Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[O:5].C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:22]([O:21][C:19]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCC(N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A 2 L 3-necked flask equipped with a magnetic stirrer and a thermometer was charged with 25.0 g of glutamic acid γ-ethyl ester (Sigma Chemical Co., St. Louis, Mo., 63178) and 1 L of distilled water. The solution was heated to 60° C. with stirring and treated with 30 g of NaHCO3 followed by 25 mL of benzyl chloroformate (Aldrich). The flask was allowed to cool to RT and stirring was continued for 2 h. The mixture was extracted with ethyl ether (5×100 mL) and the ether extracts were discarded. The aqueous phase was acidified to a congo red end point by addition of concentrated aqueous HCl and the resulting emulsion was extracted with CH2Cl2 (5×100 mL). The combined CH2Cl2 extracts were washed with 0.05 N aqueous HCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to a volume of 50 mL. The solution was chilled in an ice water bath and triturated with addition of 200 mL of pentane. The resulting solid was collected by vacuum filtration and dried in vacuo to afford 37.0 g (83%) of N-((benzyloxy)carbonyl)5-O-ethyl-L-glutamic acid as a white powder, m.p. 82-84° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:24]1([NH:23][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:26][CH2:25]1)([OH:29])=[O:28]
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC2(C(=O)O)CC2)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.39 mmol), 1-amino-cyclopropanecarboxylic acid (700 mg, 6.95 mmol), copper(I) iodide (159 mg, 0.85 mmol), N,N-dimethylglycine hydrochloride (155 g, 1.11 mmol) and potassium carbonate (577 mg, 4.17 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (410 mg, 77%) as a white solid: LC/MS m/e calcd for C22H24N2O4 (M+H)+: 381.45, observed: 381.2.
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:29][NH2:30]>N1C=CC=CC=1>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=3)[NH:30][N:29]=2)[CH:11]=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:9]=1[OH:16])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)c1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1

Procedure:
A solution of 4-(2-chloro-6-isopropylnicotinoyl)-2,6-di-tertiary butylphenol and hydrazine hydrate in pyridine is refluxed. After the pyridine is distilled off, to the residue is added water. The resulting crystals are recrystallized from ethanol to give 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-isopropyl-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1)=[O:15]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cccc(C)c2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 [Example 1] (11.9 mg, 0.03 mmol, 3 mol %), 3-methylphenylboronic acid (204 mg, 1.5 mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was purged with argon, and dioxane (3 mL), and 4-chloroacetophenone (0.13 mL, 1.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 195 mg (93%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][Si](C(C)C)(C(C)C)C(C)C)[CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]2[CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:11][O:12][C:8]=2[CH:7]=1.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl-].[Na+].O.CCOC(C)=O>[Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]2[CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)CC1COc2cc(OCc3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3Cl)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CC1COc2cc(OCc3ccc(O)cc3Cl)ccc21
Reaction time: 0.33 h
Yield: 68.1 %

Procedure:
To a mixture of methyl 2-(6-((2-chloro-4-((triisopropylsilyl)oxy)benzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetate (5.70 g) and THF (50 mL) cooled with an ice bath was added tetrabutylammonium fluoride (1.0 M THF solution, 14.1 mL). After being stirred for 20 min, the mixture was diluted with brine and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.68 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41](Br)[CH:42]=1)C>>[C:9]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:41]1[CH:42]=[C:37]([CH2:36][C:35]([OH:44])=[O:34])[CH:38]=[N:39][CH:40]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)Cc1cncc(Br)c1
Product: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)O)c1

Procedure:
N-Benzyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 17, Step 4 and the product was hydrolyzed to the acid as described in Example 17, Step 5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH:18]=[CH2:19])=[CH:4][CH:3]=1.[OH-].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: C=Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Temperature: 100 °C
Reaction time: 4 h
Yield: 49.6 %

Procedure:
A mixture of 2-(6-chloro-3-vinylpyridin-2-yl)-4-fluoro-1H-indole (1.0 g, 3.7 mmol), DMSO (2.5 mL), TBAC (0.3 mL, 50% aq. solution) and KOH (10 mL, 60% a.q. solution) was stirred under N2 at 100° C. for 4 h. After cooled to RT and extracted with CH2Cl2, the organic layer was washed with water, brine, dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by column chromatography (PE:EA=100:1˜10:1) to give the product of 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (0.5 g, yield: 50%). And 150 mg of un-reacted 2-(6-chloro-3-vinylpyridin-2-yl)-4-fluoro-1H-indole was recycled during the column purification. 1H-NMR (CDCl3, 400 MHz) δ 7.50 (d, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.22˜7.04 (m, 3H), 6.86˜6.71 (m, 1H), 4.27 (t, J=6.8 Hz, 2H), 3.22 (t, J=6.8 Hz, 2H). MS (M+H)+: 273.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[CH:11]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]([CH3:16])([CH3:15])[C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:11]=1
Reactant: CC(C)(C#N)n1cc(Cl)cn1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=N)C(C)(C)n1cc(Cl)cn1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a sodium ethoxide solution, prepared from sodium (20 mg, 1 mmol) and ethanol (4 mL), was added a solution of 2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanenitrile (225 mg, 1.33 mmol) in ethanol (1 mL). The reaction mixture was stirred at 70° C. for 30 min. The solvent was removed under a stream of nitrogen and the residue was dried under high vacuum to afford the crude title compound as a colorless solid, which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([O:39][NH:40][C:41](=[O:54])[CH2:42][C@H:43](O)[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][CH:47]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CN(C=O)C>[CH2:32]([O:39][N:40]1[C@@H:43]([CH2:44][O:45][C:46]2[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][CH:47]=2)[CH2:42][C:41]1=[O:54])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(C[C@H](O)COc1ccc(Br)cc1)NOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1C[C@H](COc2ccc(Br)cc2)N1OCc1ccccc1

Procedure:
A solution of triphenylphosphine (121 g) in THF (1.9 L) was treated with DEAD (80.1 g) over 30 minutes, treated with a solution of Example 3D in DMF (600 mL) at 40° C. by cannula over 90 minutes and a solution of triphenylphosphine (6.2 g) and DEAD (3.8 mL) in THF (20 mL), concentrated, treated with toluene (350 mL), and concentrated. The concentrate was treated with toluene (1.9 L), washed with water, and concentrated to half of its original volume, to provide a solution of (4R)-1-(benzyloxy)-4-((4-bromophenoxy)-methyl)-2-azetidinone. 1H NMR (300 MHz, CDCl3) δ7.4 (m, 7H), 6.70 (m, 2H), 5.00 (d, 1H, J=10), 4.92 (d, 1H, J=12 Hz), 3.86 (m, 1H), 3.82 (dd, 1H, J=1, 4 Hz), 2.81 (dd, 1H, J=6, 15 Hz), 2.66 (dd, 1H, J=2, 15 Hz).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:4]1=[O:5].[I-].[Na+].[CH3:17][N:18]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl.[Na+].[Cl-]>CO>[CH3:2][N:3]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:22][CH2:21][CH2:20][C:19]([N:18]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH3:17])=[O:24])=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:4]1=[O:5]
Reactant: CN1C(=O)CCc2cc(O)ccc21
Reactant: CN(C(=O)CCCCl)C1CCCCC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CCc2cc(OCCCC(=O)N(C)C3CCCCC3)ccc21
Yield: 42.2 %

Procedure:
0.5 Gram of metallic sodium is dissolved in 50 ml of methanol under ice cooling, followed by addition thereto of 3.4 g of 1-methyl-6-hydroxy-3,4-dihydrocarbostyril, 3.2 g of sodium iodide and 5.0 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine and 4.5-hour reflux under agitation. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from ligroin to produce 2.9 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: C1COCCN1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCOCC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
17-Hydroxywortmannin (50 mg, 0.116 mmol) is dissolved in 2 ml methylene chloride and stirred at room temperature under nitrogen atmosphere as morpholine (0.12 mmol, 10 μl) is added. The reaction solution turns orange immediately. After 30 min, the solvent is evaporated and the solid is washed with hexane (2×3 ml) and dried under vacuum to yield 50 mg of the title compound as an orange powder. UV λmax (CH3CN/H2O): 250 nm, 320 nm, 397 nm; Positive ESI-MS: m/z 540 [M+Na]+, 518 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][C:36]([CH3:38])=O.C1COCC1.[BH3-]C#N.[Na+]>CO>[OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][N:32]([CH:36]([CH3:38])[CH3:35])[CH2:33][CH2:34]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(C(C)C)CC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (25 mg, 0.054 mmol) in methanol (0.5 mL) was added acetone (0.25 mL) and 1 M THF solution of NaCNBH3 (0.2 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by prep. HPLC to yield the title compound (12 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 7.10–7.24 (6H, m), 7.08 (1H, s), 7.06 (1H, s), 6.06 (1H, d, J=7.9 Hz), 3.58–4.01 (10H, m), 3.34 (1H, m), 3.14 (1H, m), 2.98 (1H, dd, J=5.9, 13.7 Hz), 2.83 (1H, dd, J=7.9, 13.7 Hz), 2.60 (3H, s), 1.44 (6H, d, J=6.7 Hz). LCMS (M+H)+ m/z 501 (t=1.80 min.).
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[CH2:7]=[C:8]([CH3:10])[CH3:9]>>[C:8]([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])([CH3:10])([CH3:9])[CH3:7]
Reactant: CCOC(N)=O
Reactant: C=C(C)C
Product: CCOC(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
A stirred mixture of 89 g of ethyl carbamate, 10 g of ®LEWASORB AC-10 and 70 g of isobutene was heated to 70° C. in a stirred autoclave, and stirring was continued at this temperature for 4 hours. After the reaction was complete, the catalyst was separated off and the reaction mixture was analyzed by gas chromatography. It still contained 4.5 percent by weight of diisobutene, in addition to the end product. Distillation of the crude product gave 134 g (92% of theory) of ethyl N-tert.-butylcarbamate of boiling point 70°-71° C./20 mbar.
Reaction SMILES: [Na].[OH:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[C:12]2I)[CH2:4]1.C(O)C>O>[OH:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[CH:12]2)[CH2:4]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(I)=CC[C@@H]12
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC=C3C[C@@H](O)CC[C@]3(C)[C@H]1CC2

Procedure:
125 g. of sodium metal were added in small portions to a stirred solution of 21 g. of 3β-hydroxy-17-iodo androsta-5,16-diene in 1.05 l. of anhydrous ethanol. During the addition the mixture was kept at reflux temperature. After all of the sodium was dissolved the reaction mixture was cooled and water was added. The ethanol was removed by distillation under reduced pressure and the resulting aqueous suspension was extracted with methyl isobutyl ketone. The extract was washed until neutral and concentrated to dryness in vacuo. The crystalline residue was recrystallized from methanol-water and 13 g. of 3β-hydroxy-androsta-5,16-diene were obtained. Two crystallizations from acetone yielded the pure compound melting at 137°-138° C. mol. peak in mass spectrum (m/e): 272.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=1)[CH3:21]
Reactant: OB(O)c1cncnc1
Reactant: CN(C)Cc1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CN(C)Cc1cccc(NS(=O)(=O)c2ccc(-c3ncccn3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
4-Bromo-N-(3-((dimethylamino)methyl)phenyl)benzenesulfonamide (273 mg, 0.74 mmol), pyrimidine-5-boronic acid (101 mg, 0.81 mmol) and Pd(dppf)Cl2 (29 mg, 5 mol %) were dissolved in DME (4 mL) and 2M Na2CO3 solution (1.11 mL, 2.22 mmol) was added. The vessel was sealed and purged with argon for 5 minutes while it was placed in an ultrasonic bath. The flask was then placed in a pre-heated oil bath (90° C.) for 1 hour. After this time the reaction was cooled to room temperature and absorbed onto silica. The material was semi-purified by flash chromatography (Isolute II, 70 g silica cartridge, SP4) eluting with 4.5-5.5% MeOH/NH3:DCM, followed by reverse-phase HPLC and finally by trituration from 1:1 v/v Et2O:hexane to give the title compound as a colourless solid (26 mg, 10%). 1H NMR (300 MHz, DMSO-d6): δ 2.13 (6H, s), 3.32 (2H, s), 6.99 (1H, br s), 7.06 (2H, d, J=9 Hz), 7.21 (1H, t, J=8 Hz), 7.62 (2H, d, J=8.5 Hz), 7.89 (2H, d, J=8.5 Hz), 8.92 (2H, s) and 9.25 (1H, s). LCMS: (MH)+=369; (M−H)−=367.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:15]1=2)=[O:13])=[O:9])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(OC)ccc2Oc2ccc(Cl)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(O)ccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a stirred suspension of 8-chloro-2-methoxydibenz-[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-(ethyl-sulfonyl)-1-oxopropyl]hydrazide (1.00 g), prepared in the manner described above in Example 3, in methylene chloride (5 mL) at approximately 5° C. (ice water bath) under nitrogen was added dropwise boron tribromide (1.0M in 6.7 mL of methylene chloride). The ice bath was removed and the reaction stirred at room temperature for 3 hours. The reaction was carefully quenched by the addition of 1N HCl, and poured into ethyl acetate (100 mL). The solution Was washed once with 1N HCl (100 mL). The 100 mL of 1N HCl wash was extracted With ethyl acetate (100 mL). The ethyl acetate solutions were combined and washed With 1N HCl, water and brine. Evaporation of the solution in vacuo resulted in a semi-solid residue. This was treated with 10 mL of ethanol (3A) and heated on a steam bath for several minutes to break up the solid. Upon cooling, the solidified product was collected by filtration. Recrystallization from ethanol (3A) yielded 0.44 g (45%) pure product as a white solid. Melting Point: 200°14 202° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:24]=[N:25][NH:26][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nn[nH]n2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nnn(C)n2)cc1
Yield: 58.9 %

Procedure:
To a stirred solution of (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole (0.72 g, 1.86 mmol) in acetone (30 ml) was added at room temperature potassium carbonate (0.51 g, 3.72 mmol) and methyl iodide (0.23 ml, 3.72 mmol) and the reaction mixture was heated under reflux conditions for 3 h. Aqueous work-up, column chromatography on silica gel (ethyl acetate/hexane 2:3) and crystallization from ethyl acetate/hexane yielded the title compound (0.44 g, 59%) as a white solid, m.p. 150° C. and MS: m/e=402.4 (M+H+). As second product of this reaction (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-tetrazole (0.26 g, yield 35%) was obtained as a white solid, m.p. 186° C. and MS: m/e=402.4 (M+H+).