Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=O)=[O:10].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([Cl:14])(=[O:12])=[O:10]
Reactant: Cc1ccc(Br)c(S(=O)(=O)O)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
50 g of 2-bromo-5-methylbenzenesulfonic acid and 41.5 g of PCl5 are carefully heated in 500 ml of toluene until the evolution of gas commences. After the reaction has subsided the mixture is boiled under reflux until the evolution of gas has ended (2 h). The mixture is cooled and the toluene and POCl3 are removed in vacuo. The residue is carefully poured onto about 1 l of ice, the mixture is subsequently stirred for 1 h and then the product is filtered off with suction. Drying at 60° C. in vacuo gives 36 g of a colorless solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]([N:32]2[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1

Procedure:
To a stirred solution of nucleoside 40 (2.0 g, 3.7 mmol) in methanol (25 cm3) was added sodium methoxide (0.864 g, 95%, 16.0 mmol). The reaction mixture was stirred at room temperature for 10 min and neutralised with 20% aqueous hydrochloric acid. The solvent was partly evaporated and the residue was extracted with ethyl acetate (3×50 cm3). The combined organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give 41 as a white solid material (1.58 g, 95%). δH (CDCl3) 9.95 (1H, br s, NH), 7.69 (d, J 8.1, 6-H), 7.35-7.17 (10H, m, Bn), 6.02 (1H, d, J 2.3, 1′-H), 5.26 (1H, d, J 8.1, 5-H), 4.80 (1H, d, J 11.7, Bn), 4.47 (1H, d, J 11.7, Bn), 4.45-4.24 (4H, m, Bn, 2′-H, 3′-H), 3.81 (1H, d, J 11.9, 1″-Ha), 3.69 (2H, br s, 2′-OH, 1″-OH), 3.67 (2H, m, 5′-Ha, 1″-Hb), 3.48 (1H, d, J 10.3, 5′-Hb). δC (CDCl3) 163.78 (C-4), 150.94 (C-2), 140.61 (C-6), 137.33, 137.22, 128.59, 128.18, 128.01 (Bn), 102.16 (C-5), 91.46, 88.36 (C-1′, C-4′), 76.73, 74.66, 73.71, 73.29, 70.81, 62.81 (C-2′, C-3′, C-5′, C-1″, Bn). FAB-MS m/z 455 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1.[CH3:29][O:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:33]4[CH2:34][CH2:35][C@H:31]([O:30][CH3:29])[CH2:32]4)=[O:24])[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1
Reactant: CO[C@H]1CCNC1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CO[C@H]1CCN(C(=O)c2ccc3c(S(C)=O)cn(-c4ncc(-c5ccccc5F)cn4)c3c2)C1

Procedure:
Amide coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with (S)-3-methoxypyrrolidine utilizing HATU as coupling reagent. White solid. Yield: 100 mg (85% of theory)
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[NH:18][C:19](=[O:30])[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.CO.O.[OH-].[Li+]>O1CCCC1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([CH2:20][C:19]([NH:18][C:5]3[CH:6]=[C:7]([N:11]4[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]4)[CH:8]=[C:9]([F:10])[C:4]=3[C:3]([OH:31])=[O:2])=[O:30])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: COC(=O)c1c(F)cc(N2CCN(C)CC2)cc1NC(=O)Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2cc(F)c(C(=O)O)c(NC(=O)Cc3ccc4c(c3)OCO4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.15 g, 0.35 mmol) in a mixture of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stirred at room temperature overnight then the solvent was evaporated. The residue was diluted with water and 2 N HCl solution was added until pH 7. The solid precipitated was filtered and washed with water to obtain the 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid crude. 2-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid was suspended in acetic anhydride (3 mL) and the reaction mixture was heated under microwave condition at 130° C. for 10 minutes. The solvent was evaporated to obtain the 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one crude. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one in dry pyridine (3 mL) was added aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) and the mixture was heated under microwave condition at 180° C. for 15 minutes. The reaction was cooled at room temperature and diluted with water to induce the precipitation of a brown solid which was washed with a mixture MeOH/H2O 8/2, to afford the title compound (0.07 g, 46% yield).
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[C:52]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][C:53]=2[S:54][C:55]=1[C:56](O)=[O:57].C(O)(C(F)(F)F)=O>ClCCl>[Cl:50][C:51]1[C:52]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][C:53]=2[S:54][C:55]=1[C:56]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])=[O:57]
Reactant: Cc1ccc2c(Cl)c(C(=O)O)sc2c1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general method B, to a solution of A1 (110.65 mg, 0.5 mmol) in dry dichloromethane (3 mL) was added HATU (171.09 mg, 0.45 mmol), DIPEA (0.174 mL, 1 mmol) and 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid (113.34 mg, 0.50 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure gave an yellow oil. Then the oil was dissolved in 2 mL of CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using HOAc/ethyl acetate (1:100) as the eluent, gave 2a; (178.51 mg, 95.5%). [α]D25: −31.7 (c=0.36, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.80-7.75 (m, 3H), 7.41-7.24 (m, 6H), 5.03-4.97 (m, 1H), 3.44-3.26 (m, 2H), 2.50 (s, 3H); 13C NMR (300 MHz, acetone-d6): δ 171.57, 159.83, 138.30, 138.05, 136.67, 134.65, 131.57, 129.50, 128.39, 127.54, 126.87, 122.57, 122.51, 118.78, 54.03, 36.85, 20.73; HRMS (ESI): calcd for: C19H16ClNO3S [M−H]−=372.0467, obsd [M−H]−=472.0484.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[C:10]([CH3:19])[CH:9]=1>>[CH3:19][C:10]1[CH:9]=[C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:18]=[CH:17][C:11]=1[CH2:12][OH:13]
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)cc1C
Product: Cc1cc(-n2ccnc2C)ccc1CO

Procedure:
Prepared from 2-methylimidazole and ethyl 4-fluoro-2-methylbenzoate.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]4)=[CH:28][CH:27]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)cc21
Reaction time: 8 h
Yield: 44 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(4-methyl-1-piperazinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified by silica gel chromatography eluting with 90:9:1 EtOAc:MeOH:NH4OH. The product fractions were pooled and concentrated to a solid that was triturated in boiling hexanes. The solid was collected and crystallized to give 1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one (84 mg, 44%): mp (CH2Cl2 /hexanes) 188-189° C.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]#[N:33]>CCCCCC.O1CCCC1.O>[CH2:20]([C:17]1([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:32]#[N:33])([CH3:35])[CH3:34])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:18]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C#N)CCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC1(CCCCC(C)(C)C#N)c2ccccc2-c2ccccc21
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
2.4 g of butyllithium dissolved in 15 ml of hexane was slowly added during 5 minutes into 6.0 g of fluorene dissolved in 40 ml of anhydrous tetrahydrofuran at -50° C. under nitrogen protection. The mixture was stirred at -30 to 15° C. for 1 hour before it was cooled again to -40 ~-50° C. Then, 6.0 g of 1-bromohexane was added in 5 minutes. The mixture was subsequently stirred for 2 hours while the temperature was gradually increased to room temperature. The mixture was then cooled to -50° C., and 2.4 g of butyllithium dissolved in 15 ml of hexane was slowly added in 5 minutes under nitrogen protection. The mixture was stirred at -30 to 15° C. for 1 hour before it was cooled again to -40~-50° C. Then, 7.6 g of 6-bromo-2,2-dimethylhexanenitrile was added in 5 minutes. The mixture was subsequently stirred for 15 hours at room temperature, dispersed in water, and extracted with ether. The etheral solution was washed with water and brine, dried with magnesium sulfate, and evaporated. The residue was distilled to collect 12.4 g (92%) of light yellow liquid. MS (m/z): 373 (M+), 288, 249, 217, 191, 179, 165.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[Cl:18][C:7]1[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1]
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Cl

Procedure:
To a solution of 4-[(4-fluorobenzyl)oxy]pyridine-2(1H)-one (from Step 2, Example 74) (1.4 g, 5.9 mmol) in AcOH (25 mL) was added N-chlorosuccinimide (0.95 g, 7.1 mmol) and the reaction mixture was heated at reflux for 2 h. The solvent was removed under reduced pressure. 1H NMR (300 MHz, MeOD) δ 7.63-7.55 (m, 1H), 7.45 (d, J=8 Hz, 1H), 7.07-7.00 (m, 2H), 6.58 (d, J=8 Hz, 1H), 5.31 (d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:30]CC1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][CH2:2][CH2:3][OH:30])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.19 g, 2.8 mmol) in THF (30 mL) was added BH3 THF (8.5 mL, 1 mol/L, 8.5 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then NaOH (1 mol/L, 6 mL) and H2O2 (5 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (1.13 g, 92%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C@@H:17]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH:28]1([C@H:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)[C@@H](O)C1CCCCC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](OS(=O)(=O)C(F)(F)F)C1CCCCC1
Reaction time: 0.33 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (12.7 g, 45.2 mmol) in 40 mL CH2Cl2 was cooled in an ice bath. A solution of 2-(S)-hydroxy-2-(cyclohexyl)acetic acid, benzyl ester (10.7 g, 43 mmol, from Step A) and 2,6-lutidine (4.6 g, 43 mmol) in 40 mL CH2Cl2 was added dropwise over 25 min and the mixture was stirred for an additional 20 min. The mixture was washed with water and sat'd NaCl then the organic layer was dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 0→15% EtOAc/hexanes) gave the desired product. 1H NMR (500 MHz, CDCl3) δ1.09-1.33 (m, 5H), 1.66-1.73 (m, 2H), 1.75-1.83 (m, 2H), 2.01-2.08 (m, 1H), 4.98 (d, 1H), 5.27 (d, 1H), 5.29 (d, 1H), 7.35-7.4 (m, 5H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[N+:29]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[N+:29]([C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:2]2([C:26]#[N:27])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:4][CH2:3]2)=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccc([N+](=O)[O-])cc4)CC3)c(F)c2)C(=O)O1
Yield: 61 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 4-nitroaniline the compound was obtained in 61% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[N-:13]=[N+]=[N-].[Na+].FC(F)(F)S(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:13][C:7](=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(Br)ccc2CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a cooled solution of 6-bromo-3,4-dihydro-1H-naphthalen-2-one (100 g, 0.44 mol) in toluene was added sodium azide (150 g, 2.2 mol) followed by addition of trifluoromethanesulfonic acid (200 mL) dropwise. When the addition was completed, the ice bath was removed and the mixture was stirred at room temperature overnight. The reaction was poured into ice-water, basified with potassium carbonate to pH >10 slowly, and then extracted with dichloromethane (1000 mL×3). The organic layers were combined and dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was separated by column chromatography on silica gel to give 35 g of crude product. It was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 240.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].OS(O)(=O)=O>N1C=CC=CC=1>[Si:28]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Compound 2a (2.297 g, 7.26 mmol) was dissolved in anhydrous pyridine (20 mL) at RT under argon. Imidazole (1.02 g, 14.52 mmol) in anhydrous pyridine (10 mL) was the added followed by tert-butyl dimethylsilyl chloride (TBDMS-Cl, 2.25 g, 14.52 mmol) in anhydrous pyridine (20 mL). The reaction mixture was stirred at RT for 72 hours, poured into 0.5 M H2SO4 (150 mL) and extracted with diethyl ether (100 mL, 3×), The extract was washed successively with saturated aqueous NaHCO3 (100 mL) and water (100 mL), dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to obtain 3a, an oily material which was dried in a vacuum dessicator for 2 days (3.164 g, 100% yield). 1H NMR (in CDCl3): δ in ppm 0.83-0.89 (15H, m), 1.22 (29H, m), 1.52-1.53 (2H, m), 2.60 (1H, s, D2O exchangeable), 3.40-3.42 (4H, m), 3.59-3.61 (2H, m), 3.64 (1H, m); 13C NMR (in CDCl3): δ in ppm 14.3, 18.2, 18.5, 22.9, 25.8, 26.0, 26.1, 26.3, 29.6, 29.8, 29.9, 32.1, 33.0, 64.2, 70.8, 71.6, 71.9.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(O[C:19](=[O:26])[CH:20](Br)[CH2:21][CH2:22][CH2:23][CH3:24])C.C(=O)([O-])[O-].[K+].[K+].[CH3:33][C:34](=[O:37])CC>>[CH2:34]([O:37][C:10](=[O:13])[CH:11]([O:26][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:12][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=1)[CH2:8][CH3:9])[CH3:33]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(CC(CC)Oc1ccc(Cl)cc1)Oc1ccccc1

Procedure:
A solution of 64 g of 4-(4-chlorophenoxy)-phenol and 80 g of α-bromocaproic acid ethyl ester in 100 ml of butanone was refluxed for 10 hours together with 100 g of potassium carbonate. After separation from the inorganic salts by filtration, the filtrate was concentrated to dryness, the ester formed was taken up in methylene chloride, the solution was repeatedly extracted with water and the purified product was isolated by evaporating the organic solvent. It was further purified by distillation under reduced pressure. 52 Grams of 4-(4-chlorophenoxy)-α-phenoxy-caproic acid ethyl ester boiling at 223° - 225°C under 3 mm Hg were obtained. ##SPC4##
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25][C:26]#[C:27][CH2:28][CH2:29][CH3:30].C(OCC)C>CN(C)C=O.O>[NH3:5].[CH2:25]([N:5]1[CH2:6][CH:7]2[CH:3]([C:2]2([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH3:1])[CH2:4]1)/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH3:30]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: CCCC#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCC/C=C/CN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 57 mg, 0.19 mmol) dissolved in N,N-dimethylforrnamide (2 ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol) and 1-bromo-2-hexyne (H. A. J. Charles, and R. J. Batten, J. Chem. Soc., Perkin Trans 1, 1987, 1999, 33 mg, 0.2 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling diethyl ether (5 ml) and water (7 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (5 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (33 mg, 50%).
Reaction SMILES: [CH3:1][C:2](=[O:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11]CC[CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(O[C:27](=[O:29])[CH3:28])(=O)C.C1(C)C=CC(S(O)(=O)=[O:37])=CC=1>C(O)(=O)C>[OH:29][C@H:27]1[CH2:28][CH2:16][C@@:15]2([CH3:14])[C:10](=[CH:9][C@@H:8]([OH:37])[C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:6]3[CH2:5][CH2:4][C@@H:3]2[C:2](=[O:22])[CH3:1])[CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Reaction of 5α-pregnan-20-one (3) with a mixture of acetic anhydride, acetic acid, and p-toluene sulfonic acid followed by HPLC of the crude product affords the isomeric enol acetates 4 and 5. Epoxidation of 4 and 5 in benzene with m-chloro perbenzoic acid overnight at room temperature furnishes the epoxy acetates 6 and 7. Saponification of both 6 and 7 with methanolic sodium hydroxide gives 17α-hydroxy-5α-pregnan-20-one (8) as a common product.