 mg, 2.2 mmol) in DMF (6.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 2 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 100% ethyl acetate in heptane) afforded the title compound (120 mg, 29%) as an off white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([C:20]1([C:25]([NH2:27])=[O:26])[CH2:24][CH:23]=[CH:22][CH2:21]1)[C:5](=[O:19])[NH:6][CH:7]1[C:13](=[O:14])[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].[F:35][C:36]1[CH:50]=[CH:49][CH:48]=[CH:47][C:37]=1[O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br>CC#N>[F:35][C:36]1[CH:50]=[CH:49][CH:48]=[CH:47][C:37]=1[O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][N:12]1[C:13](=[O:14])[CH:7]([NH:6][C:5]([CH:4]([C:20]2([C:25]([NH2:27])=[O:26])[CH2:21][CH:22]=[CH:23][CH2:24]2)[CH2:3][CH:2]([CH3:28])[CH3:1])=[O:19])[CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]1=2
Reactant: CC(C)C[C@@H](C(=O)NC1CCc2ccccc2NC1=O)C1(C(N)=O)CC=CC1
Reactant: Fc1ccccc1Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CC(C(=O)NC1CCc2ccccc2N(Cc2cccc(Oc3ccccc3F)c2)C1=O)C1(C(N)=O)CC=CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
To a solution of 20 (11 mg) in CH3CN (2 mL) was added K2CO3 (8 mg) and 3-(2-fluorophenoxy)benzyl bromide 22 (12 mg). The reaction mixture was stirred at rt for 20 hrs before the solvent was removed under pressure. The crude product was purified by flash chromatography to give compound 23 (77%, 13 mg). 1H NMR (300 MHz, CDCl3) 7.32-6.80 (m, 12H), 5.72 (m, 1H), 5.58 (m, 1H), 5.34 (d, 1H), 4.72 (d, 1H), 4.48 (m, 1H), 3.18 (m, 1H), 2.70-2.20 (m, 8H), 1.95-1.78 (m, 2H), 1.42 (m, 1H), 1.12 (m, 1H), 0.92-0.80 (q, 6H); MS [M+H]+ 584.
Reaction SMILES: [CH:1]1([C:4]2[S:25][C:7]3[NH:8][C:9](=[O:24])[N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[O:22][CH3:23])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:25][C:7]3[N:8]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]5[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:32][CH:33]=4)[C:9](=[O:24])[N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[O:22][CH3:23])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(C4CC4)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of 6-cyclopropyl-3-(2,4-dimethoxybenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.82 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (1.38 g) and potassium carbonate (1.4 g) and acetonitrile (100 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (2.4 g, 86%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH3:61])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:70])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 92.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (76.4 mg, 93%).
Reaction SMILES: Cl.[NH2:2][C:3]([CH2:8][S:9][CH3:10])([CH2:6][OH:7])[CH2:4][OH:5].[CH2:11]([O:18][CH2:19][N:20]1[C:28]2[C:27]([Cl:29])=[N:26][CH:25]=[N:24][C:23]=2[C:22]([CH:30]=O)=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>CO>[CH2:11]([O:18][CH2:19][N:20]1[C:28]2[C:27]([Cl:29])=[N:26][CH:25]=[N:24][C:23]=2[C:22]([CH2:30][NH:2][C:3]([CH2:8][S:9][CH3:10])([CH2:6][OH:7])[CH2:4][OH:5])=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reactant: CSCC(N)(CO)CO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CSCC(CO)(CO)NCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Yield: 63.5 %

Procedure:
To a solution of 2-amino-2-(methylthiomethyl)propane-1,3-diol, hydrochloride salt (60.0 mg, 0.397 mmol) and 5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (126 mg, 0.397 mmol) in methanol (4 mL) was added sodium cyanoborohydride (27.4 mg, 0.436 mmol). After 15 h at ambient temperature the contents of the flask were concentrated under reduced pressure. Purification by flash column chromatography (CH2Cl2:7 M methanolic ammonia, 10:1) gave 2-((5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (110 mg, 0.252 mmol, 64%) as a yellow gum. 1H NMR (CD3OD) δ 8.57 (s, 1H), 7.84 (s, 1H), 7.18-7.13 (m, 5H), 5.82 (s, 2H), 4.52 (s, 2H), 3.95 (s, 2H), 3.68 (d, J=11.5 Hz, 2H), 3.61 (d, J=11.5 Hz, 2H), 2.76 (s, 2H), 2.11 (s, 3H). +ESMS Found 437.1407 (M+H+) C20H26N4O3SCl requires 437.1414.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:6]=2[O:5][C:4]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:2].S(=O)(=O)(O)[OH:21]>>[C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:6]=2[O:5][C:4]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:21])[NH2:2]
Reactant: CCOC(=O)c1oc2cc(O)ccc2c(=O)c1C#N
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1oc2cc(O)ccc2c(=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.0 g (0.097 mol) of ethyl 3-cyano-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate in 230 ml conc. sulfuric acid was stirred at room temperature overnight. The mixture was then poured into 1.5 l of ice water with stirring. The resulting solid was filtered off, washed with water, and dried. 16.5 g (60%) mp > 320° C. from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(-c3ccccc3)onc12
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2c(-c3ccccc3)onc12
Yield: 78.1 %

Procedure:
A solution of 23.5 g (0.112 mole) of 7-methyl-3-phenyl-2,1-benzisoxazole in 400 ml of carbon tetrachloride was treated with 20.0 g (0.112 mole) of N-bromosuccinimide and the mixture was heated at reflux with a white light lamp until all solid floated in the solvent. The mixture was filtered and the filtrate deposited a 15 g crop of reasonably pure product. This 15 g of material was dissolved in methylene chloride and washed with diluted sodium hydroxide to remove succinimide. The organic solution was concentrated and the residue was crystallized from isopropanol to give 25.2 g (77%) of yellow needles, m.p. 125.0°-125.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[CH2:14][CH2:13]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: Cc1cccc(C)c1N1CCN(c2ccc3nnc(C(F)(F)Cl)n3n2)CC1
Yield: 64 %

Procedure:
A mixture of 1-(2,6-dimethylphenyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(2,6-dimethylphenyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 64% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[O:15]1[CH2:19][CH2:18]OC1=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:18][CH2:19][OH:15])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2-one (21 g, 238 mmol) and cesium carbonate (16 g, 49.1 mmol) were combined in a 100 mL round bottom flask. The reaction was warmed from room temperature to 100° C. in an oil bath, by which time the carbonate had melted and served as the solvent for the reaction, which remained a slurry. After heating for 3.5 hours, the reaction was cooled to room temperature and was diluted with ethyl acetate, then filtered through diatomaceous earth washing repeatedly with ethyl acetate. The filtrate was concentrated, then purified by chromatography on an Analogix® Intelliflash™ purification system using a SF60-200 g column at a flow rate of 80 mL/minute, eluting as follows: 5 minutes at 20% ethyl acetate/hexanes, then ramped from 40% to 90% ethyl acetate/hexanes over 35 minutes, then 100% ethyl acetate for another 20 minutes, to provide the title compound. MS ESI(+) m/z 239.0 (M+H)+.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][C:16]=2[N:17]=1.[OH2:28]>COC(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([O:28][CH2:5][CH2:13][O:14][CH3:15])=[C:5]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH:6]=1)([O-:12])=[O:11]
Reactant: O
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: COC(C)O
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Yield: 79 %

Procedure:
Sodium hydride (30 mg, 1.2 mmol) was added portionwise to a stirred suspension of 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) in methoxyethanol (2 ml) at 0° C. When gas evolution had visibly ceased the mixture was allowed to warm to room temperature and then heated at 55° C. for 3 h. After being allowed to cool to room temperature the mixture was diluted with water (5 ml) and extracted with EtOAc (3×5 ml). The combined organic extracts were washed with brine (5 ml), dried (Na2SO4) and evaporated under reduced pressure to give the subtitle compound (186 mg, 79%). 1H NMR (DMSO) δ 8.90(d, 1H), 8.45(dd, 1H), 8.10(d, 1H), 7.85(d, 1H), 7.77(m, 3H), 7.52(m, 3H), 7.41(t, 1H), 4.50(t, 2H), 4.84(t, 2H), 3.40(s, 3H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[C:8]([OH:11])(=[O:10])[CH3:9]>>[C:8]([O:11][C:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)(=[O:10])[CH3:9]
Reactant: C1=CC2CCC1C2
Reactant: CC(=O)O
Product: CC(=O)OC12CCC(CC1)C2
Reaction time: 5.5 h
Yield: 95 %

Procedure:
To illustrate reaction of a cycloolefin in the process, a mixture of norbornene (bicyclo [2.2.1]-2-heptene) and acetic acid was reacted over HZSM-12 zeolite. The reaction was carried out on a steam bath at about 100° C. for 5.5 hours. The addition product, norbornyl acetate, was formed in about 95% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][Cl:6])[CH3:2].Cl.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14][Cl:15])[CH3:11].[OH:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:32])=[CH:26][CH:27]=3)[C:22](=[O:33])[C:21]=2[CH:20]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[ClH:6].[ClH:15].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][O:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[CH2:16][CH3:17])=[CH:26][CH:27]=3)[C:22](=[O:33])[C:21]=2[CH:20]=1)[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc2c(c1)C(=O)c1cc(OCCN(CC)CC)ccc1-2
Reaction time: 3 h

Procedure:
A solution of 2-diethylaminoethyl chloride [obtained from 15.5 g (0.09 mole) of 2-diethylaminoethyl chloride hydrochloride] in 100 ml of toluene (dried over molecular sieves) is added to a mixture of 6.4 g (0.03 mole) of 2,7-dihydroxyfluoren-9-one and 3.3 g (0.06 mole) of sodium methoxide in 200 ml of toluene (dried over molecular sieves). This mixture is heated to reflux with stirring for three hours. Upon cooling, the mixture is filtered to remove the precipitated sodium chloride. The toluene solution is washed three times with water, then once with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. This mixture is filtered, and the filtrate acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from butanone with enough methanol added to effect solution, and the product dried at 100°C for 24 hours under vacuum to give 2,7-bis(2-diethylaminoethoxy)fluoren-9-one dihydrochloride. M.P. 235°-237°C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:14][CH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 80 °C
Yield: 55.2 %

Procedure:
D5 (2 g, 10.97 mmol), N-bromosuccinimide (2.94 g, 16.46 mmol) and benzoyl peroxide (0.57 g, 1.65 mmol) were dissolved in carbon tetrachloride (40 ml) and heated to 80° C. for 3 h. The mixture was diluted with EtOAc (60 ml) and washed with saturated NaHCO3 solution and brine (100 ml each), dried (Na2SO4) and concentrated. Purification by column chromatography on silica (0-50% diethyl ether\40-60 pet. ether gradient) gave the title compound as a yellow oil (1.58 g). δH (CDCl3) 1.65 (9H, s), 4.49 (2H, s), 6.47 (1H, d), 8.03 (1H, d).
Reaction SMILES: [Br-].[Li+].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[CH2:26][C:25]2[C@H:20]([CH2:21][CH2:22][C:23](=[O:27])[CH:24]=2)[C@@H:19]2[C@@H:10]1[C@H:11]1[C@@:15]([CH2:17][C@@H:18]2[F:28])([CH3:16])[C:14](=[O:29])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+].O>C(#N)C.[Cu](Br)Br>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[CH2:26][C:25]2[CH:24]=[C:23]([OH:27])[CH:22]=[CH:21][C:20]=2[C@@H:19]2[C@@H:10]1[C@H:11]1[C@@:15]([CH2:17][C@@H:18]2[F:28])([CH3:16])[C:14](=[O:29])[CH2:13][CH2:12]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CC#N
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Temperature: 80 °C
Yield: 54.1 %

Procedure:
A solution of 10.34 g of lithium bromide and 53.2 g of copper(II) bromide in 280 ml of acetonitrile is added in drops to a solution of 47 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione in 470 ml of acetonitrile at a bath temperature of 80° C. After 20 ml is added, the bleaching of the solution is awaited, and the remainder of the solution is added in 12 minutes and then stirred for 5 more minutes at a bath temperature of 80° C. Then, it is cooled to 0° C., mixed with sodium bicarbonate solution, added to water, extracted 4 times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 25.3 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained. [α]D22=+115.4° (c=0.5% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:7](CCNC(=O)OC)=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[OH2:33]>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=[C:6]2[C:7]=1[N:3]([CH2:2][CH3:7])[C:4](=[O:33])[NH:15]2
Reactant: O
Reactant: COC(=O)NCCc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
59 mg (0.135 mmol) of the compound from example 14A were dissolved in 7.5 ml of tetrahydrofuran and cooled to 0° C., and 150 μl (0.150 mmol) of a 1N solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added dropwise. The mixture was stirred at 0° C. for 3 h and then at RT for 16 h. Another 150 μl (0.150 mmol) of a 1N solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added dropwise and the mixture was stirred at RT for 2 days. Water was added and the reaction mixture was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 29 mg of the title compound were obtained (53% of theory).